Results
| Mutations: M184V,T97A Comorbidities: None Comedications: Ethambutol, Pyrazinamide, Rifampin, Isoniazid Treatment history: ATV/r (Atazanavir-ritonavir/Reyataz and Norvir) , RAL (Raltegravir/Isentress) , TDF/FTC (Truvada) Current regimen: None |
Adherence: No options selected CD4: > 200 Viral load: Low (200 - 100,000) HLA-B5701: Negative Tropism: Unknown |
View results |
to help us improve HIV-ASSIST.
HIV-ASSIST calculates a regimen's weighted score on a scale of 1 to 10, in which lower values represent preferred regimens based upon current IAS and DHHS guidelines, while factoring in treatment history, comorbidities, co-medications, and other factors entered on the input page. The weighting system utilizes standardized utility weights based on current literature evidence and expert opinion. HIV-ASSIST is an educational tool and not a substitute for clinical judgement. Click on a regimen and 'Rationale' to see all steps leading to the presented weighted score. Please note that rankings would differ if if some factors were weighed more or less than those applied within HIV-ASSIST algorithms.
The Score Code is a value from 1-5 that corresponds with the chart below.
| Score Code | HIV-ASSIST Score | Efficacy (likelihood of viral suppression) | Tolerability (side-effects and pill burden) | Notes |
|---|---|---|---|---|
| 1 | ≤ 1.5 | Strong evidence | Strong evidence | Reserved for fully- or near fully- active regimens. |
| 2 | 1.5 - 2.5 | Strong or moderate evidence | Strong or moderate evidence | Includes regimens that started at better rank but were impacted by mutations, comorbidities, and drug interactions. |
| 3 | 2.5 - 4.0 | Moderate evidence | Moderate evidence | As above. Additionally, most treatment-experienced patients will see regimens in this category. |
| 4 | 4.0 - 6.0 | Moderate to poor evidence | Moderate or poor evidence | As above. Additionally, most treatment-experienced patients will see regimens in this category. |
| 5 | ≥ 6.0 | Poor evidence | Poor evidence | As above. Additionally, these represent salvage regimens in patients with limited options. |
Signifies that there may be additional regimen warnings.
Note: We do not show regimens for which there is evidence against usage.
| Score Code | Regimen | Weighted Score | Active Drugs | Total Pills | Frequency (x/day) |
|---|---|---|---|---|---|
| 2 | DTG/TDF/3TC | 2.25 | 2 | 2 | 2 |
| 2 | DTG+TDF/FTC | 2.45 | 2 | 3 | 2 |
| 3 | DTG+TAF/FTC | 2.7 | 2 | 3 | 2 |
| 5 | IBA+DTG/TDF/3TC | 6.5 | 3 | 2 | 2 |
| 5 | DTG+IBA+TDF/FTC | 6.7 | 3 | 3 | 2 |
| 5 | DTG+IBA+TAF/FTC | 6.95 | 3 | 3 | 2 |
| 5 | EFV/TDF/FTC | 7.15 | 2 | 1 | 1 |
| 5 | DTG+3TC/AZT | 7.15 | 2 | 4 | 2 |
| 5 | DTG+AZT+FTC | 7.35 | 2 | 5 | 2 |
| 5 | DTG+IBA | 7.4 | 2 | 2 | 2 |
| 5 | RAL+EFV/TDF/FTC | 7.6 | 3 | 5 | 2 |
| 5 | EFV+TAF/FTC | 8.15 | 2 | 2 | 1 |
| 5 | RAL+EFV+TAF/FTC | 8.7 | 3 | 6 | 2 |
| 5 | RAL+TDF/FTC | 8.75 | 2 | 5 | 2 |
| 5 | RAL+TAF/FTC | 8.9 | 2 | 5 | 2 |
| 5 | RAL+IBA+TDF/FTC | 9.5 | 3 | 5 | 2 |
| 5 | RAL+IBA+TAF/FTC | 9.65 | 3 | 5 | 2 |
| 5 | RAL+IBA+EFV | 9.65 | 3 | 5 | 2 |
| 5 | RAL+IBA | 9.7 | 2 | 4 | 2 |
| 5 | RAL+EFV | 10.1 | 2 | 5 | 2 |
| 5 | DTG+IBA+3TC/AZT | 10.4 | 3 | 4 | 2 |
| 5 | DTG+IBA+AZT+FTC | 10.6 | 3 | 5 | 2 |
| 5 | RAL+EFV+3TC/AZT | 12.15 | 3 | 7 | 2 |
| 5 | RAL+EFV+AZT+FTC | 12.35 | 3 | 8 | 2 |
| 5 | RAL+3TC/AZT | 12.95 | 2 | 6 | 2 |
| 5 | RAL+IBA+3TC/AZT | 13.1 | 3 | 6 | 2 |
| 5 | RAL+AZT+FTC | 13.15 | 2 | 7 | 2 |
| 5 | EFV+3TC/AZT | 13.3 | 2 | 3 | 2 |
| 5 | RAL+IBA+AZT+FTC | 13.3 | 3 | 7 | 2 |
| 5 | EFV+AZT+FTC | 13.5 | 2 | 4 | 2 |
Report
Preferred regimen based on the HIV-ASSIST algorithm: DTG/TDF/3TC
DTG/TDF/3TC had the lowest weighted score (2.25) among all regimens HIV-ASSIST evaluated. In general, lower HIV-ASSIST weighted scores are considered preferable with respect to achieving viral suppression and maximizing tolerability. Your patient may have other considerations we did not factor and this report should not be considered a guarantee of likely success with this patient. Please use clinical judgement in making final ARV selections. Other regimens you may wish to consider are listed below. A full list of ARV regimens analyzed by the HIV-ASSIST algorithm can be found by clicking the Expert Tab above.
| Score Code | Regimen | Weighted Score | Active Drugs | Total Pills | Frequency (x/day) |
|---|---|---|---|---|---|
| 2 | DTG/TDF/3TC | 2.25 | 2 | 2 | 2 |
The rationale behind why this regimen was chosen by our algorithm as the most appropriate is shown below:
Other highly ranked regimens
Other highly ranked regimens based on the HIV-ASSIST algorithm are shown below. For full details on these regimens, please click on the Expert Tab above.
| Score Code | Regimen | Weighted Score | Active Drugs | Total Pills | Frequency (x/day) |
|---|---|---|---|---|---|
| 2 | DTG+TDF/FTC | 2.45 | 2 | 3 | 2 |
| 3 | DTG+TAF/FTC | 2.7 | 2 | 3 | 2 |
| 5 | IBA+DTG/TDF/3TC | 6.5 | 3 | 2 | 2 |
| 5 | DTG+IBA+TDF/FTC | 6.7 | 3 | 3 | 2 |
Mutations
Based on the Stanford Database, we assign penalties to various regimens based on inputted (i.e., genotypic) and assumed archived mutations. We consider drugs with summed mutation scores between 10 and 29 to have low-level resistance, scores between 30 and 59 to have intermediate-level resistance, and scores above 60 to have high-level resistance.
* signifies an assumed archived mutation based on prior treatment experience.| NRTI Mutation(s) | 3TC | FTC | ABC | TAF | TDF | AZT | D4T | DDI |
|---|---|---|---|---|---|---|---|---|
| M184V | 60 | 60 | 15 | -10 | -10 | -10 | -10 | 10 |
| Total | 60 | 60 | 15 | -10 | -10 | -10 | -10 | 10 |
| NNRTI Mutation(s) | EFV | ETR | RPV | NVP | DOR |
|---|---|---|---|---|---|
| Total | 0 | 0 | 0 | 0 | 0 |
| PI Mutation(s) | LPVr | FPVr | TPVr | SQVr | IDVr | NFV | ATVr | ATVc | ATV | DRV | DRVr | DRVc |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| INSTI Mutation(s) | RAL | EVGc | DTG | BIC | CAB |
|---|---|---|---|---|---|
| T97A | 10 | 10 | 0 | 0 | 0 |
| Total | 10 | 10 | 0 | 0 | 0 |
| EI Mutation(s) | MVC | IBA | FOS |
|---|---|---|---|
| Total | 0 | 0 | 0 |
| CI Mutation(s) | LEN |
|---|---|
| Total | 0 |
Comorbidities, Side Effects, and Pregnancy Interactions
HIV-ASSIST incorporates a mathematical penalty into our algorithms for ARVs that are less preferred due to comorbidities or side-effects, based on recommendations from DHHS guidelines and HIV-ASSIST clinician and pharmacist expertise. In general, higher penalties suggest that the listed ARV is less favored in the presence of the stated comorbidity or side effect.
Co-medication Interactions
We have identified the following possible drug interactions which HIV-ASSIST factors into ARV regimen selection, based on recommendations from DHHS guidelines, University of Liverpool HIV Drug Interaction Checker, and HIV-ASSIST clinician and pharmacist expertise. Penalties less than 1.0 are typically those representing minor interactions that can be mediated by dosage adjustments, whereas a penalty of 2.0 represents medically contraindicated ARVs.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of emtricitabine and ethambutol alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Coadministration of TB treatment containing ethambutol (with rifampicin, isoniazid and pyrazinamide) and emtricitabine (with tenofovir-DF and efavirenz) increased emtricitabine AUC and Cmin by 5% and 26% and decreased Cmax by 3%; there was no effect on ethambutol concentrations.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Dose Descovy according to the concomitant antiretroviral.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of tenofovir-DF and ethambutol alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Coadministration of TB treatment containing ethambutol (with rifampicin, isoniazid and pyrazinamide) and tenofovir-DF (with emtricitabine and efavirenz) increased tenofovir AUC and Cmin by 13% and 9% and decreased Cmax by 2%; there was no effect on ethambutol concentrations.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of efavirenz and ethambutol alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Coadministration of TB treatment containing ethambutol (with rifampicin, isoniazid and pyrazinamide) and efavirenz (with emtricitabine and tenofovir-DF) increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; there was no effect on ethambutol concentrations.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically relevant drug interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Ibalizumab, a monoclonal antibody binding to the CD4 receptor, is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of emtricitabine and pyrazinamide alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase. Coadministration of TB treatment containing pyrazinamide (with rifampicin, isoniazid and ethambutol) and emtricitabine (with tenofovir-DF and efavirenz) increased emtricitabine AUC and Cmin by 5% and 26% and decreased Cmax by 3%; pyrazinamide Cmax increased by 14%.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase. Dose Descovy according to the concomitant antiretroviral.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of tenofovir-DF and pyrazinamide alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase. Coadministration of TB treatment containing pyrazinamide (with rifampicin, isoniazid and ethambutol) and tenofovir-DF (with emtricitabine and efavirenz) increased tenofovir AUC and Cmin by 13% and 9% and decreased Cmax by 2%; pyrazinamide Cmax increased by 14%.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied. Pyrazinamide is mainly metabolized by xanthine oxidase. As didanosine is also metabolized by this enzyme, competition could increase pyrazinamide exposure and possibly increase the risk of arthralgia (resulting from the inhibition of urate tubular secretion by pyrazinamide). No a priori dosage adjustment is recommended but monitoring for side effects is suggested.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of efavirenz and pyrazinamide alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase. Coadministration of TB treatment containing pyrazinamide (with rifampicin, isoniazid and ethambutol) and efavirenz (with emtricitabine and tenofovir-DF) increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; pyrazinamide Cmax increased by 14%.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0.1
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically relevant drug interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- HIV-ASSIST Notes:
- Possible risk of hepatoxicity when used with Pyrazinamide. Monitor liver function.
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Pyrazinamide is mainly metabolized by xanthine oxidase whereas ibalizumab, a monoclonal antibody binding to the CD4 receptor, is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Moderate Quality of Evidence)
- Liverpool Notes:
- The effect of rifampicin-based TB therapy on the population pharmacokinetics of lamivudine was determined using data from 16 HIV+ subjects. The estimated population pharmacokinetic parameters during and after rifampicin were similar once between-occasional variability in bioavailability and absorption rate constant were accounted for. The interaction between lamivudine and rifampicin is unlikely to be of clinical significance. The effect of rifampicin-based tubercular therapy on the population pharmacokinetics of lamivudine. Van der Walt J, Cohen K, McIlleron H et al. 10th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, April 2009, abstract P24., Summary:The interaction between lamivudine and rifampicin is unlikely to be of clinical significance. Estimated population pharmacokinetic parameters for lamivudine during and after rifampicin were similar once between-occasional variability in bioavailability and absorption rate constant were accounted for.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of emtricitabine and rifampicin alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as rifampicin is deacetylated. Coadministration of TB treatment containing rifampicin (with ethambutol, isoniazid and pyrazinamide) and emtricitabine (with tenofovir-DF and efavirenz) increased emtricitabine AUC and Cmin by 5% and 26% and decreased Cmax by 3%; rifampicin Cmax decreased by 14%.
- Penalty:
- 0.25
- Liverpool Interaction Status:
- Yellow/Moderate-low: Potential Weak Interaction (Very Low Quality of Evidence)
- Liverpool Notes:
- Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir. Ziagen Summary of Product Characteristics, ViiV Healthcare UK Ltd, December 2018., Summary:Coadministration has not been studied. Rifampicin may decrease abacavir concentrations due to induction of UGTs, although to a moderate extent. No a priori dose adjustment is required.
- Penalty:
- 0.25
- HIV-ASSIST Notes:
- There is a risk of P-gp induction causing reductions in TAF and would consider TDF. Magnitude of this effect is likely greatest for daily RPT and RIF, more so than for weekly rifapentine, and likely least for RBT. Currently, 'coadministration is NOT recommended unless benefits outweigh risks. ' Of note, however, coadministration of emtricitabine/tenofovir alafenamide (200/25 mg once daily) and rifampicin (600 mg once daily) decreased TFV-DP AUC by 47% and intracellular TFV-DP concentrations decreased by 40%. However, when compared to historical control TDF 300 mg/d, intracellular tenofovir-DP concentrations were ~82% higher (Cerrone et al CROI 2018). Clinical significance unknown. Some guidelines (EACS) suggest using TAF BID when coadministered with rifamycins
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- The co-administration of Descovy is not recommended with rifampicin. Interaction not studied with either of the components of Descovy. Co-administration of rifampicin, a P-gp inducer, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2022. Coadministration is expected to decrease concentrations of tenofovir alafenamide and is not recommended. Descovy US Prescribing Information, Gilead Sciences Inc, January 2022. The pharmacokinetics of tenofovir alafenamide and tenofovir diphosphate were determined in healthy volunteers following administration of tenofovir alafenamide alone (25 mg once daily, with emtricitabine) and with rifampicin (600 mg once daily). Rifampicin decreased tenofovir alafenamide AUC and Cmax by 55% and 50%. Plasma tenofovir Cmax, C24 and AUC decreased by 65%, 55% and 54% respectively. Intracellular tenofovir diphosphate (i.e. active entity) concentrations Cmax, C24 and AUC decreased by 38%, 43% and 36%, respectively, but AUC was still 4.21-fold higher than that achieved with standard dose tenofovir-DF alone (300 mg once daily). Rifampicin did not alter emtricitabine pharmacokinetics. Rifampin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide. Cerrone M, Alfarisi O, Neary M, et al. J Antimicrob Chemother 2019; 74:1670-8. The pharmacokinetics of tenofovir alafenamide and tenofovir diphosphate (TDF-DP) were determined following administration of tenofovir alafenamide alone (25 mg once daily, with bictegravir and emtricitabine) or tenofovir alafenamide (25 mg twice daily, with bictegravir and emtricitabine) and rifampicin (600 mg once daily). Following twice daily administration with rifampicin, the plasma AUC of tenofovir alafenamide and its active intracellular metabolite (TFV-DP) were modestly decreased by ~14% and ~24% when compared to tenofovir alafenamide once daily alone. This modest change is not expected to alter the efficacy of tenofovir alafenamide. Twice daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. Custodio JM, et al. 16th European AIDS Conference (EACS). October 2017, Milan, abstract PS13/4., Summary:Rifampicin induces the transporters P-gp, BCRP, OATP1B1 which results in lower exposure of tenofovir alafenamide. Coadministration of emtricitabine/tenofovir alafenamide (200/25 mg twice daily with bictegravir) and rifampicin (600 mg once daily) in healthy volunteers decreased the AUC of tenofovir and tenofovir-DP by ~14% and 24%, respectively, when compared to once daily administration alone. Of interest, coadministration of emtricitabine/tenofovir alafenamide (200/25 mg once daily) and rifampicin (600 mg once daily) decreased plasma exposure of tenofovir alafenamide and tenofovir by ~55%. Intracellular tenofovir-DP AUC decreased by 36%, however, intracellular tenofovir-DP exposure was 4.2-fold higher than that achieved with standard dose tenofovir-DF alone (300 mg once daily). Thus, this study suggests that use of tenofovir alafenamide 25 mg once daily with rifampicin may be acceptable.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Low Quality of Evidence)
- Liverpool Notes:
- There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was coadministered with rifampicin. Viread Summary of Product Characteristics, September 2016. Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113. The pharmacokinetic interaction of rifampicin (600 mg once daily) and tenofovir-DF (300 mg once daily) was assessed in 23 HIV-negative subjects. Coadministration of rifampicin reduced tenofovir AUC by 12%, Cmax by 16% and Cmin by 15%. However, 90% confidence intervals for these PK parameters were within the limits required for pharmacokinetic equivalence. Rifampicin pharmacokinetic parameters were comparable to historical controls. The addition of rifampicin to tenofovir-DF was well tolerated and the small decrease in tenofovir exposure suggests that these drugs can be coadministered without the need for dose adjustments. Pharmacokinetic study of tenofovir disproxil fumarate combined with rifampin in healthy volunteers. Droste JAH, et al. Antimicrob Agents Chemother, 2005, 49: 680-684. , Summary:No significant interaction was observed when tenofovir-DF (300 mg once daily) and rifampicin (600 mg once daily) were coadministered. Tenofovir AUC, Cmax and Cmin decreased by 12%, 16% and 15%, respectively and rifampicin pharmacokinetic parameters were comparable to historical controls.
- Penalty:
- 1
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (Moderate Quality of Evidence)
- Liverpool Notes:
- The concomitant use of rifampicin with zidovudine should be avoided. Limited data suggests that co-administration of zidovudine with rifampicin decreases the AUC of zidovudine by 48% ± 34%. This may result in a partial loss or total loss of efficacy of zidovudine. Retrovir Summary of Product Characteristics, ViiV Healthcare UK, Ltd, December 2018. Coadministration of zidovudine (200 mg three times daily for 14 days) and rifampicin (600 mg daily for 14 days) to 8 subjects resulted in a 47% decrease in zidovudine AUC. Routine dose modification of zidovudine is not warranted with coadministration. Retrovir Prescribing Information, ViiV Healthcare, September 2018. The effect of rifampicin (600 mg once daily) on the pharmacokinetics of zidovudine (200 mg three times daily) was studied in 8 HIV-infected subjects. Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. Coadministration of rifampicin for 14 days significantly increased zidovudine oral clearance (89%) with corresponding decreases in Cmax (43%) and AUC (47%). After stopping rifampicin for 14 days, values returned to within 26% of baseline. Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Gallicano KD, et al. Br J Clin Pharmacol, 1999, 48: 168-179. Zidovudine pharmacokinetics were determined in 4 HIV-infected subjects receiving long term (>6 months) therapy with various doses of zidovudine (100-300 mg) and rifampicin (600 mg once daily). When compared to a reference population, subjects receiving rifampicin had lower zidovudine AUCs and consequently a higher apparent clearance. Zidovudine Cmax were within the low to normal range. Zidovudine glucuronide levels were determined in 3 subjects and Cmax and AUC were found to be increased relative to the control populations. Pharmacokinetic interaction between rifampin and zidovudine. Burger DM, et al. Antimicrob Agents Chemother, 1993, 37: 1426-1431. , Summary:Coadministration with rifampicin significantly decreased zidovudine AUC and Cmax by 47% and 43%. The European product label for zidovudine recommends that coadministration should be avoided, however, the US product label states that routine dose modification is not warranted.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as rifampicin is deacetylated.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as rifampicin is deacetylated.
- Penalty:
- 0.25
- HIV-ASSIST Notes:
- AUC of EFV decreased by 26%. Maintain EFV dose at 600 mg once daily and monitor for virologic response. Consider therapeutic drug monitoring. Some clinicians suggest EFV 800 mg dose in patients who weigh more than 60kg.
- Liverpool Interaction Status:
- Yellow/Moderate-low: Potential Weak Interaction (High Quality of Evidence)
- Liverpool Notes:
- If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg/day may be considered. Coadministration of rifampicin (600 mg once daily) and efavirenz (600 mg once daily) decreased efavirenz AUC, Cmax and Cmin by 26%, 20% and 32%, respectively. When taken with rifampicin in patients weighing 50 kg or greater, increasing efavirenz daily dose to 800 mg may provide exposure similar to a daily dose of 600 mg when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment. No dosage adjustment is necessary for rifampicin. Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, December 2017. If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg once daily is recommended. Coadministration of rifampicin (600 mg) with efavirenz (600 mg) in 12 subjects caused a 20% decrease in efavirenz Cmax, a 26% decrease in AUC, and a 32% decrease in Cmin. Sustiva Prescribing Information, Bristol-Myers Squibb Company, October 2017. The effect of a higher dose of rifampicin (35 mg/kg) on the pharmacokinetics of dolutegravir or efavirenz was evaluated in coinfected HIV/TB adults. Newly-diagnosed TB patients were randomized to either a standard (10 mg/kg) or a higher (35 mg/kg) dose of rifampicin. Antiretroviral treatment naïve patients were assigned to dolutegravir or efavirenz based regimens. Patients on dolutegravir or efavirenz based regimens at enrolment were maintained on the same regimen, however, dolutegravir was adjusted from once daily to twice daily dosing. Pharmacokinetic sampling was performed 6 weeks post TB treatment initiation with sampling for dolutegravir 12 hours (Ctrough) after the last dose and a mid-dose sampling for efavirenz. Overall, 149 participants were enrolled in the study. Geometric mean (95% CI) dolutegravir trough concentration for patients on higher dose rifampicin was lower than for those receiving standard dose rifampicin: 0.46 (0.31-0.67) mg/L versus 0.80 (0.56-1.14) mg/L, with a GMR of 0.57 (0.34-0.97). Using a threshold of 0.3 mg/L, a higher proportion of participants on higher dose rifampicin failed to attain the target dolutegravir through concentration compared to those on standard dose (39% vs 7%), P = 0.014. Using a lower target threshold of 0.064 mg/L, the difference in target attainment between higher and standard dose rifampicin was not statistically significant (4.4% vs 3.6%), P = 0.999. No patients with dolutegravir concentrations below either target thresholds had a detectable HIV viral load at week 24. The geometric mean for efavirenz mid-dose concentrations for patients on higher dose rifampicin was 37% lower than those receiving the standard dose: 2.94 (95% CI, 1.98-4.36) mg/L vs 4.64 (3.31-6.50) mg/L, with a GMR of 0.63 (0.38-1.07), P = 0.083. The proportion of patients who failed to attain the target mid-dose efavirenz concentrations of 1 mg/L was not significantly different between the 2 groups. No patients below the target had a detectable HIV viral load at week 24. Grade 3-4 adverse effects were similar in the high vs standard dose rifampicin arms. Sputum conversion at week 8 was higher in high dose versus standard dose arms. In conclusion, compared to the standard dose, a three-fold dose increase for rifampicin reduced plasma exposure of dolutegravir and efavirenz without loss of virological control of HIV. Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with tuberculosis and human immunodeficiency virus receiving high-dose rifampicin. Sekaggya-Wiltshire C, Nabisere R, Musaazi J, et al. Clinical Infectious Diseases 2022 [epub ahead of print]. This systematic review analysed 22 studies of efavirenz and rifampicin-isoniazid coadministration in patients from high TB/HIV burden countries. Rifampicin induces CYP2B6 (the enzyme responsible for the majority of efavirenz metabolism) and the product labels for efavirenz recommends an increase in efavirenz dosing from 600 mg to 800 mg once a day, when coadministered with rifampicin to patients weighing 50 kg or more. However, the WHO recommends maintaining the 600 mg once a day dose in high HIV burden countries due to an increased risk of CNS toxicity with increased efavirenz concentrations. This meta-analysis found that efavirenz C12 or Cmin was within the therapeutic range (1000-4000 ng/ml) when the 600 mg daily dose was coadministered with rifampicin-isoniazid. Only in one study (in children) were efavirenz concentrations subtherapeutic and this is likely to be driven by adherence, CYP2B6 polymorphism or low EFV dosing in children. The results of this systematic review support efavirenz dosing of 600 mg once daily with rifampicin-isoniazid administration in coinfected African and Asian patients. Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review. Atwine D, Bonnet M, & Taburet A-M. British Journal of Clinical Pharmacology, 2018, 8:1641-1658. Efavirenz pharmacokinetics were determined in HIV-infected patients without TB receiving EFV (400 mg once daily, with FTC/TDF) and rifampicin-isoniazid at baseline (n=26) and after 4 weeks (n=22) and 12 weeks (n=17) of treatment. Coadministration with rifampicin-isoniazid was associated with limited changes in efavirenz exposure (decreases of 16%, 25% and 16% for Cmax, C24 and AUC at week 12) and concentrations were maintained within the range measured in the ENCORE-1 study irrespective of CYP2B6 genotype. All patients had viral loads below 50 copies/ml at baseline and this was maintained throughout this study. These results suggest that efavirenz can be administered at 400 mg once daily with rifampicin, but these results should be confirmed in HIV/TB-coinfected patients. Pharmacokinetics of efavirenz 400 mg once daily coadministered with isoniazid and rifampicin in Human Immunodeficiency Virus-infected individuals. Cerrone M, Wang X, Neary M, et al. Clin Infect Dis, 2019; 68(3): 446-452. Efavirenz pharmacokinetics were evaluated in Ugandan HIV/TB co-infected patients receiving high-dose rifampicin (20 mg/kg) as part of their standard TB treatment with efavirenz 600 mg once daily (n=31) or 800 mg once daily (n=33) and compared to values obtained in patients receiving rifampicin (10 mg/kg) with efavirenz 600 mg once daily (n=33). No relationship could be evidenced between viral load decline and efavirenz concentrations. Despite a trend to lower efavirenz concentrations when rifampicin dosing was doubled, concentrations remained in the therapeutic window and there was no sign of decreased tolerance. Effect of high-dose rifampicin on efavirenz pharmacokinetics: drug–drug interaction randomized trial. Atwine D, Baudin E, Gele T, et al. J Antimicrob Chemother, 2020; 75:1250-1258. Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:In contrast to its effect on other NNRTIs, rifampicin only leads to modest reduction in efavirenz concentrations. No dose adjustment is recommended when efavirenz and rifampicin are administered at standard doses (efavirenz 600 mg once daily, rifampicin 10 mg/kg). The product labels for efavirenz suggest an increase in efavirenz dose from 600 mg to 800 mg once daily with rifampicin in patients weighing 50 kg or more. However, current American NIH and British HIV Association guidelines recommend to maintain efavirenz at 600 mg once daily in the presence of rifampicin irrespective of body weight and to monitor virologic response. A meta-analysis of studies (mainly from African and Asian populations) found that efavirenz C12 or Cmin was within the therapeutic range when the 600 mg daily dose was coadministered with rifampicin-isoniazid. Only one study (in children) had subtherapeutic efavirenz concentrations (possibly due adherence issue, CYP2B6 polymorphism or low efavirenz dosing in children). Although coadministration of efavirenz (400 mg once daily) with rifampicin (10 mg/kg)-isoniazid was associated with limited changes in efavirenz exposure (~25% decrease in C24) in HIV-infected patients without TB, these results need to be confirmed in HIV/TB-coinfected patients. Thus, patients maintained on efavirenz 400 mg once daily (following the results of the ENCORE clinical trial) should increase to efavirenz 600 mg once daily while treated with rifampicin. Note: coadministration with rifampicin at a dose of 35 mg/kg showed a tendency towards lower efavirenz mid-dose concentrations but the variability was high therefore caution is advised when using with high dose rifampicin.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Significant decrease in ETR expected. Do not coadminister.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied. The combination is not recommended. Rifampicin is expected to decrease plasma concentrations of etravirine. Etravirine should be used in combination with a boosted protease inhibitor, but rifampicin is contraindicated in combination with boosted PIs. Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, March 2019. Rifampicin is a potent inducer of CYP450 enzymes. Etravirine should not be used with rifampicin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine. Intelence US Prescribing Information, Janssen Therapeutics, July 2019. A case report described two patients successfully treated with etravirine and rifampicin. Patient 1 received rifampicin (450 mg, once daily), ethambutol (400 mg, twice daily), pyrazinamide (1,000 mg, once daily) and isoniazid (replaced by moxifloxacin 400 mg, once daily, after 4 weeks because of isoniazid resistance), followed one week later with ARVs (tenofovir/emtricitabine 300/100 mg once daily, etravirine 200 mg twice daily). Patient 2 was stable on tenofovir/emtricitabine (300/100 mg once daily) and darunavir/ritonavir (800/100 mg once daily) and switched darunavir/ritonavir for etravirine (200 mg twice daily) when starting rifampicin (600 mg once daily), ethambutol (400 mg three times a day), pyrazinamide (500 mg three times a day) and isoniazid (300 mg once daily). A large increase in etravirine exposure was observed in both patients (+13279 and +8325 ng h/mL, respectively) after discontinuation of rifampicin. Etravirine measured in the two CSF samples obtained from the first patient was undetectable. Despite clinical success, the etravirine plasma levels were significantly reduced by rifampicin co-administration. However, the etravirine plasma concentrations were always well above the IC50(0.39–2.4 ng/mL), and HIV-RNA suppression was achieved/maintained in both patients.Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis. Gagliardini R, Fabbiani M, Fortuna S, et al. Infection, 2014, 42:775-778., Summary:Rifampicin is a potent inducer of CYP450 enzymes. Etravirine should not be used with rifampicin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in RPV AUC by 80%. Contraindicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (High Quality of Evidence)
- Liverpool Notes:
- Rilpivirine should not be co-administered with rifampicin as significant decreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction), which may result in loss of therapeutic effect of rilpivirine. Coadministration of rifampicin (600 mg once daily) and a higher than the recommended dose of rilpivirine had no effect on AUC or Cmax of rifampicin. The AUC of 25-O-desacetyl rifampicin decreased by 9%, but Cmax was unchanged. Rilpivirine AUC, Cmin and Cmax decreased by 80%, 89% and 69%, respectively, due to induction of CYP3A enzymes. Rilpivirine must not be used in combination with rifampicin as co-administration is likely to result in loss of therapeutic effect of rilpivirine. Edurant Summary of Product Characteristics, Janssen-Cilag Ltd, January 2019. Coadministration is contraindicated due to the potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. Coadministration of rilpivirine (150 mg once daily) and rifampicin (600 mg once daily) was studied in 16 subjects. Rilpivirine Cmax, AUC and Cmin decreased by 69%, 80% and 89%, respectively. Rifampicin Cmax increased by 2% and AUC decreased by 1%. There was no change in Cmax of 25-desacetylrifampicin, but AUC decreased by 9%. Edurant US Prescribing Information, Janssen Therapeutics, May 2019. Coadministration of rilpivirine (150 mg once daily) and rifampicin (600 mg once daily) was studied in 16 HIV-negative subjects. Rilpivirine Cmax, AUC and Cmin decreased by 69%, 80% and 89%, respectively. Rifampicin Cmax increased by 2% and AUC decreased by 1%. There was no change in Cmax of 25-desacetyl-rifampicin, but AUC decreased by 9%.van Heeswijk R, et al. The effects of CYP3A4 modulation on the pharmacokinetics of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor. 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, April 2006, abstract 74., Summary:Coadministration is contraindicated as significant decreases in rilpivirine plasma concentrations may occur. Coadministration of rilpivirine (150 mg once daily) and rifampicin (600 mg once daily) decreased rilpivirine Cmax, AUC and Cmin by 69%, 80% and 89%, respectively. There was no significant effect on rifampicin Cmax and AUC, nor on the Cmax of 25-desacetylrifampicin, but AUC of the metabolite decreased by 9%. [Note: this interaction study has been performed with a dose higher than the licensed dose for rilpivirine assessing the maximal effect on the co-administered drug. The recommendation is applicable to the licensed dose of rilpivirine 25 mg once daily.]
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in NVP levels by 20%-58%. Do not coadminister.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (High Quality of Evidence)
- Liverpool Notes:
- The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended. Coadministration of nevirapine and rifampicin (600 mg once daily) increased rifampicin AUC and Cmax by 11% and 6%, respectively. In contrast, rifampicin produced a significant lowering of nevirapine AUC (58% decrease), Cmax (50% decrease) and Cmin (68% decrease) compared to historical controls. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine containing regimen may consider use of rifabutin instead. Viramune Summary of Product Characteristics, Boehringer Ingelheim Ltd, November 2019. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with rifampicin (600 mg once daily) in 14 HIV+ patients caused an 11% increase in rifampicin AUC but no alteration in Cmax. Rifampicin Cmin was below the limit of detection for the assay. Administration of rifampicin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Nevirapine and rifampicin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with TB and using a nevirapine containing regimen may use rifabutin instead. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, October 2019. Participants were randomly selected to receive either nevirapine at 200 mg twice daily (n=256) or efavirenz at 600 mg daily (n=270), combined with two nucleoside analogues. Sixteen participants participated in an extensive pharmacokinetic study of nevirapine. Nevirapine concentrations at the end of the first week of treatment (on antituberculosis drugs) did not differ from concentrations off tuberculosis treatment, but declined thereafter. Concentrations at steady-state were 4111 ng/mL at week 12 versus 6095 ng/mL at week 48 (P < 0.0001). Nevirapine concentrations <3000 ng/mL were found to be a risk factor for virological failure. Efavirenz concentrations were higher on than off tuberculosis treatment (2700 versus 2450 ng/mL, P<0.0001). The omission of the 2 week lead-in dose of nevirapine prevented low concentrations at treatment initiation but did not prevent the risk of virological failure. Nevirapine or efavirenz for tuberculosis and HIV coinfected patients: exposure and virological failure relationship. Bhatt NB, Baudin E, Meggi B, et al. J Antimicrob Chemother, 2015, 70:225-232. Patients with HIV-1 and TB were randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment. In the NVP arm, 29% of patients had an unfavourable outcome at 6 months compared to 9% in EFV arm (P<0.08). The mean NVP and EFV levels estimated at 1 and 6 months did not significantly differ between favourable and unfavourable responders. Logistic regression analysis showed CYP2B6 516G>T polymorphism significantly associated with virologic outcome in patients receiving EFV-based regimen. Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on anti-TB treatment and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV. Lack of association between plasma levels of non-nucleoside reverse transcriptase inhibitors & virological outcomes during rifampicin co-administration in HIV-infected TB patients. Ramachandran G, Kumar AK, Ponnuraja C, et al. Indian J Med Res, 2013, 138:955-961. A randomised open label trial was conducted in ART naive HIV-TB patients, randomly assigned to receive either nevirapine or efavirenz based ART with concomitant rifampicin based anti-tubercular therapy (ATT). Participants were followed for 24 months. Of the 135 HIV-TB patients, who were receiving rifampicin based ATT, 68 were selected randomly to receive efavirenz based ART and 67 to receive nevirapine based ART. The virological failure rates in the overall population, and the nevirapine and efavirenz groups were 14.1% (19/135); 14.9% (10/67) and 13.2% (9/68), respectively (p =0.94). No significant difference was found between the groups in the rate of clinical, immunological or virological failures. The overall mortality was 17% with no significant difference between the two groups. Except for the lead in period on day 14, the mean nevirapine concentration remained above 3 mg/L. No association was found between plasma levels of nevirapine and incidence of unfavourable outcomes in this group. Outcome of ART in HIV-TB patients on rifampicin based ATT showed no significant difference, irrespective of whether efavirenz or nevirapine was used. Therefore, nevirapine based ART could be an alternative in the resource limited settings in patients with HIV and tuberculosis co-infection. Nevirapine versus efavirenz-based antitretroviral therapy regimens in antiretroviral-naïve patients with HIV and tuberculosis infection in India: a pilot study. Sinha S, Raghunandan P, Chandrashekhar R, et al. BMC Infect Dis, 2013, 13:482. ARV-naïve HIV-infected TB patients were initiated on an intermittent short-course regimen and randomized to receive didanosine and lamivudine with either NVP (400 mg) or EFV (600 mg) once-daily. Of the 168 patients included (79% men, median CD4 count 93 cells/mm3, median viral load 242,000 copies/ml), 104 were on EFV-based ART and 64 on NVP-based ART. There was a small but statistically significant elevation in ALT and SAP at 2 weeks and AST at 6 weeks after ART initiation. The proportion of patients with rate-limiting toxicity of liver enzymes was small. None had treatment terminated because of hepatotoxicity. Hepatotoxicity is not a major concern when HIV-infected TB patients, with normal baseline liver function initiate treatment for both infections simultaneously. Early changes in hepatic function among HIV-tuberculosis patients treated with nevirapine or efavirenz along with rifampin-based anti-tuberculosis therapy. Padmapriyadarsini C, Bhavani PK, Tang A, et al. Int J Infect Dis, 2013, 17:e1154-1159. A cross sectional study of 40 HIV patients (16 with HIV/TB coinfection, and 24 HIV without TB) was conducted in Jakarta. Nevirapine plasma levels (mean±SD) in HIV patients was 7.5±2.2 ug/ml, while in HIV/TB patients it was 5.5±2.7 µg/ml (p=0.018). In most of patients receiving rifampicin, the plasma nevirapine concentration was still in therapeutic range. Influence of rifampicin on nevirapine plasma concentration in HIV-TB coinfected patients. Nafrialdi, Nugroho AW, Yunihastuti E, et al. Acta Med Indones, 2012, 44:135-139. Twenty-two children received antituberculosis and ART concurrently for 4 weeks before pharmacokinetic sampling. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis. Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/L (range: 22.6-159.7) compared with 90.9 mg.h/L (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/L in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P=0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter. Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based tuberculosis treatment. Oudijk JM, McIlleron H, Mulenga V, et al. AIDS, 2012, 26:1523-1528. The pharmacokinetics of nevirapine in HIV and tuberculosis-coinfected children was assessed while receiving nevirapine-containing fixed-dose combination tablets with rifampicin-based tuberculosis treatment and after discontinuation. The median age (range) was 9.7 (4.4-11.7) years. The nevirapine area under the concentration versus time curve from 0 to 12 hours and trough concentration with rifampicin were 85.3 (40.5-170.7) mg.h/mL and 6.4 (3.00-13.27) mg/mL, respectively, providing adequate exposure. Pharmacokinetics of nevirapine in HIV and tuberculosis-coinfected children receiving antiretroviral fixed-dose combination tablets while receiving rifampicin-containing tuberculosis treatment and after rifampicin discontinuation. Prasitsuebsai W, Cressey TR, Capparelli E, et al. Pediatr Infect Dis, 2012, 31:389-391. Coadministration of nevirapine-containing HAART and rifampicin-containing ATT was assessed in 63 antiretroviral treatment naïve HIV/TB co-infected patients with CD4 counts less than 200 cells/mm3 who were started on rifampicin-containing ATT followed by nevirapine-containing HAART. A control group including 51 HIV patients without tuberculosis and on nevirapine-containing HAART was assessed. 97 out of 114 (85.1%) patients were alive at the end of 48 weeks. The CD4 cell count showed a mean increase of 108 vs.113 cells/mm3 (p=0.83) at 24 weeks of HAART in cases and controls respectively. Overall, 58.73% patients in cases had viral loads <400 copies/ml at the end of 48 weeks. The mean (± SD) Nevirapine concentrations of cases and control at 14, 28, 42 and 180 days were 2.19 ± 1.49 vs. 3.27 ± 4.95 (p=0.10), 2.78 ± 1.60 vs. 3.67 ± 3.59 (p=0.08), 3.06 ± 3.32 vs. 4.04 ± 2.55 (p=0.10) respectively and 3.04 μg/ml (in cases). Good immunological and clinical response can be obtained in HIV/TB co-infected patients receiving rifampicin and nevirapine concomitantly despite somewhat lower nevirapine trough concentrations. This suggests that rifampicin-containing ATT may be co administered in resource limited setting with nevirapine-containing HAART regimen without substantial reduction in antiretroviral effectiveness. The antiretroviral efficacy of highly active antiretroviral therapy and plasma nevirapine concentrations in HIV-TB-co-infected Indian patients receiving rifampicin based antituberculosis treatment. Sinha S, Dhooria S, Kumar S, et al. AIDS Res Ther, 2011, 8:41. A randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2 months of ethambutol, isoniazid, rifampicin, pyrazinamide / 4 months of isoniazid and rifampicin) thrice weekly, and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm(3), and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P=0.024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P=.058). Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial. Swaminathan S, Padmapriyadarsini C, Venkatesan P, et al. Clin Infect Dis, 2011, 53:716-724. Data from a randomized trial comparing treatment outcomes between 71 TB/HIV-1 co-infected patients receiving efavirenz (EFV)-based and nevirapine (NVP)-based ART; all of whom were receiving RMP-containing anti-TB treatment were analysed. Of 142 patients, 8 patients were excluded. Among the remaining 134 patients, the mean+/-SD age was 36.8+/-8.6 years and 67.2% were male. Severe hepatotoxicity (grade 3 or 4) developed in 4 patients (2.9%); 3 patients (4.6%) in the NVP group and 1 patient (1.4%) in the EFV group. Severe hyperbilirubinemia (grade 3 or 4) occurred in 7 patients (5.2%); 5 patients (7.7%) in the NVP group and 2 patients (2.9%) in the EFV group. Grade 1 or 2 hepatotoxicity occurred in 34 patients (31.4%). Hepatitis C virus co-infection (adjusted OR 3.03; 95%CI 1.26-7.29) was an independent risk factor associated with grade 1-4 hepatotoxicity (p=0.013). Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen. Mankhatitham W, Lueangniyomkul A, Manosuthi M. Southeast Asian J Trop Med Public Health, 2011, 42:651-658. A cross-sectional study was conducted in 30 HIV infected children on ART with nevirapine or efavirenz. Patients on simultaneous rifampicin and nevirapine were given higher doses of nevirapine with regular monitoring of liver function tests. Thirty patients (14 males) were enrolled in the study with 20 on nevirapine and 10 (33.3%) on efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean nevirapine dose given to the patients was 350.9±59.8 mg/m2/day (on simultaneous rifampicin) and 309.2±54.6 mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough nevirapine had values in the normal range, 1 (6.3%) had low nevirapine trough levels and 2 (12.5%) had high nevirapine trough levels. Of the post 2 hours nevirapine levels, 1 (5%) had low levels and 3 (15%) had high nevirapine blood levels. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of nevirapine. The efavirenz drug levels were 1.9±1.1 g/mL. Concurrent rifampicin administration does not alter blood levels of nevirapine; provided the dose of nevirapine is increased by 20-30%. Serum nevirapine and efavirenz concentrations and effect of concomitant rifampicin in HIV infected children on antiretroviral therapy. Shah I, Swaminathan S, Ramachandran G, et al. Indian Pediatr, 2011, 48:943-947. HIV-1/TB co-infected Ugandan adults (n=18) receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Day 7 geometric mean nevirapine C12 [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C12 on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean AUC was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng•h/mL versus 43 195 (35 607-57 035) ng•h/mL in the NVP400 arm (P < 0.01). Similarly, on Day 14, nevirapine AUC was lower in the NVP200 arm 23 668 (18 253-32 218) ng•h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng•h/mL (P = 0.03). In co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered. Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin. Lamorde M, Byakika-Kibwika P, Okaba-Kayom V, et al. J Antimicrob Chemother, 2011, 66:180-183. Seventy HIV-infected patients receiving rifampin for active TB (TB group) and 70 HIV-mono-infected patients (control group) received nevirapine 400mg/day-based ART. All were followed through 4 years of ART. Thirty-nine (55.7%) patients in the TB group were diagnosed with extrapulmonary/disseminated TB. The median duration of concurrent administration of nevirapine and rifampin was 5.4 (4.6-6.1) months. By intention-to-treat analysis, the percentage of patients who achieved HIV-1 RNA <50 copies/ml was 52.9% in the TB group and 50% in control group (p=0.866; odds ratio 1.121, 95% confidence interval 0.578-2.176); median (IQR) CD4 counts were 352 (271-580) cells/mm3 and 425 (308-615) cells/mm3 in the corresponding groups (p=0.238). The proportion of ART discontinuation due to any reason at 1, 2, 3, and 4 years was 21%, 34%, 37%, and 46% in the TB group and 21%, 36%, 43%, and 49% in the control group, respectively (p=0.651). The 4-year mortality rate was 6.4% in both groups. Nevirapine-based ART is an option for HIV-infected patients who receive rifampin in resource-limited countries or those who cannot tolerate efavirenz. Treatment outcomes of patients co-infected with HIV and tuberculosis who received a nevirapine-based antiretroviral regimen: a four-year prospective study. Manosuthi W, Tantanathip P, Chimsuntorn S, et al. Int J Infect Dis, 2010, 14:e1013-1017. Of a total of 156 HIV-infected TB patients who started NVP-based antiretroviral treatment, 136 (87%) completed TB treatment successfully, 16 (10%) died and 5 (4%) were transferred out. Mean body weight and CD4 gain (adults) were respectively 4.4 kg (95%CI 3.3-5.4) and 140 cells/mm3 (95%CI 117-162). Seventy-four per cent of patients who completed TB treatment and had a viral load performed (n=74) had undetectable levels (<50 copies/ml), while 17 (22%) had a viral load of 50-1000 copies/ml. Hepatotoxicity was present in 2 (1.3%) patients at baseline. Two patients developed Grade 2 and one developed Grade 3 alanine transaminase enzyme elevations during TB treatment (incidence rate per 10 years of follow-up 4.2, 95%CI 1.4-13.1). There were no reported deaths linked to hepatotoxicity. In a rural district in Malawi, concomitant NVP and RMP treatment is associated with good TB treatment outcomes and appears safe. Further follow-up of patients would be useful to ascertain the longer-term effects of this concurrent treatment. Outcomes and safety of concomitant nevirapine and rifampicin treatment under programme conditions in Malawi. Moses M, Zachariah R, Tayler-Smith K, et al. Int J Tuberc Lung Dis, 2010, 14:197-202. The pharmacokinetics of nevirapine were investigated in HIV/TB-coinfected subjects receiving rifampicin who were randomised to start nevirapine with dose escalation (200 mg once daily for 14 days and then 200 mg twice daily) or at full dose (200 mg twice daily). Nevirapine trough concentrations were below target (3000 ng/ml) in the escalation arm at Days 7, 14 and 21. In the full dose arm, Day 7 trough concentrations were above target, but steady state trough concentrations (Days 14 and 21) were below target. This study raises two questions, i) is the commonly used target of 3000 ng/ml appropriate for Ugandan patients, and ii) should a higher dose of nevirapine (e.g. 600 mg daily) be considered after the first 14 days. Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis Co-infected Ugandan adults on rifampicin. Lamorde M, et al. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2010, abstract 602. HIV-1-infected patients with CD4+ count ≤100 cells/ml and TB diagnosis received standard anti-TB therapy and a fixed-dose combination of stavudine, lamivudine, and NVP. In 16 enrolled subjects, the median value of the area under the curve of NVP was reduced by 25.6% at T1 compared with NVP alone (43.7 vs. 58.7 µg/ml.h; P=0.02). The reduction was only 7.5% at T2 (54.3 vs. 58.7 µg/ml.h; P=0.17). The median C trough was reduced of 19.5% at T1 compared with T3 (3.3 vs. 4.2 µg/mL; P=0.02) and of 7.1% at T2 compared with T3 (3.9 vs. 4.2 µg/mL; P=0.17). The proportion of subjects with C trough values <or=3 µg/mL was 31.2% (5 of 16), 40.0% (6 of 15), and 7.7% (1 of 13) at T1, T2, and T3, respectively. The reduction of the area under the curve of NVP during concomitant RFM treatment substantially decreases over time. Reversible reduction of nevirapine plasma concentrations during rifampicin treatment in patients coinfected with HIV-1 and tuberculosis. Matteelli A, Saleri N, Villani P, et al. J Acquir Immune Defic Syndr, 2009, 52:64-69. Patients were divided into two groups: (1) patients receiving nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n=27); (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n=26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated. Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ=0.025 mg/L). The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis. Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients. Elsherbiny D, Cohen K, Jansson B, et al. Eur J Clin Pharmacol, 2009, 65:71-80. The pharmacokinetics of nevirapine when started at full dose (200 mg twice daily, with no dose escalation) was studied in TB/HIV+ subjects receiving rifampicin. Nevirapine trough concentrations (mean ± sd) two weeks after commencing nevirapine were 5.83 ±2.29 mg/L. Pharmacokinetic profiles were determined during rifampicin dosing 4 weeks after commencing nevirapine, and 4 weeks after completion of rifampicin dosing. Nevirapine Cmin, Cmax and AUC increased by 14%, 13% and 20%, respectively, in the absence of rifampicin (Cmin 4.86 vs 5.74 mg/L; Cmax 6.86 vs 7.77 mg/L; AUC 70.05 vs 80.03 h.mg/L). When nevirapine was started at full dose in patients receiving rifampicin, therapeutic nevirapine concentrations (>3 mg/L) were attained and there was a potent decline in viral load. Pharmacokinetic parameters of nevirapine when initiated without 2-weeks leading dose in tuberculosis-HIV co-infected patients receiving rifampicin: substudy of the CARINEMO-ANRS 12146 trial in Maputo (Mozambique). Bonnet M, Bhatt NB, Jani IV, et al. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, July 2009, abstract WEPEB253. Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake. Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024). Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine. Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication. Stohr W, Back D, Dunn D, et al. Antivir Ther, 2008, 13:675-685. Patients starting ART with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or=5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0. Virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. Boulle A, Van Cutsem G, Cohen K, et al. JAMA, 2008, 300, 530-539. Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. From week 4, 12 h PK studies showed that NVP400 had lower median NVP AUC0-12 h, Cmax and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable. In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended. Pharmacokinetics and 48-weel efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin. Avihingsanon A, Manosuthi W, Kantipong P, et al. Antivir Ther, 2008, 13:529-536. Single center prospective data were collected on all TB/HIV-coinfected patients who received concomitant NNRTI and rifampicin. Of 103 TB/HIV coinfected patients, 26 received concomitant rifampicin with efavirenz (EFV) and 17 with nevirapine (NVP). NNRTIs were commenced after rifampicin in 18/26 (69%) and 7/17 (41%) subjects treated with EFV and NVP, respectively. Of these 88% completed antituberculosis therapy. There were two (5%) deaths, both due to lymphoproliferative malignancy. Three (7%) patients transferred care or discontinued therapy. Of subjects 83% had normal liver function tests (LFTs) and 11% had Grade 1-2 and 6% Grade 3-4 LFT abnormalities during concomitant therapy. Plasma concentrations were measured in 31 patients. The first were within the therapeutic range in 5/7 on NVP 200 mg twice daily, 2/4 on NVP 300 mg twice daily, 3/7 EFV 600 mg once daily, and 7/13 on EFV 800 mg once daily. Concentrations were subtherapeutic in 4/11 (36%) and 3/20 (20%) subjects on NVP and EFV, respectively. No virological rebounds were observed. Of subjects receiving concomitant NVP or EFV with rifampicin, 64% and 80%, respectively, had therapeutic NNRTI plasma concentrations. Subtherapeutic concentrations were not associated with virological failure. Good clinical outcomes and a low incidence of hepatotoxicity were observed. Concomitant use of nonnucleoside analogue reverse transcriptase inhibitors and rifampicin in TB/HIV type 1-coinfected patients. Sathia L, Obiorah I, Taylor G, et al. AIDS Res Hum Retroviruses, 2008, 24:897-901. A retrospective cohort study was conducted in all ART-naïve patients who were receiving rifampicin. Of 188 patients, 77 and 111 patients were initiated on EFV-based ART (EFV group) and NVP-based ART (NVP group), respectively. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV-1 RNA <50 copies/mL (P=0.140, odds ratio=0.590, 95% confidence interval=0.302-1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/muL in the EFV group and 156 and 218 cells/microL in the NVP group (P>0.05). By binary logistic regression, treatment group was not associated with HIV-1 RNA <50 copies/mL (P>0.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P=0.084). For HIV-TB co-infected patients who receive rifampicin, efficacy of 600 mg EFV-based and 400 mg NVP-based ART may be similar, although adverse events tend to be higher in NVP-based ART. Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin. Manosuthi W, Mankatitham W, Lueangniyomkul A, et al. HIV Med, 2008, 9:294-299. Sixteen South African patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy. Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for Cmax, 0.64 (90% CI 0.52-0.80) for AUC and 0.68 (90% CI 0.53-0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC to the AUC of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism. Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis. Cohen K, van Cutsem G, Boulle A, et al. J Antimicrob Chemother, 2008, 61, 389-393. 27 HIV-infected adult Malawians after starting Triomune (stavudine, lamivudine and nevirapine) in the second week of tuberculosis treatment were studied. At baseline, 88% had CD4+ T… <a href="https://www.hiv-druginteractions.org/" target="_blank">Read more</a>
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in DOR AUC by 88%. Contraindicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Co-administration is contraindicated. Co-administration with medicinal products that are strong cytochrome P450 (CYP) 3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine. Co-administration of single dose rifampicin (600 mg) and doravirine (100 mg single dose) decreased doravirine AUC and C24 by 9% and 10%, but increased Cmax by 40%. Co-administration of multiple doses of rifampicin (600 mg once daily) and doravirine (100 mg single dose) decreased doravirine AUC, Cmax and C24 by 88%, 57% and 97%, respectively. Pifeltro Summary of Product Characteristics, Merck Sharp & Dohme Ltd, November 2018. Co-administration is contraindicated with rifampin. Co-administration of doravirine (100 mg single dose) with rifampin (600 mg once daily) was studied in 10 subjects. Doravirine AUC, Cmax and C24 decreased by 88%, 57% and 97% respectively. At least a 4-week cessation period is recommended prior to initiation of doravirine. Pifeltro US Prescribing Information, Merck & Co Inc, August 2018. Co-administration of doravirine (100 mg, single dose) and rifampicin (600 mg, single dose or once daily) was studied in 10 healthy subjects. Doravirine AUC and C24 were unchanged when administered with a single dose of rifampicin; doravirine Cmax increased by 40%. From this, the authors conclude that interaction through P-gp inhibition by rifampicin is unlikely to be an issue. Conversely, when a single dose of doravirine was administered alongside once daily rifampicin, doravirine AUC, Cmax and C24 reduced by 88%, 57% and 97%, respectively. This reduction in doravirine exposure is likely to be due to CYP3A induction by rifampicin. The authors do not recommend co-administration of doravirine and rifampicin, as doravirine C24 concentrations fall below levels required for an antiviral effect. The effect of single and multiple doses of rifampin on the pharmacokinetics of doravirine in healthy subjects. Yee KL, Khalilieh SG, Sanchez RI, et al. Clin Drug Investig, 2017, 37(7): 659-667., Summary:Coadministration decreased doravirine exposure by 82% and is contraindicated as this may result in loss of therapeutic effect and development of resistance. At least a 4-week cessation period is recommended prior to initiation of doravirine due to the persisting inducing effect upon discontinuation of a moderate/strong inducer. Coadministration of doravirine (100 mg single dose) and rifampicin (600 mg once daily) decreased doravirine AUC, Cmax and C24 by 88%, 57% and 97%, respectively (n=10).
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (High Quality of Evidence)
- Liverpool Notes:
- Coadministration of Kaletra with rifampicin is not recommended. Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations due to CYP3A induction by rifampicin. The decrease in lopinavir concentrations may in turn significantly decrease the lopinavir therapeutic effect. A dose adjustment of Kaletra 400 mg/400 mg twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin. However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders. Therefore, this coadministration should be avoided unless judged strictly necessary. If this coadministration is judged unavoidable, increased dose of Kaletra at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring. The Kaletra dose should be titrated upward only after rifampicin has been initiated. Kaletra Summary of Product Characteristics, AbbVie Ltd, January 2021. Coadministration of rifampicin and Kaletra is contraindicated as it may lead to loss of virologic response and possible resistance to Kaletra or to the class of protease inhibitors or to other coadministered antiretroviral agents. Kaletra is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. Coadministration of rifampicin (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) to 22 HIV- subjects results in decreases in lopinavir Cmax, AUC and Cmin of 55%, 75% and 99% respectively. Data from 10 subjects receiving rifampicin and lopinavir/ritonavir (800/200 mg twice daily) showed a 2% increase in lopinavir Cmax, but decreases of 16% and 57% for AUC and Cmin, when compared to lopinavir/ritonavir 400/100 mg twice daily alone. Coadministration of rifampicin with lopinavir/ritonavir (400/400 mg twice daily) to 9 HIV- subjects resulted in decreases of 7% and 2% for lopinavir Cmax and AUC and an increase of 3% for Cmin, when compared to 400/100 mg alone. Kaletra Prescribing Information, AbbVie Ltd, October 2020. The steady-state pharmacokinetics of lopinavir were evaluated in HIV-infected adults stable on LPV/r tablets (400/100 mg twice daily) who were given rifampicin (600 mg daily), and the dose of the LPV/r gradually increased over a period of two weeks ( first to 600/150 twice daily and then to 800/200 mg twice daily). Twenty one subjects started the study, but two were withdrawn due to grade 3/4 transaminitis. The median [IQR) pre-dose LPV concentrations were 8.1 (6.2 to 9.8) mg/L at baseline, 1.7 (0.3 to 3.0) mg/L after 7 days of rifampicin, 5.9 (2.1 to 9.9) mg/L with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/L with double-dose LPV/r. There were no significant differences in the LPV AUC, Cmax, pre-dose concentrations, 12 h concentration, or half-life between the baseline and double-dose LPV/r time points. Doubling the dose of the tablet formulation of LPV/r overcame induction by rifampicin, with less hepatotoxicity occurring in this cohort of HIV-infected participants than reported in healthy-volunteer studies. The cohort consisted of HIV-infected patients who were virologically suppress with high CD4 counts – the risk of hepatotoxicity may be different in HIV-infected individuals with TB and/or with different CD4 counts.Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Decloedt EH, McIlleron H, Smith P, et al. Antimicrob Agents Chemother, 2011, 55(7): 3195-3200. A study looking at the interaction between rifampicin (600 mg once daily) and LPV/RTV (600/150 or 800/200 mg twice daily) in 11 HIV- subjects had to be terminated early due to severe nausea, vomiting and elevated AST/ALT. No major complaints or laboratory abnormalities were noted during the first phase of the study (rifampicin alone), but 10/11 subjects suffered from nausea and/or vomiting following the addition of LPV/RTV. No LPV was detected in trough samples from 5/11 subjects (due to either no drug intake or vomiting); trough concentrations in 3 subjects receiving 600/150 mg were 6.7, 7.2 and 10.3 µg/ml and in 3 subjects receiving 800/200 mg were 8.3, 11.5 and 13.8 µg/ml. The reasons for the adverse events may be related to a) the sequence of drug administration, b) non-linear pharmacokinetics of LPV/RTV after intake of higher doses, or c) unknown factors which make healthy volunteers more susceptible to adverse events. Unexpected high incidence of nausea, vomiting and asymptomatic elevations of AST/ALT enzymes in healthy volunteers receiving rifampin and adjusted doses of lopinavir/ritonavir tablets. Nijland H, et al. 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, April 2007, abstract 51. Two twice-daily adjusted-dose regimens of lopinavir/ritonavir were tested in combination with rifampicin in healthy subjects. All subjects were treated with LPV/r 400/100 mg from days 1-15. From days 16-24 half the subjects were given LPV/r 800/200 mg (Arm 1) in dose titration and half LPV/r 400/400 mg (Arm 2) in dose titration. Rifampicin was given to all subjects between days 11-24. PK data was available from 19 subjects. The geometric mean ratio for lopinavir AUC12, Cmin and Cmax were 0.84, 0.43 and 1.02 respectively in arm 1 (800/200 mg) were 0.98, 1.03 and 0.93 respectively in arm 2 (400/400 mg). There was toxicity observed with the higher dose of LPV/r and rifampicin with discontinuation in 9/29 subjects (31%). The treatment of HIV-infected patients with TB with these agents must be approached with caution and close monitoring of liver function is essential. Judicious use of TDM will aid ensuring LPV levels are above the minimum required. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. la Porte CJ, Colbers EP, Bertz R, et al. Antimicrob Agents Chemother, 2004, 48: 1553-1560., Summary:Coadministration of lopinavir/ritonavir with rifampicin is not recommended as it causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of lopinavir/ritonavir (400/400 mg twice daily) is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this coadministration should be avoided unless judged strictly necessary.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (High Quality of Evidence)
- Liverpool Notes:
- Combination of rifampicin with fosamprenavir with concomitant low-dose ritonavir is contraindicated. No drug interaction studies with fosamprenavir/ritonavir have been performed. Coadministration with amprenavir (600 mg once daily) decreased amprenavir AUC by 82%. The decrease in amprenavir AUC can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.Telzir Summary of Product Characteristics, ViiV Healthcare UK Ltd, January 2021. Coadministration with rifampicin is contraindicated as it decreases amprenavir concentrations and may lead to loss of virologic response and possible resistance to amprenavir or to the class of protease inhibitors. Coadministration of rifampicin (300 mg once daily for 4 days) and amprenavir (1200 mg twice daily for 4 days) to 11 subjects resulted in decreases in amprenavir Cmax, AUC and Cmin of 70%, 82% and 92% respectively. There was no change in Cmax or AUC for rifampicin, but the interaction for Cmin could not be determined as Cmin was below the lower limit of quantification. Lexiva Prescribing Information, ViiV Healthcare, October 2020. A study was conducted in 12 volunteers taking amprenavir (1200 mg twice daily) and rifampicin (600 mg once daily). Amprenavir had no effect on rifampicin pharmacokinetics. Rifampicin significantly decreased the AUC of amprenavir by 82%, Cmax by 70% and Cmin by 92%. Although the two drugs were well tolerated, amprenavir clearance was markedly increased (5.45-fold). Pharmacokinetic interaction between amprenavir and rifabutin or rifampicin in healthy males. Polk RE, Brophy DF, Israel DS, et al. Antimicrob Agents Chemother, 2001, 45:502–8., Summary:Coadministration is contraindicated as rifampicin reduces amprenavir concentrations by ~90%. This may lead to loss of virologic response and possible resistance to amprenavir or to the class of protease inhibitors
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Concomitant use of tipranavir co-administered with low dose ritonavir, and rifampicin is contraindicated. Alternate antimycobacterial agents such as rifabutin should be considered. Co-administration of protease inhibitors with rifampicin substantially decreases protease inhibitor concentrations. In the case of tipranavir co-administered with low dose ritonavir, concomitant use with rifampicin is expected to result in sub-optimal levels of tipranavir which may lead to loss of virologic response and possible resistance to tipranavir. Aptivus Summary of Product Characteristics, Boehringer Ingelheim Ltd, July 2020. Coadministration is contraindicated as this may lead to loss of virologic response and possible resistance to tipranavir or other coadministered antiretroviral agents. Aptivus Prescribing Information, Boehringer Ingelheim, June 2020., Summary:Coadministration is contraindicated as it may cause large decreases in tipranavir concentrations which may result in sub-optimal concentrations and may lead to the loss of virological response.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (High Quality of Evidence)
- Liverpool Notes:
- The use of rifampicin with indinavir or indinavir/ritonavir is contraindicated. Coadministration of indinavir (800 mg three times daily) and rifampicin (600 mg once daily) decreased indinavir AUC by 92%. This effect is due to an induction of CYP3A4 by rifampicin and can result in virological failure and resistance development. The interaction with indinavir/ritonavir has not been studied. During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with ritonavir, a high frequency of liver reactions was seen. Crixivan Summary of Product Characteristics, Merck Sharp & Dohme Ltd, October 2018. Rifampicin should not be coadministered with indinavir as this may lead to loss of virologic response and possible resistance to indinavir or the class of protease inhibitors or other coadministered antiretroviral agents. Coadministration of rifampicin (600 mg once daily for 8 days) and indinavir (800 mg three times daily for 7 days) to 12 subjects resulted in decreases in indinavir Cmax and AUC of 87% and 92% respectively. Crixivan Prescribing Information, Merck & Co Inc, May 2018. The safety and efficacy of a higher dose of indinavir/ritonavir (600/100 mg twice daily) with rifampicin (and 2 NRTIs) was studied in Thai patients. Indinavir pharmacokinetics were obtained at week 2 and trough concentrations were determined at weeks 4, 8 and 12. Indinavir/ritonavir was reduced to the Thai standard of 400/100 mg twice daily after discontinuation of rifampicin with trough concentrations being obtained at least 4 weeks after dose reduction. Geometric mean (90% CI) indinavir AUC at week 2 was 8.11 (5.56-11.82) mg/L.h. Geometric mean (90% CI) trough concentration at week 2 was 0.03 (0.02-0.04) mg/L. Geometric mean trough concentration after stopping rifampicin and subsequent dose reduction was 0.68 mg/L (p=0.004). Rifampicin had a significant effect on indinavir concentrations resulting in suboptimal concentrations, despite which the majority of patients had undetectable viral load (<50 copies/ml). Pharmacokinetics, safety and 24 weeks efficacy of ritonavir-boosted indinavir (600/100 mg bid) in HIV/TB co-infected Thai patients receiving rifampicin. Avihingsanon A, van der Lugt, Singphore U, et al. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, July 2009, abstract TUPEB144. A study was performed in 6 HIV+ patients to evaluate whether the inducing effect of rifampicin could be overcome by the inhibitory effect of ritonavir. Pharmacokinetic evaluations were performed at steady stated following administration of indinavir/ritonavir (800/100 mg twice daily) before and after administration of rifampicin (300 mg once daily for 4 days). Reductions in median concentrations were seen 12 h after the last dose of rifampicin; indinavir concentrations reduced by 87% (from 837 to 112 ng/ml) and ritonavir concentrations by 94% (from 431 to 27 ng/ml). These results strongly indicate that the administration of rifampicin with indinavir/ritonavir (800/100 mg twice daily) could lead to subtherapeutic concentrations of indinavir. Pharmacokinetic interaction between rifampicin and the combination of indinavir and low-dose ritonavir in HIV-infected patients. Justesen US, Anderson AB, Klitgaard NA, et al. Clin Infect Dis, 2004, 38: 426-429. The effects of indinavir (800 mg three times daily) on the pharmacokinetics of rifampicin (600 mg single dose) were studied in eleven HIV-infected patients. With concomitant indinavir medication, the mean AUC0-24 of rifampicin was increased by 73%. Effect of indinavir on the pharmacokinetics of rifampicin in HIV-infected patients. Jaruratanasirikul S, Sriwiriyajan S. J Pharm Pharmacol, 2001, 53:409-12. A study was conducted on three HIV-negative TB patients receiving rifampicin and indinavir/ritonavir (800/100 mg) and six healthy volunteers receiving indinavir/ritonavir (800/100 mg) without rifampicin. The AUCs of indinavir and ritonavir were decreased by 81% and 89%, respectively. The AUCs of rifampicin and its active metabolite were increased by 25% and 63% but their peak and trough concentrations were not influenced.Double trouble: A pharmacokinetic study of indinavir/ritonavir (800 +100 mg bid) and rifampicin for patients co–infected with TB and HIV. de Gast M, Burger D, van Crevel R, et al. 2nd International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, the Netherlands, 2001, abstract 1.10., Summary:Coadministration with indinavir alone or indinavir/ritonavir is contraindicated as indinavir concentrations are decreased by >80%.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration with rifampicin is contraindicated. Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of Reyataz or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen. Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, October 2018. Coadministration with rifampin is contraindicated. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance. Coadministration of rifampin (600 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) was studied in 16 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 53%, 72% and 98%, respectively. Reyataz US Prescribing Information Bristol-Myers Squibb Company, March 2018. A study was performed to determine if a dose escalation of atazanavir/ritonavir could safely overcome the interaction with rifampicin used at standard and double doses in people living with HIV without tuberculosis in Uganda. Four pharmacokinetic visits were performed at steady-state: PK1 300/100 mg once daily (baseline); PK2 300/100 mg once daily with rifampicin 600 mg; PK3 300/100 mg twice daily with rifampicin 600 mg QD and PK4 300/100 mg twice daily with rifampicin 1200 mg once daily. Due to the potential risk of sub-therapeutic atazanavir concentrations with rifampicin, dolutegravir 50 mg twice daily was co-administered. Overall, 26 participants were enrolled, of those, 88% were female. Compared with PK1, atazanavir concentrations were significantly reduced at PK2: geometric mean ratios (GMR, 90% CI) of Cmin and AUC24 were 0.04 (0.03-0.05) and 0.15 (0.12-0.18), respectively. The escalation to BID dosing (PK3) when compared to PK1, had a GMR of 0.83 (0.68-1.02) and 1.08 (0.97-1.09), respectively. Comparable atazanavir/ritonavir exposures were maintained with double doses of rifampicin, GMR of Cmin and AUC24 0.81 (0.67-1.00) and 1.01 (0.93-1.09) compared to PK1, respectively. The percentage of participants with concentrations below the MEC target (i.e. 0.15 mg/L) was 4%, 100%, 23% and 19% during PK1, PK2, PK3 and PK4 visits, respectively. No participant developed significant elevation of liver enzymes, reported an serious adverse effects or experienced rebound viremia. In summary, increasing the dose of atazanavir/ritonavir to twice daily was well-tolerated and achieved acceptable atazanavir plasma concentrations. Twice daily dosing of atazanavir safely overcomes the interaction with rifampicin. Kamunkhwala G, Mugerwa H, Siccardi M, et al. CROI 2023, Seattle February 19-22, abstract 751. A phase 1, open-label, one-arm (with 3 sequential periods) study was designed to assess the pharmacokinetic interactions and safety of atazanavir, ritonavir and rifampicin in 14 HIV- volunteers. During period 1, participants received rifampicin (600 mg once daily) for 8 days. During period 2, participants continued the same dose of rifampicin and added atazanavir/ritonavir (300/100 mg twice daily) for at least 11 days. During period 3, atazanavir was to be increased to 400 mg twice daily. However, on adding atazanavir/ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated. The authors concluded that coadministration of rifampicin with protease inhibitors may not be a viable treatment option if rifampicin administration precedes protease inhibitor initiation. Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. Haas DW, Koletar SL, Laughlin L, et al. J Aquir Immune Defic Syndr, 2009, 50(3): 290-293. Pharmacokinetics of steady-state atazanavir and ritonavir were evaluated in three HIV/TB co-infected patients treated with a rifampicin-containing regimen (rifampicin 600 mg per day) and antiretroviral therapy including NRTIs plus atazanavir/ritonavir (300/100 mg once daily). Data were compared to historical data for atazanavir alone (400 mg once daily). In all three cases there was a marked decrease in exposure (median of 64% compared to atazanavir alone) and for more than 50% of the time the atazanavir level was below the minimum recommended trough plasma level (150 ng/ml according to current pharmacokinetic guidelines) to inhibit HIV wild-type replication. The administration of rifampicin with a combination of atazanavir/ritonavir must be avoided because subtherapeutic concentrations of atazanavir are produced. Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients. Mallolas J, Sarasa M, Nomdedeu M, et al. HIV Med, 2007, 8(2): 131-134. Coadministration of rifampicin (600 mg, once daily) with) atazanavir/ritonavir (300 mg/100 mg, 300 mg/200 mg or 400 mg/200 mg once daily) was studied in healthy subjects. Atazanavir (300/100 mg dose) AUC, Cmax and Cmin decreased 72%, 53% and, 98%, respectively. Atazanavir (300/200 mg dose) AUC, Cmax and Cmin decreased 55%, 37%, and 94%, respectively. Atazanavir (400/200 mg dose) AUC, Cmax and Cmin decreased 28%, 14%, and 89%, respectively. The authors conclude that the ritonavir-boosting regimens tested were unable to overcome the decrease in atazanavir exposure associated with rifampicin (CYP3 inducer). Atazanavir should not be coadministered with rifampicin. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Burger DM, Agarwala S, Child M et al. Antimicrob Agents Chemother, 2006, 50(10): 3336-3342., Summary:Coadministration is contraindicated as it may significantly decrease atazanavir concentrations, leading to loss of therapeutic effect and possible development of resistance. Coadministration of rifampicin (600 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) to 16 subjects decreased atazanavir Cmax, AUC and Cmin by 53%, 72% and 98% respectively. Note, a pharmacokinetic study in people living with HIV showed that a double dose of atazanavir/ritonavir (300/100 mg twice daily) was able to overcome the interaction with rifampicin given at a dose of 600 mg once daily or 1200 mg once daily. Coadministration of atazanavir/ritonavir (300/100 mg twice daily) with rifampicin 600 mg once daily decreased atazanavir Cmin by 17% and increased AUC by 8% compared to atazanavir/ritonavir 300/100 mg alone once daily. Furthermore, coadministration with rifampicin 1200 mg once daily decreased atazanavir Cmin by 19% and increased AUC by 1%. No participant developed significant elevation of liver enzymes or experienced rebound viremia.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Very Low Quality of Evidence)
- Liverpool Notes:
- Rifampicin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect of Evotaz and development of resistance to atazanavir. The combination of rifampicin and Evotaz is contraindicated. Coadministration is contraindicated with medicinal products that are strong inducers of the CYP3A4 isoform of cytochrome P450 (e.g. rifampicin) due to the potential for decreased plasma concentrations of atazanavir and/or cobicistat, leading to loss of therapeutic effect and possible development of resistance to atazanavir. Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. Evotaz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, November 2018. Coadministration is contraindicated. Rifampicin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance. Evotaz US Prescribing Information Bristol-Myers Squibb Company, March 2018., Summary:Coadministration with atazanavir/ritonavir has not been studied and is contraindicated as it may significantly decrease atazanavir/cobicistat concentrations, leading to loss of therapeutic effect and possible development of resistance. Coadministration with atazanavir/ritonavir decreased atazanavir AUC by 72% and coadministration with twice daily atazanavir alone failed to provide adequate atazanavir exposure and a high frequency of liver reactions was seen.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Low Quality of Evidence)
- Liverpool Notes:
- Coadministration with rifampicin is contraindicated. Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of Reyataz or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen. Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, October 2018. Coadministration with rifampin is contraindicated. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance. Coadministration of rifampin (600 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) was studied in 16 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 53%, 72% and 98%, respectively. Reyataz US Prescribing Information Bristol-Myers Squibb Company, March 2018. The safety and pharmacokinetic interaction of atazanavir and rifampicin were assessed in 10 healthy volunteers receiving atazanavir (300 mg twice daily) alone (period 1) or with rifampicin (600 mg once daily; period 2), or atazanavir (400 mg twice daily) with rifampicin (600 mg once daily; period 3). Despite the twice-daily administration of atazanavir, the mean C12h values for atazanavir were 44 ng/ml (period 2) and 113 ng/ml (period 3) which were markedly below those seen in period 1 (811 ng/ml) or historical data from atazanavir 400 mg once daily. The authors speculate that a strategy that warrants further investigation is to combine atazanavir (either 300 or 400 mg) with ritonavir (100 mg) both given twice daily with rifampicin once daily. Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily. Acosta EP, Kendall MA, Gerber JG, et al. Antimicrob Agents Chemother, 2007, 51(9): 3104-3110. The magnitude of the interaction between rifampicin and unboosted atazanavir given twice daily was studied in 10 HIV- subjects. Coadministration of rifampicin (600 mg once daily) and atazanavir (300 mg twice daily) decreased atazanavir AUC (80%), Cmax (66%) and Cmin (95%). Increasing atazanavir to 400 mg twice daily with rifampicin decreased atazanavir AUC (59%), Cmax (41%) and Cmin (86%) compared to atazanavir 300 mg alone. Although safe and generally well tolerated, neither atazanavir regimen maintained adequate plasma exposure when given with rifampicin. Effect of rifampin on pharmacokinetics and safety of twice-daily atazanavir: ACTG Protocol A5213. Acosta E, et al. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract 575., Summary:Coadministration is contraindicated as it may significantly decrease atazanavir concentrations, leading to loss of therapeutic effect and possible development of resistance. Coadministration of rifampicin (600 mg once daily) and atazanavir/ritonavir (300/100 mg once daily) to 16 subjects decreased atazanavir Cmax, AUC and Cmin by 53%, 72% and 98% respectively. Coadministration of twice daily atazanavir alone with rifampicin failed to provide adequate atazanavir exposure and a high frequency of liver reactions was seen.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied. The combination of rifampicin and boosted darunavir is contraindicated. Rifampicin is a strong CYP3A inducer and has been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin. Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, September 2022. Coadministration with darunavir/ritonavir may decrease darunavir concentrations. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Prezista Prescribing Information, Janssen Pharmaceuticals Inc, March 2023. Concentrations of darunavir/ritonavir were measured in peripheral blood mononuclear cells (PBMC) from PLWH enrolled in a dose-escalation cross-over study (NCT03892161). Patients started with darunavir/ritonavir 800/100 mg once daily, then rifampicin (600-750 mg once daily) and dolutegravir (50 mg twice daily) were added, ritonavir dose was increased to 200 mg. They then received either darunavir/ritonavir 800/100 twice daily followed by 1600/200 once daily or vice versa. After the addition of rifampicin, intra-PBMC darunavir Ctrough concentrations dropped significantly from a value of 215 ng/mL (IQR 144-374) to 119 ng/mL (IQR 13-694) and 68 ng/mL (IQR 16-164) for 800/100 twice daily and 1600/200 once daily dosages, respectively. However, a significant increase in the intra-PBMC/plasma ratio was observed for darunavir, from a median value of 0.17 (IQR 0.09-0.26) to 0.23 (IQR 0.20-0.26) and 0.28 (IQR 0.21-0.41) for 800/100 twice daily and 1600/200 mg once daily regimens, respectively. This study suggests that the relative intracellular exposure of darunavir increases with rifampicin thus intracellular concentrations should be considered in future studies evaluating drug-drug interactions with rifampicin. Intracellular disposition of darunavir/ritonavir and dolutegravir with rifampicin. De Nicolo A, Calcagno A, Motta I, et al. Virtual Conference on Retroviruses and Opportunistic Infections 2021, March 6-10, 2021, Abstract 371. The safety and pharmacokinetics of adjusted doses of darunavir/ritonavir (1600/200 mg once daily and 800/100 mg twice daily) in presence of rifampicin were evaluated in virologically suppressed PLWH without TB and compared to the pharmacokinetics of darunavir/ritonavir (800/100 mg once daily) without rifampicin in a cross-over study design. Baseline darunavir/ritonavir steady state pharmacokinetics was determined and rifampicin added for 7 days, then the dose of ritonavir was increased to 200 mg; 7 days later the dose of darunavir was increased; after another 7 days participants were crossed over to the alternative adjusted darunavir dose. Clinical adverse events, ALT, and bilirubin were monitored every 2 to 3 days during treatment with rifampicin. Seventeen PLWH were enrolled and started on study treatment before the study was stopped due to high rates of hepatotoxicity. Only 4 participants completed the study. Six (35%) of the participants were withdrawn for DAIDS grade 3 (n=3) or 4 (n=3) ALT elevations developing after 9-12 days of rifampicin; 3 participants were symptomatic. Hepatotoxicity resolved in all cases after withdrawal of study treatment and participants were successfully re-established on their standard of care ART regimen. Darunavir trough concentrations were below the protein-adjusted EC50 of 200 ng/mL in 2 participants in the darunavir/ritonavir 1600/200 mg once daily group in presence of rifampicin whereas no participant had trough concentrations below the EC50 in the darunavir/ritonavir 800/100 mg twice daily group. Adjusted doses of darunavir/ritonavir with rifampicin were associated with unacceptable risk of hepatotoxicity in PLWH without TB. Twice daily but not once daily, double dose darunavir/ritonavir may achieve adequate darunavir trough concentrations in presence of rifampicin. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in PLWH. Ebrahim I, Maartens G, Wiesner L, et al. J Antimicrob Chemother, 2020, 75(4): 1019-1025. Using a population pharmacokinetic approach, darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n=51, 7 female). Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; no rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for plus rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily with rifampicin were simulated. Compared with no rifampicin, simulated darunavir AUC0-24 was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily plus rifampicin, respectively; but 39% higher with 1200/150 mg twice daily plus rifampicin. Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. Simulation of the impact of rifampicin on once-daily darunavir/ritonavir pharmacokinetics and dose adjustment strategies: a population pharmacokinetic approach. Dickinson L, Winston A, Boffito M, et al. J Antimicrob Chemother, 2016, 17: 1041-1045., Summary:Coadministration is contraindicated as it may cause significant decreases in darunavir concentrations. A population pharmacokinetic approach indicates that the coadministration of rifampicin (600 mg once daily) decreases darunavir AUC by 57%, 26%, 1% and 16% when administering darunavir/ritonavir at 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily, and 800/100 mg twice daily, respectively, but is 39% higher with 1200/150 mg twice daily. It was suggested that darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. However, increasing the dose of darunavir/ritonavir in the presence of rifampicin led to an unacceptable risk of hepatotoxicity in HIV-infected subjects.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied. The combination of rifampicin and boosted darunavir is contraindicated. Rifampicin is a strong CYP3A inducer and has been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin. Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, September 2022. Coadministration with darunavir/ritonavir may decrease darunavir concentrations. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Prezista Prescribing Information, Janssen Pharmaceuticals Inc, March 2023. Concentrations of darunavir/ritonavir were measured in peripheral blood mononuclear cells (PBMC) from PLWH enrolled in a dose-escalation cross-over study (NCT03892161). Patients started with darunavir/ritonavir 800/100 mg once daily, then rifampicin (600-750 mg once daily) and dolutegravir (50 mg twice daily) were added, ritonavir dose was increased to 200 mg. They then received either darunavir/ritonavir 800/100 twice daily followed by 1600/200 once daily or vice versa. After the addition of rifampicin, intra-PBMC darunavir Ctrough concentrations dropped significantly from a value of 215 ng/mL (IQR 144-374) to 119 ng/mL (IQR 13-694) and 68 ng/mL (IQR 16-164) for 800/100 twice daily and 1600/200 once daily dosages, respectively. However, a significant increase in the intra-PBMC/plasma ratio was observed for darunavir, from a median value of 0.17 (IQR 0.09-0.26) to 0.23 (IQR 0.20-0.26) and 0.28 (IQR 0.21-0.41) for 800/100 twice daily and 1600/200 mg once daily regimens, respectively. This study suggests that the relative intracellular exposure of darunavir increases with rifampicin thus intracellular concentrations should be considered in future studies evaluating drug-drug interactions with rifampicin. Intracellular disposition of darunavir/ritonavir and dolutegravir with rifampicin. De Nicolo A, Calcagno A, Motta I, et al. Virtual Conference on Retroviruses and Opportunistic Infections 2021, March 6-10, 2021, Abstract 371. The safety and pharmacokinetics of adjusted doses of darunavir/ritonavir (1600/200 mg once daily and 800/100 mg twice daily) in presence of rifampicin were evaluated in virologically suppressed PLWH without TB and compared to the pharmacokinetics of darunavir/ritonavir (800/100 mg once daily) without rifampicin in a cross-over study design. Baseline darunavir/ritonavir steady state pharmacokinetics was determined and rifampicin added for 7 days, then the dose of ritonavir was increased to 200 mg; 7 days later the dose of darunavir was increased; after another 7 days participants were crossed over to the alternative adjusted darunavir dose. Clinical adverse events, ALT, and bilirubin were monitored every 2 to 3 days during treatment with rifampicin. Seventeen PLWH were enrolled and started on study treatment before the study was stopped due to high rates of hepatotoxicity. Only 4 participants completed the study. Six (35%) of the participants were withdrawn for DAIDS grade 3 (n=3) or 4 (n=3) ALT elevations developing after 9-12 days of rifampicin; 3 participants were symptomatic. Hepatotoxicity resolved in all cases after withdrawal of study treatment and participants were successfully re-established on their standard of care ART regimen. Darunavir trough concentrations were below the protein-adjusted EC50 of 200 ng/mL in 2 participants in the darunavir/ritonavir 1600/200 mg once daily group in presence of rifampicin whereas no participant had trough concentrations below the EC50 in the darunavir/ritonavir 800/100 mg twice daily group. Adjusted doses of darunavir/ritonavir with rifampicin were associated with unacceptable risk of hepatotoxicity in PLWH without TB. Twice daily but not once daily, double dose darunavir/ritonavir may achieve adequate darunavir trough concentrations in presence of rifampicin. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in PLWH. Ebrahim I, Maartens G, Wiesner L, et al. J Antimicrob Chemother, 2020, 75(4): 1019-1025. Using a population pharmacokinetic approach, darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n=51, 7 female). Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; no rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for plus rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily with rifampicin were simulated. Compared with no rifampicin, simulated darunavir AUC0-24 was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily plus rifampicin, respectively; but 39% higher with 1200/150 mg twice daily plus rifampicin. Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. Simulation of the impact of rifampicin on once-daily darunavir/ritonavir pharmacokinetics and dose adjustment strategies: a population pharmacokinetic approach. Dickinson L, Winston A, Boffito M, et al. J Antimicrob Chemother, 2016, 17: 1041-1045., Summary:Coadministration is contraindicated as it may cause significant decreases in darunavir concentrations. A population pharmacokinetic approach indicates that the coadministration of rifampicin (600 mg once daily) decreases darunavir AUC by 57%, 26%, 1% and 16% when administering darunavir/ritonavir at 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily, and 800/100 mg twice daily, respectively, but is 39% higher with 1200/150 mg twice daily. It was suggested that darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. However, increasing the dose of darunavir/ritonavir in the presence of rifampicin led to an unacceptable risk of hepatotoxicity in HIV-infected subjects.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Decrease in concentration of PI by >75%. Do NOT coadminister with rifampin. Additional RTV does not overcome this interaction and increases hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Very Low Quality of Evidence)
- Liverpool Notes:
- Based on theoretical considerations rifampin is expected to decrease darunavir and/or cobicistat plasma concentrations (CYP3A induction). The combination of rifampicin and darunavir/cobicistat is contraindicated due to the potential for loss of therapeutic effect. Rezolsta Summary of Product Characteristics, Janssen-Cilag Ltd, July 2023. Coadministration is expected to decrease concentrations of darunavir and cobicistat. Coadministration is contraindicated with rifampicin due to the potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. Prezcobix US Prescribing Information, Janssen Pharmaceuticals Inc, March 2023., Summary:Coadministration has not been studied and is contraindicated as it may significantly decrease darunavir/cobicistat concentrations, leading to loss of therapeutic effect and possible development of resistance.
- Penalty:
- 1
- HIV-ASSIST Notes:
- Decrease in AUC of RAL by 40% when dosed at 400 mg BID. Dose RAL at 800 mg BID (Do not use once-daily RAL). Monitor closely for virologic response or consider using rifabutin as an alternative.
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin (400 mg single dose) decreased raltegravir AUC, C12 and Cmax by 40%, 61% and 38%, respectively. If co-administration with rifampicin is unavoidable, a doubling of the dose of twice daily raltegravir can be considered. Rifampicin has not been studied with raltegravir 1,200 mg once daily, but could result in decreased raltegravir trough plasma levels; based on the reduction in trough concentrations observed with raltegravir 400 mg twice daily; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. Isentress 600 mg Summary of Product Characteristics, Merck Sharp & Dohme Ltd, September 2021. Coadministration with rifampin decreased raltegravir concentrations. The recommended dose of raltegravir coadministered with rifampin is 800 mg twice daily. There are no data to guide coadministration of raltegravir with rifampin in patients below 18 years of age. Coadministration is not recommended with once daily raltegravir. Coadministration of rifampin (600 mg once daily) and raltegravir (400 mg single dose) to 9 subjects decreased raltegravir AUC (40%), Cmax (38%) and Cmin (61%). Coadministration of rifampin (600 mg once daily) and raltegravir (400 mg twice daily given alone or 800 mg twice daily given with rifampin) to 14 subjects increased raltegravir AUC (27%) and Cmax (62%), but decreased Cmin (53%).Isentress Prescribing Information, Merck & Co Inc, August 2021. The pharmacokinetics of raltegravir were determine following the administration of chewable raltegravir given at 12 mg/kg (twice the usual paediatric dose) to HIV/TB coinfected children receiving rifampicin. Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old; n=12) and cohort 2 (6 to <12 years old; n=12). Pharmacological targets (AUC12 h of 14-45 μmol/L.h and C12 h ≥75 nmol/L) were reached in both cohort 1 (28.8 μmol/L. h and 229 nmol/L) and cohort 2 (38.8 μmol/L.h and 228 nmol/L. Raltegravir-based ART was well tolerated by most participants and at week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml, with 19 of 24 (79%) being below 50 copies/ml. These results suggest that in HIV and TB co-infected children aged 2 to 12 years, the chewable formulation of raltegravir at a dose of 12mg/kg twice daily safely achieved pharmacokinetic levels similar to HIV-1-infected children receiving the current recommended dose of 6 mg/kg/dose and not on treatment for TB. Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2-12 years on rifampicin for tuberculosis. Meyers T, Samson P, Acosta EP, et al. AIDS. 2019;33(14):2197-2203. The pharmacokinetic of raltegravir were determined in 13 HIV/TB coinfected infants and children (aged 4 weeks to two years) receiving rifampicin. Raltegravir chewable tablets were crushed and dispersed in liquid and administered at 12 mg/kg twice daily (twice the approved dose). Raltegravir pharmacokinetic targets were defined as 14-45 µM.h for AUC12h and ≥75 nM (33 ng/mL) for C12h. Cohort pharmacokinetic targets were achieved for AUC12h (32.7 µM.h) and C12h (106.5 nM). None of the 13 participants who received raltegravir experienced any adverse events deemed at least possibly related to raltegravir. Evaluable efficacy data at week 8 was available in 12 of the 13 participants (1/13 discontinued raltegravir prior to the week 8 visit, but after PK collection, due to disallowed medications). Protocol-defined virologic responses occurred in 11/12 participants, with a median change in HIV viral load of –3.05 log10 copies/mL. The one participant who did not meet the virological response criterion 8 had PK values that were within the range of target values but was ill at the time of virological failure. Malabsorption was suspected but not proven. Further experience with raltegravir and other integrase inhibitors during treatment with rifampicin is needed in children in this age range to better define the potency of such regimens. Pharmacokinetics and safety of a raltegravir-containing regimen in children aged 4 weeks to 2 years living with human immunodeficiency virus and receiving rifampin for tuberculosis. Krogstad P, Samson P, Acosta EP, et al. J Pediatric Infect Dis Soc. 2020, ePub ahead of print. Coadministration of rifampicin (10 mg/kg/day) and raltegravir (in combination with tenofovir-DF and lamivudine) was studied in two groups. Patients in arm 1 (n=21), received raltegravir (400 mg twice daily) whereas in arm 2 (n=16), patients received raltegravir at a higher dose (800 mg twice daily initially then 400 mg twice daily 4 weeks after rifampicin discontinuation). Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of raltegravir together with rifampicin (period 1), 4 weeks after rifampicin discontinuation (period 2), and after the raltegravir dose reduction in arm 2 (period 3).In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for AUC, and 0.69 (90% CI, .42-1.13) for C12. In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3. The double dose of raltegravir overcompensated for rifampicin induction, but the standard dose was associated with only small decreases in AUC and C12 during rifampicin coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection. Pharmacokinetics of raltegravir in HIV-infected patients on rifampicin-based antitubercular therapy. Taburet AM, Sauvageon H, Grinsztejn B, et al. Clin Infect Dis, 2015, 61:1328-1335. Over a period of 38 days, healthy subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated. This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone. Effect of intermittent rifampicin on the pharmacokinetics and safety of raltegravir. Reynolds HE, Chrdle A, Egan D, et al. J Antimicrob Chemother, 2015, 70:550-554. In a multicentre, randomised trial at eight sites in Brazil and France, 155 antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) were randomised to receive raltegravir 400 mg twice daily, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine. Patients began study treatment after the start of tuberculosis treatment. 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment. Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicenter, phase 2, non-comparative, open-label, randomized trial. Grinsztejn B, de Castro N, Arnold V, et al. Lancet Infect Dis, 2014, 14:459-467. Two studies were conducted to examine the effect of rifampicin administration on raltegravir pharmacokinetics. Study 1 examined rifampicin (600 mg once daily) on the PK of single dose raltegravir (400 mg); study 2 examined rifampicin (600 mg once daily) on the PK of raltegravir (800 mg twice daily) compared to raltegravir alone (400 mg twice daily). The results demonstrated a substantial effect of rifampicin. In study 1 raltegravir exposure decreased by 61% (C12h), 40% (AUC) and 38% (Cmax). In study 2, raltegravir trough concentrations decreased by 53%, but AUC and Cmax increased by 27% and 62%. Doubling the dose of raltegravir to 800 mg when given with rifampicin compensated for the effect on AUC but not on C12h. On the basis of these data, the recommendation is that if coadministration is unavoidable, a doubling of the raltegravir dose should be considered. Effect of rifampin, a potent inducer of drug metabolising enzymes, on the pharmacokinetics of raltegravir. Wenning LA, Hanley WD, Brainard DM, et al. Antimicrob Agents Chemother, 2009, 53(7): 2852-2856. It was investigated whether increasing raltegravir to 800 mg twice daily when given with rifampicin (600 mg once daily) could overcome the inducing effect of rifampicin. When compared to raltegravir alone (400 mg twice daily), coadministration of the higher dose with rifampicin decreased raltegravir trough concentrations by 53%, but increased AUC and Cmax by 27% and 62%, respectively. Therefore, doubling the dose of raltegravir does not overcome the effect of rifampicin on raltegravir trough concentrations. Doubling the dose of raltegravir does not increase trough levels in the presence of rifampin. Brainaird DM, Petry A, Hanley WD, et al. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October 2008, abstract A-964. The effect of rifampicin (600 mg once daily for 14 days) on the pharmacokinetics of a single dose of raltegravir (400 mg) was studied in 10 HIV- subjects. Rifampicin reduced the Cmin, AUC and Cmax of raltegravir by 61%, 40% and 38%, respectively. Rifampin modestly reduces plasma levels of MK-0518. Iwamoto M, et al. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2006, abstract 299., Summary:Coadministration decreases raltegravir concentrations. The recommended dose of raltegravir when coadministered with rifampicin is 800 mg twice daily. Coadministration with once daily raltegravir is not recommended. Coadministration of rifampicin and raltegravir (400 mg single dose) decreased raltegravir AUC by 40%, Cmax by 38% and Cmin by 61%. An interaction study has shown that, when compared to raltegravir alone (400 mg twice daily), coadministration of raltegravir (800 mg twice daily) with rifampicin decreased raltegravir trough concentrations by 53%, but increased AUC and Cmax by 27% and 62%, respectively and thus did not overcome the effect of rifampicin on trough concentrations. Data from HIV/TB coinfected infants and children (aged 4 weeks to 12 years) receiving rifampicin suggest that the chewable formulation of raltegravir at a dose of 12 mg/kg twice daily safely achieved pharmacokinetic levels similar to HIV-infected children receiving the recommended dose of 6 mg/kg/dose and not on treatment for TB.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Significant decrease in EVG and COBI levels. Do not coadminister rifampin with EVGc or EVGr.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Very Low Quality of Evidence)
- Liverpool Notes:
- Co-administration with rifampicin is contraindicated as it may result in significantly decreased cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.Genvoya Summary of Product Characteristics, Gilead Sciences International Ltd, November 2021. Coadministration is contraindicated due to potential for decreased concentrations of elvitegravir, cobicistat and tenofovir alafenamide, and loss of therapeutic effect and development of resistance. Genvoya US Prescribing Information, Gilead Sciences Inc, September 2021. The pharmacokinetics of tenofovir alafenamide and tenofovir diphosphate were determined in healthy volunteers following administration of tenofovir alafenamide alone (25 mg once daily, with emtricitabine) and with rifampicin (600 mg once daily). Rifampicin decreased tenofovir alafenamide AUC and Cmax by 55% and 50%. Plasma tenofovir Cmax, C24 and AUC decreased by 65%, 55% and 54% respectively. Intracellular tenofovir diphosphate (i.e. active entity) concentrations Cmax, C24 and AUC decreased by 38%, 43% and 36%, respectively, but AUC was still 4.21-fold higher than that achieved with standard dose tenofovir-DF alone (300 mg once daily). Rifampicin did not alter emtricitabine pharmacokinetics. Rifampin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide. Cerrone M, Alfarisi O, Neary M, et al. J Antimicrob Chemother 2019; 74:1670-8. The pharmacokinetics of tenofovir alafenamide and tenofovir diphosphate (TDF-DP) were determined following administration of tenofovir alafenamide alone (25 mg once daily, with bictegravir and emtricitabine) or tenofovir alafenamide (25 mg twice daily, with bictegravir and emtricitabine) and rifampicin (600 mg once daily). Following twice daily administration with rifampicin, the plasma AUC of tenofovir alafenamide and its active intracellular metabolite (TFV-DP) were modestly decreased by ~14% and ~24% when compared to tenofovir alafenamide once daily alone. This modest change is not expected to alter the efficacy of tenofovir alafenamide. Twice daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. Custodio JM, et al. 16th European AIDS Conference (EACS). October 2017, Milan, abstract PS13/4., Summary:Coadministration is contraindicated as it may significantly decrease concentrations of elvitegravir and cobicistat, which may result in loss of therapeutic effect and development of resistance. In addition, rifampicin induces the transporters P-gp, BCRP, OATP1B1 which results in lower exposure of tenofovir alafenamide. Emtricitabine does not interact with this metabolic pathway.
- Penalty:
- 1
- HIV-ASSIST Notes:
- Rifampin induces DTG metabolism and decreases DTG concentrations. It is recommend to give DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation. If being used with Triumeq (ABC/3TC/DTG) or Dovato (DTG/3TC), give Triumeq or Dovato once/daily in the morning, and give an additional dose of DTG 50mg once in the evening. Alternatives to rifampin should be considered in patients with certain suspected or documented INSTI associated resistance substitutions. In general, consider using rifabutin which can be used with normal dose of DTG.
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (High Quality of Evidence)
- Liverpool Notes:
- Coadministration decreased dolutegravir AUC, Cmax and Ctrough by 54%, 43% and 72%, respectively by induction of UGT1A1 and CYP3A. The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of integrase class resistance. In paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance this combination should be avoided. Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019. Coadministration of rifampin (600 mg once daily) and dolutegravir (50 mg twice daily) to 11 subjects decreased dolutegravir Cmax, AUC and Ctrough by 43%, 54% and 72%, respectively. When coadministration of these doses was compared to once daily dolutegravir (50 mg once daily, n=11), dolutegravir Cmax, AUC and Ctrough increased by 18%, 33% and 22%, respectively. Adjust dose of dolutegravir to 50 mg twice daily in treatment-naïve or treatment experienced, INSTI-naïve patients. In pediatric patients, increase the weight-based dose to twice daily. Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents. Tivicay US Prescribing Information, ViiV Healthcare, July 2019. The effect of a higher dose of rifampicin (35 mg/kg) on the pharmacokinetics of dolutegravir or efavirenz was evaluated in coinfected HIV/TB adults. Newly-diagnosed TB patients were randomized to either a standard (10 mg/kg) or a higher (35 mg/kg) dose of rifampicin. Antiretroviral treatment naïve patients were assigned to dolutegravir or efavirenz based regimens. Patients on dolutegravir or efavirenz based regimens at enrolment were maintained on the same regimen, however, dolutegravir was adjusted from once daily to twice daily dosing. Pharmacokinetic sampling was performed 6 weeks post TB treatment initiation with sampling for dolutegravir 12 hours (Ctrough) after the last dose and a mid-dose sampling for efavirenz. Overall, 149 participants were enrolled in the study. Geometric mean (95% CI) dolutegravir trough concentration for patients on higher dose rifampicin was lower than for those receiving standard dose rifampicin: 0.46 (0.31-0.67) mg/L versus 0.80 (0.56-1.14) mg/L, with a GMR of 0.57 (0.34-0.97). Using a threshold of 0.3 mg/L, a higher proportion of participants on higher dose rifampicin failed to attain the target dolutegravir through concentration compared to those on standard dose (39% vs 7%), P = 0.014. Using a lower target threshold of 0.064 mg/L, the difference in target attainment between higher and standard dose rifampicin was not statistically significant (4.4% vs 3.6%), P = 0.999. No patients with dolutegravir concentrations below either target thresholds had a detectable HIV viral load at week 24. The geometric mean for efavirenz mid-dose concentrations for patients on higher dose rifampicin was 37% lower than those receiving the standard dose: 2.94 (95% CI, 1.98-4.36) mg/L vs 4.64 (3.31-6.50) mg/L, with a GMR of 0.63 (0.38-1.07), P = 0.083. The proportion of patients who failed to attain the target mid-dose efavirenz concentrations of 1 mg/L was not significantly different between the 2 groups. No patients below the target had a detectable HIV viral load at week 24. Grade 3-4 adverse effects were similar in the high vs standard dose rifampicin arms. Sputum conversion at week 8 was higher in high dose versus standard dose arms. In conclusion, compared to the standard dose, a three-fold do Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with tuberculosis and human immunodeficiency virus receiving high-dose rifampicin. Sekaggya-Wiltshire C, Nabisere R, Musaazi J, et al. Clinical Infectious Diseases 2022 [epub ahead of print]. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions and the related recommendations for dose adjustment. Virtual clinical drug-drug interaction studies were conducted using physiologically modelling to compare the magnitude of the drug interaction between dolutegravir (50 mg twice daily) and rifampicin (600 mg daily) in non-obese (BMI 18.5-30 kg/m2), obese (BMI 30-40 kg/m2) and morbidly obese (BMI 40-50 kg/m2) individuals. Rifampicin was predicted to decrease dolutegravir AUC by 72% in obese and by 77% in morbidly obese vs 68% in non-obese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. In conclusion, the combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m2. Impact of obesity on the drug-drug interaction between dolutegravir and rifampicin or any other strong inducers. Berton M, Bettonte M, Stader F, et al. Open Forum Infectious Diseases 2023, epub ahead of print. This study presented the 48-week outcome of the RADIANT-TB, a phase 2b, non-comparative, randomized, double-blind, placebo-controlled trial of standard vs double dose dolutegravir in individuals with tuberculosis and on rifampicin-based therapy. Participants were randomized to receive dolutegravir/lamivudine/tenofovir and either supplemental dolutegravir or placebo continued for 2 weeks after stopping TB treatment. The outcome was the proportion of individuals with HIV-RNA <50 copies/mL at week 48, treatment emergent dolutegravir resistance and adherence assessed by tenofovir-diphosphate (TFV-DP) on dried blood spots. Overall, 108 participants were included. The proportion of individuals with virologic suppression at weeks 24 and 48 were similar between arms but lower at week 48 than at week 24 likely due to declining adherence. None of the 19 participants with study defined virological failure developed treatment emergent resistance to dolutegravir. Standard vs double dose dolutegravir in HIV-associated tuberculosis: week 48 results. Griesel R, Zhao Y, Simmons B, et al. CROI 2023, Seattle February 19-22, abstract 110. Tenofovir/lamivudine/dolutegravir (TLD) is the WHO-preferred first-line regimen but there are limited data on the effectiveness of TLD + 50 mg dolutegravir to overcome the interaction with rifampicin in TB/HIV co-infected individuals. 91 participants with TB/HIV co-infection were included. Of those, 75 were ART-naïve participants starting TLD + 50 mg dolutegravir after 15 days on TB treatment; 10 ART naïve participants starting TLD + 50 mg dolutegravir together with rifampicin, 5 starting TB treatment and changing to TLD + 50 mg dolutegravir after a median of 3.3 y on TLD and 1 starting rifampicin and TLD + 50 mg dolutegravir after changing from EFV/3TC/TDF. Among 89 surviving participants, 6 were lost of follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Thus, the virological outcome was assessed in 73, of whom 69 (95%) had HIV-1 RNA <1000 copies/mL and 68 (94%) had HIV-1 RNA <200 copies/mL. No dolutegravir resistance mutations were detected among 4 participants with HIV-1 RNA >1000 copies/mL. Concomitant rifampicin containing TB treatment and TLD + 50 mg dolutegravir was well tolerated and achieved excellent viral suppression in a cohort of predominantly ART-naïve people with TB/HIV. Effectiveness of dolutegravir in people on rifampicin-based tuberculosis treatment. Shah S, Kityo C, Hughes MD, et al. CROI 2023, Seattle February 19-22, abstract 755. Food has been shown to increase dolutegravir concentrations in healthy volunteers by 33-66%. This study aimed to evaluate whether dolutegravir dosed at 50 mg once daily taken with food would be sufficient to compensate the rifampicin inducing effect. The pharmacokinetic study conducted in Bangkok enrolled TB/HIV coinfected adults (stable on rifampicin-containing regimen for drug-susceptible TB), to receive the fixed dose combination dolutegravir/3TC/TDF 50 mg once daily with food or the same drug combination plus an additional dose of dolutegravir 50 mg administered 12 hours later. Geometric mean ratio (GMR) of dolutegravir 50 mg once daily vs 50 mg twice daily were determined and the percent of individuals with dolutegravir Cmin above the protein adjusted IC90 (i.e. 0.064 µg/mL) calculated. Twelve and sixteen participants were enrolled in the study (i.e. dolutegravir 50 mg once daily + food) and control arm (i.e. dolutegravir 50 mg twice daily), respectively. The majority were male (86%) with a median body weight of 57.5 kg. At baseline, median CD4 was 201 cells/µL (IQR 46-304) and median HIV-RNA was 4.9 log10 copies/mL (IQR 3.6-5.6). Dolutegravir Cmax was not statistically different when comparing the study arm versus the control arm. However, dolutegravir AUC was significantly lower (46% decrease) in the study arm with a GMR (90% CI) of 0.54 (0.36-0.81). Similarly, dolutegravir Cmin was significantly lower (70% decrease) in the study arm with a GMR of 0.30 (0.26-0.36) but with 83% and 94% of the study and control arm participants having dolutegravir Cmin above the protein adjusted IC90. At week 12, 83.3% and 75% of the participants in the study and control arm had HIV-RNA <50 copies/mL, respectively. The authors highlighted that even though substantial reductions in dolutegravir Cmin were observed in presence of rifampicin when dosed once daily + food, dolutegravir Cmin levels were mostly above the protein adjusted IC90 and the majority of participants were virologically suppressed at week 12. Efficacy and PK of dolutegravir 50 mg QD with food versus 50 mg BID with rifampicin. Ueaphongsukkit T, Gatechompol S, Sophonphan J, et al. Virtual Conference on Retroviruses and Opportunistic Infections, March 2021, Abstract 370. This study investigated whether doubling the dolutegravir dose with a once daily dose can mitigate the reduction in dolutegravir exposure seen with rifampicin. Fourteen healthy subjects received dolutegravir (50 mg or 100 mg once daily for 7 days) alone and in combination with rifampicin (600 mg once daily). Rifampicin decreased the Cmax, AUC and C24 of dolutegravir by 35%, 57% and 86% (50 mg once daily) and by 36%, 58% and 88% (100 mg once daily). When compared to 50 mg once daily alone, doubling the dose of dolutegravir to 100 mg once daily in the presence of rifampicin increased dolutegravir Cmax by 9% and decreased AUC and C24 by 26% and 76%, respectively. Although there were substantial reductions in the dolutegravir key pharmacokinetic parameter of C24, dolutegravir concentrations when administered as 100 mg once daily with rifampicin remained above the protein binding-adjusted IC of 64 ng/ml. The authors suggest further study of this dose is required. Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin. Wang X, Cerrone M, Ferretti F et al. Int J Antimicrob Agents, 2019, pii: S0924-8579(19)30095-0. Coadministration of twice daily dolutegravir (50 mg twice daily, with lamivudine/tenofovir 300/300 mg, once daily) was studied in 10 HIV-1/TB co-infected subjects receiving rifampicin (600 mg once daily) with isoniazid, ethambutol and pyrazinamide. Dolutegravir trough concentrations were determined after at least 4 weeks of therapy and were 1123 ng/ml (820-1746 mg; median with range). Rifampicin did not significantly impact lamivudine and tenofovir plasma concentrations. After 48 weeks of therapy, two patients had plasma viral loads >50 copies/ml and were found to have dolutegravir trough concentrations below the target of 640 ng/ml, corresponding to an inhibitory quotient of 0.1 and 5. These results suggest that dolutegravir 50 mg twice daily and rifampicin should only be used in subjects without HIV integrase resistance. Pharmacokinetic and virological efficacy of dolutegravir (50 mg BID) containing regimen in association with rifampin in HIV-infected patients using Dried Blood Spot: ANRS-12313 NAMSAL substudy in Cameroon. Le M, Cournil A, Eymard-Duverney S, et al. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy, Baltimore, May 2018, Abstract 7. Healthy volunteers received dolutegravir 50 mg once daily for 7 days, then dolutegravir 50 mg twice daily for 7 days and then dolutegravir 50 mg twice daily together with rifampicin 600 mg once daily for 14 days. Dolutegravir 50 mg twice daily in presence of rifampicin achieved 33% increase in mean AUC and 22% increase in Ctrough compared to dolutegravir 50 mg once daily alone. The authors conclude that rifampicin containing regimens including twice daily dolutegravir may represent a new treatment option for patients who require concomitant treatment of HIV and TB Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. Dooley KE, Sayre P, Borland J, et al. J Acquir Immune Defic Syndr, 2013, 62(1): 21-27., Summary:Coadministration decreased dolutegravir concentrations and a dose adjustment of dolutegravir is recommended. Coadministration of rifampicin (600 mg once daily) and twice daily dolutegravir (50 mg twice daily) decreased dolutegravir Cmax, AUC and Ctrough by 43%, 54% and 72%, respectively, compared to twice daily dolutegravir alone. When coadministration of these doses was compared to once daily dolutegravir (50 mg once daily), dolutegravir Cmax, AUC and Ctrough increased by 18%, 33% and 22%, respectively. A dose adjustment of dolutegravir to 50 mg twice daily is recommended when coadministered with rifampicin in the absence of integrase class resistance. A modelling study showed that this dose adjustment is also sufficient in individuals with a high BMI. This dose adjustment should be maintained for approximately 2 weeks after stopping rifampicin as the inducing effect may persist after discontinuation of a strong inducer. In the presence of integrase class resistance this combination should be avoided. Of note: a high dose of rifampicin (35 mg/kg) compared to the standard dose (10 mg/kg) resulted in 43% decrease in dolutegravir trough concentrations (0.46 mg/L vs 0.80 mg/L). Most patients had dolutegravir concentrations above the IC90 target (0.064 mg/L), however, a higher proportion of participants on higher dose rifampicin failed to attain the 0.3 mg/L target. Importantly, no patient below either target thresholds had a detectable HIV viral load at week 24.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Significant decreased in AUC of BIC by 75% when combined with rifampin. Contraindicated
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Moderate Quality of Evidence)
- Liverpool Notes:
- Co-administration with rifampicin is contraindicated due to the effect of rifampicin on the bictegravir component of Biktarvy. Coadministration of rifampicin (600 mg once daily) and bictegravir (75 mg single dose) decreased bictegravir AUC and Cmax by 75% and 28% (due to induction of CYP3A, UGT1A1, and P-gp). The interaction has not been studied with tenofovir alafenamide. Co-administration of rifampicin may decrease tenofovir alafenamide plasma concentrations. Biktarvy Summary of Product Characteristics, Gilead Sciences Ltd, June 2019. Biktarvy is contraindicated to be coadministered with rifampin due to decreased bictegravir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to Biktarvy. Coadministration of rifampin (600 mg once daily) and bictegravir (75 mg single dose) decreased bictegravir Cmax and AUC by 28% and 75%. Biktarvy Prescribing Information, Gilead Sciences Inc, August 2019. The effect of rifampicin (600 mg once daily) on the pharmacokinetics of bictegravir when administered twice daily (bictegravir/emtricitabine/tenofovir 50/200/25 mg, twice daily postprandial, for 28 days) was investigated in two cohorts of HIV-negative subjects (n=26 per cohort). Cohort 1 received bictegravir/emtricitabine/tenofovir alone while cohort 2 received the same plus rifampicin. Coadministration reduced bictegravir AUC, Cmax and Ctrough by approximately 61%, 47% and 80%, respectively. The authors note that although bictegravir Ctrough decreased by ~80%, trough concentrations in all subjects were above the protein adjusted EC95 of 162 ng/ml. They conclude that administering bictegravir twice daily with rifampicin did not mitigate the enzyme inducing effect of rifampicin sufficiently to replicate the Ctrough concentrations seen in phase three bictegravir clinical trials. Custodio JM, West SK, Collins S, et al. Pharmacokinetics of bictegravir administered twice daily in combination with rifampin. Conference on Retroviruses and Opportunistic Infections, March 2018, Boston, Abstract 34., Summary:Coadministration is contraindicated. Coadministration of rifampicin (600 mg once daily) and bictegravir alone (75 mg single dose) decreased bictegravir Cmax and AUC by 28% and 75%. Coadministration of rifampicin (600 mg once daily) and twice daily bictegravir/emtricitabine/tenofovir (50/200/25 mg, twice daily) decreased bictegravir AUC, Cmax and Ctrough by approximately 61%, 47% and 80%, respectively, and did not mitigate the enzyme inducing effect of rifampicin sufficiently to replicate the Ctrough concentrations seen in phase three bictegravir clinical trials. Furthermore, rifampicin is an inducer of P-gp and is expected to decrease the absorption of tenofovir alafenamide and thereby plasma concentrations.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Coadministration of intramuscular cabotegravir and rifampin is contraindicated. Rifampin 600 mg once daily and oral 30 mg once daily cabotegravir resulted in decreased cabotegravir AUC by 59% and oral clearance was increased by 2.4 fold.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration is contraindicated with Apretude due to potential for significant decreases in plasma concentration of Apretude due to induction of uridine diphosphate glucuronosyltransferase (UGT1A1). Coadministration of rifampin (600 mg once daily) and oral cabotegravir (30 mg single dose) was studied in 15 subjects. Cabotegravir Cmax, AUC and Ctau decreased by 6%, 59% and 50%, respectively. Apretude Prescribing Information, ViiV Healthcare, December 2021. Coadministration of oral cabotegravir (30 mg once daily) and rifampicin (600 mg once daily) was studied in 15 subjects and was found to decrease cabotegravir AUC, Cmax and C24 by 21%, 17% and 26%, respectively. Rifampicin decreased cabotegravir AUC and Cmax by 59% and 6%. Half-life decreased by 57% and oral clearance was increased by 2.4-fold. Concomitant administration of rifampicin with oral and long-acting formulations of cabotegravir is not recommended currently without further study. Effect of rifampin on the single-dose pharmacokinetics of oral cabotegravir in healthy subjects. Ford SL, Sutton K, Lou Y, et al. Antimicrob Agents Chemother. 2017;61(10):e00487-17. PBPK modelling was used to simulate the interaction between long-acting (LA) intramuscular cabotegravir and the strong inducer rifampicin. At steady-state, rifampicin was predicted to reduce the exposure of LA cabotegravir by 61% with a large proportion of individuals predicted to have concentrations below 664 ng/mL (i.e., 4x PA-IC90) for cabotegravir at the end of the dosing interval. An increase in the dosing frequency did not overcome the interaction with rifampicin. Increasing the dosing frequency of cabotegravir to 4 weeks or to 3 weeks did not significantly improve cabotegravir exposure. Therefore, coadministration of long-acting intramuscular cabotegravir should be avoided with strong inducers. Management of drug-drug interactions between long-acting cabotegravir and rilpivirine and comedications with inducing properties: a modelling study. Bettonte S, Berton M, Stader F, et al. Clin Infect Dis, 2022, online ahead of print., Summary:Coadministration with intramuscular cabotegravir has not been studied. Similarly to oral cabotegravir, concomitant administration with rifampicin is contraindicated due to the potential for loss of therapeutic effect and development of resistance. Coadministration of rifampicin (600 mg once daily) and oral cabotegravir (30 mg once daily) decreased cabotegravir Cmax by 6%, AUC by 59% and oral clearance was increased by 2.4-fold. Using PBPK modelling, rifampicin was predicted to reduce the exposure of long-acting intramuscular cabotegravir by 61%. The interaction with rifampicin was not overcome by shortening the dosing interval of intramuscular cabotegravir.
- Penalty:
- 1
- HIV-ASSIST Notes:
- AUC of MVC decreases by 64%. If coadministration is necessary, use MVC 600mg BID. If coadministered with a strong CYP3A inhibitor, consider rifabutin.
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (High Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin (600 mg once daily) and maraviroc (100 mg twice daily) decreased maraviroc AUC by 63% and Cmax by 66%. Rifampicin concentrations were not measured, but no effect expected. Maraviroc dose should be increased to 600 mg twice daily when co-administered with rifampicin in the absence of a potent CYP3A4 inhibitor. This dose adjustment has not been studied in HIV patients. Celsentri Summary of Product Characteristics, ViiV Healthcare, September 2018. The CYP3A inducer rifampicin decreased the Cmax and AUC of maraviroc. Coadministration of rifampicin (600 mg once daily) and maraviroc (100 mg twice daily) decreased maraviroc AUC, Cmax and Cmin by 63%, 66% and 78%, respectively (n=12). When compared to maraviroc 100 mg twice daily alone, coadministration of rifampicin (600 mg once daily) and maraviroc (200 mg twice daily) to 12 subjects increased maraviroc AUC by 4% and decreased Cmax and Cmin by 3% and 34%. The recommended dose of maraviroc when coadministered with rifampicin (without a potent CYP3A inhibitor) is 600 mg twice daily. No additional maraviroc dose adjustment when coadministered with potent CYP3A inducers is required in patients with CrCl 30-80 mL/min. Maraviroc is contraindicated in patients with severe renal impairment (<30 mL/min) or ESRD on regular hemodialysis who are receiving potent CYP3A inducers.Selzentry Prescribing Information, ViiV Healthcare, July 2018. Coadministration of maraviroc (100 mg twice daily) and rifampicin (600 mg once daily) was studied in 12 HIV- subjects. In the presence of rifampicin, maraviroc AUC and Cmax decreased by 67% and 70%, respectively. Dose adjustment of maraviroc to 200 mg twice daily adequately compensated for the interactions (GMR for AUC and Cmax of 0.99 and 0.97, respectively). Measurement of 6ß-OH cortisol/cortisol ratio indicated that CYP3A4 was highly induced by rifampicin (6.6-fold). The effect of P450 inducers on the pharmacokinetics of CCR5 antagonist UK-427,857 in healthy volunteers. Jenkins T, et al. 5th International Workshop on Clinical Pharmacology of HIV Therapy, Rome, April 2004, abstract 37 Rifampicin and EfavirenzConcomitant use of maraviroc and rifampicin and efavirenz is not recommended. Combination with two inducers has not been studied. There may be a risk of suboptimal levels with risk of loss of virologic response and resistance development. Celsentri Summary of Product Characteristics, ViiV Healthcare, September 2018., Summary:Increase maraviroc to 600 mg twice daily when coadministered with rifampicin. Coadministration of a non-licensed dose of maraviroc (100 mg twice daily) and rifampicin (600 mg once daily) decreased maraviroc exposure by 60-70%. Concomitant use of maraviroc with rifampicin and efavirenz is not recommended as the combination of two CYP inducers may further decrease maraviroc concentrations. The US Prescribing Information contraindicates coadministration in patients with creatinine clearance less than 30 ml/min or on haemodialysis.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Induction of metabolism by rifampicin is unlikely to affect ibalizumab, a monoclonal antibody binding to the CD4 receptor, which is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies.
- Penalty:
- 2
- HIV-ASSIST Notes:
- Temsavir AUC decreased 82%. Contraindicated. Consider rifabutin.
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Low Quality of Evidence)
- Liverpool Notes:
- Coadministration decreased temsavir AUC and Cmax by 82% and 76%. Rifampicin co-administration may lead to loss of virologic response to fostemsavir due to significant decreases in temsavir plasma concentrations caused by strong CYP3A4 induction. Therefore, the concomitant use of fostemsavir and rifampicin is contraindicated. Rukobia Summary of Product Information, ViiV Healthcare, June 2021. Coadministration with strong cytochrome P450 (CYP)3A inducers is contraindicated as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include rifampin. Coadministration of rifampin (600 mg once daily) and fostemsavir (1200 mg single dose) decreased temsavir Cmax, and AUC by 76% and 82% (n=15). Rukobia US Prescribing Information, ViiV Healthcare, July 2020. Coadministration of rifampin (600 mg once daily) and fostemsavir (1200 mg single dose) to 15 HIV-negative subjects decreased temsavir Cmax and AUC by 76% and 82%. The similar magnitude of reduction in both AUC and Cmax in conjunction with a similar elimination rate suggests that the interaction is likely primarily mediated via presystemic P-gp induction; however, a contribution of CYP3A-mediated presystemic metabolism cannot be ruled out. The effect of rifampin on the pharmacokinetics of the HIV-1 attachment inhibitor prodrug BMS-663068 in healthy subjects. Hruska M, Anderson J, Bedford B, et al. 14th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, April 2013, abstract P_05., Summary:Coadministration with rifampicin is contraindicated as it may result in a potential loss of therapeutic effect. Fostemsavir is a prodrug and is hydrolysed to the active compound temsavir in the small intestine. Temsavir is mainly metabolized by esterase-mediated hydrolysis with a small contribution of CYP3A4. Coadministration of fostemsavir (1200 mg single dose) in 15 individuals on rifampicin treatment (600 mg once daily) substantially decreased temsavir Cmax and AUC by 76% and 82%.
- Penalty:
- 2
- Liverpool Interaction Status:
- RED/High: Do Not Coadminister (Low Quality of Evidence)
- Liverpool Notes:
- Co-administration with strong inducers of CYP3A, P-gp, and UGT1A1, such as rifampicin, is contraindicated. Rifampicin, may significantly decrease plasma concentrations of lenacapavir resulting in loss of therapeutic effect and development of resistance. Coadministration of lenacapavir (300 mg single oral dose) and rifampicin (600 mg once daily) decreased lenacapavir AUC and Cmax by 84% and 55%. Sunlenca Summary of Product Characteristics, Gilead Sciences Ltd, August 2022. Concomitant administration of rifampin decreased lenacapavir concentrations and may result in loss of therapeutic effect and development of resistance. Concomitant administration of lenacapavir with rifampin is contraindicated. Coadministration of lenacapavir (300 mg single oral dose) and rifampicin (600 mg once daily) decreased lenacapavir Cmax and AUC by 55% and 84%. Sunlenca Prescribing Information, Gilead Sciences Inc, December 2022., Summary:Coadministration is contraindicated. Lenacapavir is mainly cleared as unchanged drug and is a substrate of CYP3A4, P-gp and UGT1A1. Coadministration of the strong inducer rifampicin (600 mg once daily) and lenacapavir (300 mg single oral dose) decreased lenacapavir AUC and Cmax by 84% and 55%. The decrease in lenacapavir concentrations may result in loss of therapeutic effect and development of resistance and therefore coadministration is contraindicated. At least a 4-week cessation period is recommended prior to initiation of lenacapavir due to the persisting inducing effect after discontinuation of a strong inducer.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of emtricitabine and isoniazid alone has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Coadministration of TB treatment containing isoniazid (with rifampicin, ethambutol and pyrazinamide) and emtricitabine (with tenofovir-DF and efavirenz) increased emtricitabine AUC and Cmin by 5% and 26% and decreased Cmax by 3%; isoniazid Cmax decreased by 5%.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway. Dose Descovy according to the concomitant antiretroviral.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113., Summary:Coadministration of tenofovir-DF and isoniazid alone has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Coadministration of TB treatment containing isoniazid (with rifampicin, ethambutol and pyrazinamide) and tenofovir-DF (with emtricitabine and efavirenz) increased tenofovir AUC and Cmin by 13% and 9% and decreased Cmax by 2%; isoniazid Cmax decreased by 5%.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Amber/Moderate: Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine (d4T). Isoniazid Summary of Product Characteristics, UCB Pharma Ltd, April 2007., Summary:There may be an increased risk of distal sensory neuropathy when isoniazid is used with stavudine (d4T).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Moderate Quality of Evidence)
- Liverpool Notes:
- The effect of the antacid in didanosine tables on isoniazid pharmacokinetics was investigated in 12 HIV-negative subjects. Isoniazid pharmacokinetics were determined following administration of a single dose of isoniazid (300 mg) alone and in combination with a single dose of didanosine placebo tablets (2 tablets containing antacid component only) and were not significantly different when administered alone or in combination with antacids. Effect of antacids in didanosine tablet on bioavailability of isoniazid. Gallicano K, et al. Antimicrob Agents Chemother, 1994, 38:894-897. , Summary:No significant effect of the antacid component of didanosine tablets on isoniazid pharmacokinetics. The effect of didanosine on isoniazid was not studied.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Low Quality of Evidence)
- Liverpool Notes:
- Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters. Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. Semvua H, Mtabho C, Fillekes Q, et al. Antivir Ther, 2013, 18(1): 105-113. Plasma pharmacokinetics of isoniazid were determined in 15 HIV/TB coinfected patients during a study investigating dose increase of rifabutin following commencement of efavirenz. When isoniazid (15 mg/kg twice weekly) was administered with rifabutin (300 mg twice weekly), geometric mean values for isoniazid AUC and Cmax were 29.9 µg/ml.h and 6.8 µg/ml, respectively. After the commencement of efavirenz (600 mg once daily) and an increase in rifabutin to 600 mg twice daily, there was no significant change in isoniazid exposure (AUC 28.6 µg/ml.h, Cmax 7.0 µg/ml). Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis. Weiner M, Benator D, Peloquin CA, et al. Clin Infect Dis, 2005, 41(9): 1343-9., Summary:Coadministration of efavirenz and isoniazid alone has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Coadministration of TB treatment containing isoniazid (with rifampicin, ethambutol and pyrazinamide) and efavirenz (with emtricitabine and tenofovir-DF) increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; isoniazid Cmax decreased by 5%. Coadministration of efavirenz (600 mg once daily) to 15 HIV/TB coinfected subjects receiving isoniazid (15 mg/kg twice weekly, plus rifabutin 600 mg twice weekly) had no significant effect on isoniazid AUC or Cmax (relative to values obtained when the same dose of isoniazid was administered with rifabutin 300 mg twice weekly without efavirenz).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Doravirine does not interfere with isoniazid’s metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Moderate Quality of Evidence)
- Liverpool Notes:
- Coadministration of isoniazid (5 mg/kg, up to 300 mg once daily, with pyridoxine) and lopinavir/ritonavir (400/100 mg twice daily) was studied in 16 HIV positive subjects in a cross-over trial. There was no significant effect of isoniazid on the pharmacokinetics of lopinavir (AUC and Cmax increased ~15% and ~13%) or ritonavir (AUC and Cmax unchanged). The results of this study indicate that a clinically significant drug-drug interaction is unlikely. The pharmacokinetics of lopinavir/ritonavir when given with isoniazid in South African HIV-infected individuals. Decloedt E, van der Walt J, McIlleron H et al. Int J Tuberc Lung Dis, 2015, 19(10): 1194-6., Summary:Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. No significant effect on isoniazid is expected. Coadministration of isoniazid (5 mg/kg, up to 300 mg, once daily) and lopinavir/ritonavir (400/100 mg, twice daily, n=16) had no significant effect on the pharmacokinetics of lopinavir (AUC and Cmax increased ~15% and ~13%) or ritonavir (AUC and Cmax unchanged).
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Low Quality of Evidence)
- Liverpool Notes:
- Indinavir and isoniazid can be co-administered without dose adjustment. Coadministration of indinavir (800 mg three times daily) and isoniazid (300 mg once daily) had no effect on the AUC or Cmin of indinavir or isoniazid. Crixivan Summary of Product Characteristics, Merck Sharp & Dohme Ltd, October 2018. Coadministration of isoniazid (300 mg once daily for 8 days) and indinavir (800 mg three times daily for 7 days) to 11 subjects resulted in decreases in indinavir Cmax. AUC and Cmin of 5%, 1% and 11% respectively. Isoniazid Cmax and AUC increased by 34% and 12% respectively, and there was no change in Cmin. Crixivan Prescribing Information, Merck & Co Inc, May 2018. Coadministration of indinavir (800 mg every 8 h) and isoniazid (300 mg once daily) was studied in HIV+ individuals. There were no clinically significant interactions and no dosage modification is required.Indinavir (MK639) drug interaction studies. The Indinavir (MK 639) Pharmacokinetic Study Group. 11th International Conference on AIDS, 1996, abstract Mo.B.174., Summary:No data with indinavir/ritonavir. Coadministration with indinavir alone increased Isoniazid Cmax (34%) and AUC (12%) with no change in Cmin. Indinavir Cmax. AUC and Cmin decreased by 5%, 1% and 11%, respectively. The effects are not considered clinically significant and no dose adjustment is required.
- Penalty:
- 0
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid. The latter is further hydrolysed to isonicotinic acid and acetylhydrazine. Atazanavir/ritonavir is unlikely to interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid. The latter is further hydrolysed to isonicotinic acid and acetylhydrazine. Atazanavir/cobicistat is unlikely to interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid. The latter is further hydrolysed to isonicotinic acid and acetylhydrazine. Atazanavir is unlikely to interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid. The latter is further hydrolysed to isonicotinic acid and acetylhydrazine. Darunavir/cobicistat is unlikely to interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Elvitegravir/cobicistat, emtricitabine and tenofovir alafenamide do not interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- An open-label, intrasubject drug interaction study in HIV-negative healthy volunteers comprised investigated the pharmacokinetics of dolutegravir once daily alone and with once weekly isoniazid and rifapentine. Of 4 enrolled subjects (3 males, 1 female, age 22-46 years), 3 completed the study and 1 withdrew prior to the 3rd dose of isoniazid/rifapentine. The study was stopped prematurely due to the development of multiple AEs in 2 subjects. In both subjects, flu-like syndrome with symptoms of nausea, vomiting, and fever (Grades 2 and 3) began ~8 hours after the last doses of dolutegravir, rifapentine, and isoniazid and lasted 24-48 hours. One subject required a 24-hour hospitalization for management of orthostatic hypotension (Grade 3). Transaminase elevations (Grades 2-4) occurred in both subjects. Exposure to rifapentine and its active metabolite were similar to reference PK data, but isoniazid exposure was 67-92% higher than expected in the 2 subjects who developed AEs. Limited pharmacokinetic data suggested isoniazid/rifapentine decreased dolutegravir AUC and Cmin by 46% and 74%. Given that flu-like syndrome was reported in <4% of subjects in studies of the efficacy of weekly isoniazid/rifapentine alone, these data suggest that co-administration of dolutegravir and weekly isoniazid/rifapentine should be avoided.Early termination of a PK study between dolutegravir and weekly isoniazid/rifapentine. Brooks KM, Pau AK, George JM, et al. CROI 2017, Seattle, February 2017, abstract 409a. INSPIRING (NCT02178592) is a Phase 3b, non-comparative, active control, randomised, open-label study in HIV-1 infected ART-naïve adults (CD4+ ≥50 cells/µL) with drug-sensitive TB. Participants on rifampin-based TB treatment for up to 8 weeks were randomised (3:2) to receive dolutegravir (50 mg twice daily during and for 2 weeks post-TB therapy, followed by 50 mg once daily) or efavirenz (600 mg once daily), with 2 investigator-selected NRTIs for 52 weeks. Of 113 subjects enrolled, 69 were randomised to dolutegravir and 44 to efavirenz. Interim Week 24 results show that dolutegravir 50 mg twice daily appears to be effective and well-tolerated in HIV/TB co-infected adults receiving rifampin-based TB therapy. Rates of IRIS were low. There were no new toxicity signals for dolutegravir and no discontinuations due to liver events.Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. Dooley K, Kaplan R, Mwelase N, et al. CROI 2018, Boston, March 2018, abstract 33., Summary:Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Dolutegravir is unlikely to interfere with this metabolic pathway. However, a study of coadministration of dolutegravir and isoniazid with rifapentine was ended early due to intolerance. In healthy volunteers receiving weekly isoniazid and rifapentine, the addition of dolutegravir resulted in flu-like symptoms and LFT elevations in 2 out of 4 patients (with higher than expected isoniazid concentrations), leading to study termination. Limited pharmacokinetic data suggested lower dolutegravir exposure. Intolerance is likely to be related to rifapentine (+/- healthy volunteer status) rather than isoniazid, since in the INSPIRING study, the addition of dolutegravir to daily isoniazid and rifampicin was well tolerated in 69 HIV-TB coinfected adults at 24 week analysis.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Bictegravir, emtricitabine and tenofovir alafenamide do not interfere with isoniazid’s metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Cabotegravir is unlikely to interfere with this metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Isoniazid undergoes hepatic metabolism whereas ibalizumab, a monoclonal antibody binding to the CD4 receptor, is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Fostemsavir does not interfere with isoniazid’s metabolic pathway.
- Penalty:
- 0
- Liverpool Interaction Status:
- Green/Low: No Interaction Expected (Very Low Quality of Evidence)
- Liverpool Notes:
- Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Lenacapavir is mainly cleared as unchanged drug and does not interfere with isoniazid’s metabolic pathway.