1 EI 1 PI | HIV-ASSIST

This is a generic educational information sheet for 1 EI + 1 PI

Overview

There are multiple Entry Inhibitors (EIs), including Maraviroc (MVC), Ibalizumab (IBA), Enfuvirtide (T-20), and Fostemsavir (BMS-663068; not FDA approved). While considered together here, each has a different mechanism of action, requirement for usage and mode of delivery. Most ART regimens have historically included 3 active drugs including an INSTI, PI or NNRTI as an anchor, and 2 NRTI’s as a backbone. Most studies evaluating inclusion of an EI have done so in the context of an optimized background regimen (OBR); in some situations, PI have been included as part of that OBR, based on treatment history and resistance testing. Our assessment of regimens containing EI + PI are largely extrapolated from such studies, which contain limited data explicitly studying the effectiveness of these combinations.

MVC is the only CCR5 antagonist currently approved by the FDA. Importantly, it can only be used to treat CCR5-tropic virus, and a co-receptor tropism assay—either phenotypic or genotypic—must be performed prior to MVC initiation and in cases of suspected virologic failure on MVC. There is greater evidence available for the use of phenotypic assays, making them the preferred test to determine tropism; however, genotypic assays, which are less expensive and less time-intensive than their phenotypic counterparts, are also available. There is limited data on the OBR components when using MVC as part of salvage regimens, and this combination is generally not recommended. Testing for CCR5 tropism is recommended each time when considering MVC.

IBA is a CD4 post-attachment inhibitor that has been studied in combination with at least one other active antiretroviral medication in treatment-experienced individuals with extensive resistance. IBA is not affected by resistance to other classes of antiretroviral medications, nor it is impacted by HIV tropism status (CCR5 versus CXCR4), or renal insufficiency, and there are no significant drug interactions. This medication requires administration via intravenous infusion. It is given as an initial loading dose, followed by a 15-30 minute intravenous infusion every 14 days. Based on the need to give IBA via an intravenous infusion, the use of this agent will likely be reserved for rare instances in which an adult has developed multiclass antiretroviral drug resistance and for whom a complete regimen cannot be crafted using other available options. In the primary clinical trials leading to FDA approval, 67% of individuals in the trial (18 out of 27) had inclusion of Darunavir (PI) as part of their OBR(personal communication). In heavily treatment-experienced patients with MDR HIV-1, IBA was effective in combination with Darunavir (DRV). Furthermore, safety and efficacy of IBA observed at Week 25 were maintained through 96 weeks.

Recommendations for MVC + PI in treatment-naive patients

DHHS (Dec. 2019): MVC in combination with 1 INSTI is not discussed as initial therapy. MVC is not recommended due to a lack of virologic benefit of MVC when compared to other available drug classes (PIs, NNRTIs, or INSTIs), as well as its requirements for CCR5 tropism testing and twice-daily dosing. Mostly recommended initial regimens include a PI (or INSTI or NNRTI) as an anchor along with 2 NRTIs as a backbone; only in exceptional circumstances should substitution of these other classes with a CCR5 inhibitor be considered in ART-naïve patients. It could be considered if all other ARV classes are contra-indicated, but such situations would be rare.

IAS-USA (2018): MVC in combination with 1 PI is not discussed for treatment of naïve patients and is not listed as one of the preferred options in patients with other treatment options. In a rare circumstance in which MVC might be included in initial therapy, initiation should not occur before confirmation of CCR5 tropism.

Recommendations for MVC + PI in treatment-experienced patients

DHHS (Dec. 2019): MVC appears to be active against some HIV-2 isolates, however, there are no FDA-approved assays that can determine HIV-2 co-receptor tropism, and HIV-2 is known to use many other minor co-receptors in addition to CCR5 and CXCR4. In a randomized controlled trial, patients with virologic suppression who were on a regimen of two NRTIs plus a boosted PI and who had only CCR5-tropic HIV (as detected by proviral DNA testing) were randomized to continue their current regimen switch was associated with higher rates of virologic failure and treatment of discontinuation than the other two regimens. Based on these results, a regimen consisting of a boosted PI and MVC cannot be recommended.

In virally suppressed patients, there may be situations in which a between-class switch is considered. Between-class switches involving the replacement of an INSTI, NNRTI or boosted PI with MVC are discussed as an option but should not be attempted if there is any doubt about the activity of the other agents (e.g., NRTI backbone) in the regimen. Switching to MVC should only be attempted in individuals that are R5 tropic; determining tropism in a suppressed patient can be difficult. When switching to MVC, co-receptor usage in virologically suppressed patients can be determined from pro-viral DNA obtained from peripheral blood mononuclear cells[1, 2]. This strategy was used successfully in a randomized trial that switched virologically suppressed individuals from a regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted PI to two NRTIs plus MVC[3].

In cases of virologic failure, the DHHS does not specifically discuss this regimen, but recommends that patients start a regimen with at least 2 to 3 active agents. In cases where there is resistance to PIs, NNRTIs, or INSTIS, MVC can be considered as a replacement. The MOTIVATE 1 and 2 trials[4, 5] have suggested that MVC in combination with an optimized background regimen has significantly higher rates of viral suppression and increases in CD4 compared to placebo.

IAS-USA (2018): For virologic failure with complex treatment history, therapy with at least 2 fully active drugs from different antiretroviral classes, including MVC in the setting of CCR5-tropic virus, is recommended. Testing for CCR5 tropism is recommended each time when considering MVC.

Recommendations for IBA + PI in treatment-naïve patients

DHHS (Dec. 2019): IBA in treatment-naïve patients is not recommended, as it has only been studied in a very small number of patients with virologic failure and requires IV therapy.

IAS-USA (2018): This regimen is not discussed in the IAS-USA guidelines for treatment-naïve patients.

Recommendations for IBA + PI in treatment-experienced patients

DHHS (Dec. 2019): IBA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. There are no data yet on the activity of ibalizumab against HIV-2.

Considered separately from IBA, darunavir (DRV), lopinavir and saquinavir are more active against HIV-2 than other approved PIs. Older, unboosted PI-based regimens, including nelfinavir or indinavir plus zidovudine and lamivudine, and atazanavir-based regimens have shown poor clinical success rate.

IAS-USA (2018): IBA, an anti-CD4 monoclonal antibody that inhibits HIV cell entry via CD4 binding, is active against CCR5- and C-X-C chemokine receptor 4 (CXCR4)–tropic HIV isolates and may be useful as a fully active agent for patients with multiclass-resistant virus (evidence rating BII). Almost 50% of adults with virologic failure from multi-drug resistant HIV achieved undetectable HIV RNA levels at 24 weeks after receipt of biweekly intravenous IBA (800 mg) with at least one other active drug. IBA and PI combination is not specifically discussed.

Other Considerations

MVC

Requires performing an HIV tropism assay prior to use and is ineffective in patients who do not have pure R5-tropic HIV
Generally well-tolerated with few long-term side effects
Twice daily dosing
Generally reserved for salvage therapy; however, often not an option for treatment-experienced patients with advanced disease, as the likelihood of X4-tropic HIV increases as patients develop more advanced immunosuppression
Possible side effects include upper respiratory tract symptoms, diarrhea, stomach upset, insomnia, rash

IBA

Risk of infusion-related adverse events
Can cause Immune Reconstitution Inflammatory Syndrome
Intravenous infusion (do not administer as intravenous push or bolus) every 2 weeks
Not affected by resistance to other classes of antiretroviral medications or HIV tropism status (CC45 versus CXCR4), or renal insufficiency
Recommended in heavily treatment-experienced patients who are failing current ART

Atazanavir

Potent, once-daily anchor agent when given with a pharmacokinetic enhancer
Causes indirect hyperbilirubinemia that can lead to jaundice
May cause nephrolithiasis and gallstones
Concomitant use of certain acid suppressive agents can decrease absorption
Can be given with or without a pharmacokinetic booster (recommended to combine with pharmacokinetic enhancer)

Atazanavir-Cobicistat

Fixed-dose one-pill combination
May cause indirect hyperbilirubinemia, kidney stones and gallstones
Typically causes benign small increase in serum creatinine
Can cause significant drug interactions

Darunavir (DRV)

Must be combined with pharmacokinetic booster (cobicistat or ritonavir)
Retains activity following development of drug resistance with most other PIs

Darunavir-Cobicistat

Fixed-dose combination pill consisting of a PI and pharmacologic booster
Option for initial ART and as a component of salvage regiments for tx-experienced if once-daily dosing is indicated
Similar tolerability to once-daily darunavir plus ritonavir
High potency and barrier to resistance as anchor drug
Gastrointestinal side effects and drug interactions
Has sulfonamide moiety (use with caution for patients with sulfonamide allergy)

Fosamprenavir

Prodrug of amprenavir (discontinued PI)
Replaced by newer ART anchor drugs that involve fewer pills and side effects
For tx-naïve, can be administered unboosted 2x daily, boosted by ritonavir once daily, or boosted by ritonavir twice daily
For PI-experienced, 2x daily dosing with ritonavir boosting is recommended
Virologic failure can lead to resistance mutations that decrease efficacy of darunavir
Contains sulfonamide moiety so use caution in patients with sulfonamide allergy
Clinicians should change fosamprenavir to a currently recommended anchor drug to lower risk of adverse events and pill burden

Indinavir

No longer used as ART because of toxicity
Frequently causes kidney stones (advise patients to drink 1.5 liters of water per day)
Requires more frequent dosing than currently recommended agents, has strict food requirements, associated with cosmetically disturbing lipoaccumulation
Patients should switch to a safer and currently recommended agent

Lopinavir-Ritonavir

Fixed-dose combination of PI (lopinavir) and booster (ritonavir)
Widely used for pregnant women with HIV and PrEP
Rarely used in U.S. because of newer anchor drugs with lower pill burden and lower adverse effects
May be dosed once-daily for tx-naive and some tx-experienced individuals
Only twice-daily dosing recommended for the following patients: with 3 or more lopinavir-associated resistance mutations, taking certain other ART medications that interact with lopinavir, and if pregnant
Common drug interactions, gastrointestinal side effects, and metabolic adverse effects (e.g. hyperlipidemia)

Nelfinavir

Replaced in clinical practice with newer, more portent, better-tolerated medications
Administered without pharmacokinetic booster
Relatively low potency, low genetic barrier to resistance
If patient develops drug resistance to nelfinavir, they usually respond to newer PI
Not recommended for use in ART regimens: patient should switch to current recommendation

Saquinavir

Different formulations: hard-gel capsule, soft-gel capsule (discontinued), tablet
Not recommended for use in ART regimens: patient should switch to current recommendation

Tipranavir

Developed as salvage therapy for patients with resistance mutations to other PIs (also studied as component of initial therapy)
Unique resistance profile
FDA black box warning: fatal and nonfatal intracranial hemorrhage, severe hepatoxicity
Requires 2x daily dosing with ritonavir boosting
Required dosing is higher than with other PIs
Tipranavir + ritonavir causes frequent GI side effects and drug interactions

Efficacy in Clinical Trials

IBA

Trial Name	Drugs Compared	Participants	Results
TMB-301	IBA + optimized background regimen (OBR) (single arm)	40 tx-experienced with MDR HIV-1	All participants were monitored on their failing antiretroviral therapy for 7 days, then received a loading dose of ibalizumab (2,000 mg by IV infusion) and were monitored for another 7 days, then their background regimen was optimized (including at least one other active ARV), and then they continued this optimized background regimen along with ibalizumab 800 mg by IV infusion every 2 weeks. At 7 days after the loading dose of ibalizumab, the proportion of participants with at least a 0.5 log drop in HIV RNA level was 83% (the primary outcome) and the proportion with at least a 1 log drop was 60%. After 24 weeks, the mean viral load decrease from baseline was 1.6 log, 24% achieved an undetectable viral load, and 50% achieved a viral load below 200 copies/mL. There was only one drug-related adverse event leading to treatment discontinuation[6].
TMB-311(open-label extension of TMB-301)	IBA + OBR	27 tx-experienced with MDR HIV-1	Twenty-seven individuals completed TMB-301 and enrolled in an open-label extension and continued ibalizumab infusions every 2 weeks plus optimized background regimen until completing 48 weeks of therapy. By that time point, 3 had discontinued for nondrug-related reasons, 59% achieved an undetectable HIV RNA level, and 63% achieved an HIV RNA level below 200 copies/mL[7].

MVC

Trial Name	Drugs Compared	Participants	Results
MOTIVATE 1 & 2	MVC qd + OBT vs. MVC bid + OBT vs. placebo + OBT	1,049 tx-experienced	At 48 weeks, 55% of participants receiving MVC once daily and 60% of participants receiving the drug twice daily achieved a viral load less than 400 copies/mL compared with 26% of those taking placebo with optimized background therapy (OBT, consisting of 3-6 drugs based on treatment history and resistance testing); about 44% of the once-daily and 45% of the twice-daily MVC group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4+ count of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group[5].
MERIT	MVC qd+AZT+3TC vs. MVC bid +AZT+3TC vs. EFV+AZT+3TC	916 tx-naive	Once daily MVC was discontinued for not meeting pre-specified non-inferiority criteria. At 48 weeks, twice daily MVC was non-inferior to EFV for <400 copies/mL (70.6% vs. 73.1%) but not for <50 copies/mL (65.3% vs. 69.3%) at a threshold of -10%[8].
ROCnRAL	MVC+RAL (single arm)	44 tx-experienced	In long-term experienced patients, MVC+RAL therapy lacks virologic robustness despite a benefit in lipid profile and bone density. Among 44 patients, seven failed MVC+RAL therapy, including five with virologic failure and two with serious adverse events. Upon DSMB recommendation, the study was prematurely discontinued[9].
MARCH	MVC + 2 NRTIs vs. PI/r + 2 NRTIs	238 tx-experienced	At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms[3].
N/A	MVC-based regimen vs. NNRTI- or PI/r-based regimen	30 tx-experienced	Switching to maraviroc was well tolerated and associated with small, but statistically significant, declines in total, high-density lipoprotein and low-density lipoprotein cholesterol. Switching the third drug (either an NNRTI or PI/r) to maraviroc was safe, efficacious and improved lipid parameters[2].
N/A	MVC-containing regimen (single arm)	20 tx-experienced	Switching suppressive ART to a MVC-CR based upon genotypic tropism prediction from proviral DNA improves tolerability. Over median 7.5 months of follow-up, 3/20 patients discontinued MVC due to severe headache, fatigue and VL rebound. A significant reduction in soluble CD30 levels in MVC-treated patients was observed during follow-up at both 2 (p = 0.027) and 6 months (p = 0.001)[1].

1. Vitiello P, Brudney D, MacCartney M, Garcia A, Smith C, Marshall N, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated patients with suppressed plasma HIV-1-RNA load. Intervirology. 2012;55(2):172-8.

2. Bonjoch A, Pou C, Perez-Alvarez N, Bellido R, Casadella M, Puig J, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial. J Antimicrob Chemother. 2013;68(6):1382-7.

3. Pett SL, Amin J, Horban A, Andrade-Villanueva J, Losso M, Porteiro N, et al. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study. HIV Med. 2018;19(1):65-71.

4. Hardy WD, Gulick RM, Mayer H, Fatkenheuer G, Nelson M, Heera J, et al. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010;55(5):558-64.

5. Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359(14):1429-41.

6. Emu B, Fessel J, Schrader S, Kumar P, Richmond G, Win S, et al. Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1. N Engl J Med. 2018;379(7):645-54.

7. Ibalizumab Plus Optimized Background Regimen in Treatment-Experienced Patients With Multi-Drug-Resistant HIV-1. [Internet]. Google Scholar. 2018.

8. Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-13.

9. Katlama C, Assoumou L, Valantin MA, Soulie C, Duvivier C, Chablais L, et al. Maraviroc plus raltegravir failed to maintain virological suppression in HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study. J Antimicrob Chemother. 2014;69(6):1648-52.