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1 EI 1 INSTI

1 INSTI + 1 EI 

 

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

 

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. In general, regimens containing an EI and INSTI are not routinely used for treatment-naïve or treatment-experienced patients, but they can be considered in specific circumstances for treatment-experienced patients with significant resistance profiles. 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, INSTI have been included as part of that OBR, based on treatment history and resistance testing. Our assessment of regimens containing EI + INSTI are largely extrapolated from such studies, which contain limited data explicitly studying the effectiveness of these particular 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 MCR as part of salvage regimens.

 

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 [personal communication], 65% of individuals in the trial (26 out of 40) had inclusion of DTG as part of their OBR. IBA was effective in combination with Dolutegravir (DTG).

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Recommendations for MVC + 1 INSTI in treatment-naive patients

DHHS (Dec. 2019): MVC in combination with 1 INSTI is not discussed as initial therapy. MVC (with NRTI backbone) 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 an INSTI (or PI 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 INSTI is not discussed for treatment of naïve patients and is not listed as one of the preferred options in patients with other treatment options.

Recommendations for MVC+ 1 INSTI in treatment-experienced patients

DHHS (Dec. 2019): 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): In a nonrandomized pilot study, patients with virologic suppression were switched from their prescribed regimen to MVC plus Raltegravir (RAL). This combination led to virologic relapse in five out of 44 patients. Based on these study results, use of MVC plus RAL is not recommended.

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Recommendations for IBA + 1 INSTI  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, requires IV therapy.

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

Recommendations for IBA + 1 INSTI in treatment-experienced patients

DHHS (Dec. 2019): IBA, in combination with at least one or two additional active antiretroviral agent(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. Guidelines do not specifically state an INSTI to pair with IBA.

IAS-USA (2018): Ibalizumab, 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 ibalizumab (800 mg) with at least 1 other active drug. In trial [6]subjects received a loading dose of IBA, followed 7 days later by the initiation of an OBR including at least one agent to which the subject’s virus was susceptible. Two weeks after loading dose, another dose was administered IBA, continuing every 2 weeks through week 25. Guidelines do not specifically state an INSTI to pair with IBA, however, the trial specifically reports on DTG as part of the OBR (personal communication).

 

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

Dolutegravir (DTG)

  • High potency against susceptible virus
  • High genetic  barrier to drug resistance
  • Excellent tolerability for most patients
  • No food requirements
  • Few significant drug interactions
  • Dosage adjustment required if certain integrase mutations are present or if certain interacting drugs are given concurrently

Raltegravir (RAL)

  • Relatively good tolerability
  • No food requirements
  • Few drug interactions
  • Limited metabolic adverse effects
  • Originally approved only for twice daily dosing (400 mg twice daily dosing)
  • Recently approved by FFDA for once daily dosing with 1200 mg (two 600 mg tablets)
  • Failure of regimen with raltegravir often results in drug resistance mutations that confer resistance to raltegravir and elvitegravir
  • Cross-resistance to dolutegravir may also be present with more extensive raltegravir resistance
  • Recommended for individuals who are already pregnant

Cabotegravir (investigational; not approved by FDA)

  • Dose once daily
  • Potent anti-HIV activity
  • Few bothersome adverse effects
  • Does not have high barrier to resistance
  • Being studied in oral form (half-life 40 hours) and long-acting injectable nanosuspension (half-life 21-50 days)
  • Potential risk for drug resistance to cabotegravir if person discontinues injectable cabotragevir abruptly or misses doses (upon discontinuation, may need standard oral antiretroviral therapy to prevent development of resistance)

 

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.[7]

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.[6]

 

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 [4] [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]

  

MARCH

Pett SL, Amin J, Horban A, et al. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study. HIV Med. 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28703491.

 

MERIT

Cooper DA, Heera J, Goodrich J, 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;201:803-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20151839

 

ROCnRAL

Katlama C, Assoumou L, Valantin MA, 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;69:1648-52. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24535278

 

Responses to switching to maraviroc-based antiretroviral therapy

Vitiello P, Brudney D, MacCartney M, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated patients with suppressed plasma HIV-1-RNA load. Intervirology. 2012;55(2):172-178. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22286889

 

Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects

Bonjoch A, Pou C, Perez-Alvarez N, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial. The Journal of antimicrobial chemotherapy. 2013;68(6):1382-1387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23354282

 

TMB-301

Emu B, Fessel K, Schrader S, et al. Phase 3 Study of Ibalizumab for Multi-Drug Resistant HIV-1. N. Engl. J. Med, 2018;379(7):645-654. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30110589

 

TMB-311

Lewis S, Fessel J, Emu B, et al. Long-acting ibalizumab in patients with multi-drug resistant HIV-1: A 24-week study. CROI. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02707861

 

 

Uploaded on May 25, 2020


References

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