A Review of Late-Stage HIV Antiretroviral Candidates at IDWeek 2017

The protease inhibitor (PI) darunavir (Prezista) was first approved in the U.S. in 2006, and it is often boosted with ritonavir (Norvir) or cobicistat (Tybost) to maximize its effect. Now, the drug is being investigated as a coformulated, single-tablet combination alongside cobicistat, emtricitabine (FTC, Emtriva) and tenofovir alafenamide (TAF, Vemlidy), and known by the abbreviation D/C/F/TAF. In the Phase III EMERALD trial, from which the latest data were presented on Oct. 6 by Joseph Eron, M.D., a professor of medicine at the University of North Carolina School of Medicine, people who switched to D/C/F/TAF from an already-suppressive regimen consisting of emtricitabine/tenofovir disoproxil fumarate (Truvada or FTC/TDF) plus a boosted protease inhibitor had non-inferior outcomes at week 48.

The primary objective of the trial was to gauge the non-inferiority of D/C/F/TAF versus a control regimen by measuring the proportion of patients experiencing virologic rebound. Eron noted that one interesting feature of the study design was that patients with prior virologic failure were permitted in the study, which creates a more real-world setting -- a design approach that he said is different than previous studies. Overall, 1,141 people were randomized; of those, 18% were women, 76% were white and 15% had failed a prior non-darunavir-based regimen. Participants switched to D/C/F/TAF saw high rates of suppression (95%), no drug resistance and better bone and renal outcomes.

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Bictegravir, an investigational integrase inhibitor, is being developed in a coformulated package with emtricitabine and tenofovir alafenamide in a once-daily pill commonly referred to as B/F/TAF. Previous research has demonstrated that bictegravir has a high barrier to resistance and a low risk of drug-drug interactions.

Phase III, 48-week trial results were presented as a late-breaking abstract on Oct. 7 by Eric Daar, M.D. According to these data, coformulated B/F/TAF demonstrated high rates of virologic suppression and no drug resistance among people who were switched from another boosted PI regimen.

Specifically, the trial randomized 577 participants to either continue taking their existing virally suppressive regimen (which included a boosted protease inhibitor and, for most participants, also FTC/TDF). Seventeen percent of participants were women, 26% were black and their average age was 48.

At 48 weeks of treatment, Daar and colleagues found that people who had switched to B/F/TAF had non-inferior viral RNA outcomes (with 1.7% in each group having HIV-1 RNA ≥50 c/mL). Also, none of the B/F/TAF recipients developed resistance, while one person taking darunavir/ritonavir in the other study arm developed a mutation.

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Bictegravir was also tested in an unusually constructed Phase II trial that pitted coformulated B/F/TAF against multi-pill regimens consisting of emtricitabine/tenofovir alafenamide (Descovy, FTC/TAF) plus either bictegravir or dolutegravir. Paul Sax, M.D., presented the results on Oct. 6.

Ninety-eight treatment-naive people living with HIV were enrolled in the blinded phase of the trial; of those, 65 took bictegravir plus FTC/TAF and 33 took dolutegravir plus FTC/TAF. At week 60, the study was unblinded and all 92 people still in the study switched from the multi-pill regimen to single-pill B/F/TAF. Twelve weeks after the switch, 99% of the participants maintained their HIV-1 RNA <50 c/mL (98% on the B arm [one person withdrew] and 100% on the D arm). No participants discontinued because of serious adverse events.

B/F/TAF is being studied in two additional ongoing Phase III trials: a trial studying people who maintained dolutegravir/abacavir/lamivudine treatment compared with switching to B/F/TAF, and another studying people who maintained dolutegravir plus FTC/TAF compared with switching to B/F/TAF.

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Ibalizumab is a late-stage antiretroviral candidate that binds to the CD4 receptor, blocking the virus from entering the host cell. It's being tested as a treatment option for people with multidrug-resistant HIV. As a follow up to 24-week data presented at CROI, Brenda Emu, M.D., presented 48-week results of an open-label study evaluating its efficacy and safety in people with multidrug-resistant HIV at IDWeek on Oct 6.

Thirty-one participants completed the 24-week treatment period, and 27 entered the 24-week Phase 3 study (TMB-301). Of these, 59% had exhausted at least three antiretroviral classes, 33% had exhausted at least four and 7% had resistance to all approved antiretrovirals.

Participants continued to be suppressed after 48 weeks, with an average viral load reduction of 2.5log10 from baseline at weeks 24 and 48. Researchers determined that the three discontinuations were not related to the drug, and there were no new safety concerns after 48 weeks.

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Cabotegravir is a long-acting integrase inhibitor being tested both for HIV treatment and as pre-exposure prophylaxis (PrEP). At IDWeek, two new pharmacokinetics studies shed light on the safety of this drug in special populations.

One study, presented as a poster on Oct. 6 by Jafar Sadik Shaik, Ph.D., of GlaxoSmithKline, evaluated oral cabotegravir in people with moderate hepatic impairment and found that the blood plasma exposure of cabotegravir in these participants was similar to that in matched healthy people. The study, which evaluated 16 people with Child Pugh scores in the range of 7-9, concluded that the dose of cabotegravir would not need to be adjusted for people with mild to moderate hepatic impairment.

Another study, also presented as a poster on Oct. 6 by Ridhi Parasrampuria, Ph.D., of GlaxoSmithKline, evaluated the effect of cabotegravir in people with renal impairment, and concluded that the plasma exposure levels in people with sever renal impairment were similar those in healthy subjects, and so, once again, people with renal impairment would not need dose adjustments. Specifically, among the 16 subjects that completed the study, the pharmacokinetic parameters were similar for people with severe renal impairment and healthy subjects, although one person with renal impairment experienced a drug-related, grade-3 lipase elevation.

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