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ClinicalThought: Emerging Treatment Options
CROI 2021: Highlights From Data on Emerging Treatment Options

Released: April 06, 2021

Expiration: April 05, 2022

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I think the most exciting news from CROI 2021 included the data on new drug development, which is increasingly focused on long-acting therapies. We saw data from the longer-term follow-up of injectable long-acting cabotegravir (LA CAB) plus rilpivirine (RPV). We also saw data on several new drugs that have completely different mechanisms of action. This is encouraging because it continues to diversify the portfolio of treatment options to include agents with nonoverlapping resistance profiles and provides additional treatment options for patients with highly drug resistant virus.

ATLAS-2M Week 96 Results: Switch to Injectable LA CAB Plus RPV Every 8 Weeks vs Every 4 Weeks
LA CAB plus RPV is approved for 4-week dosing intervals in Canada and the United States and 8-week dosing intervals in Europe. ATLAS-2M compared 4-week dosing with 8-week dosing of LA CAB plus RPV in patients who were enrolled on the ATLAS study (LA CAB plus RPV arm or continued oral antiretroviral therapy ART arm) and patients outside of the ATLAS study who were virologically suppressed on standard-of-care oral ART (N = 1045). 

Now with follow-up through Week 96, every-8-week LA CAB plus RPV was noninferior to every-4-week LA CAB plus RPV, with 91% vs 90% of participants, respectively, having HIV-1 RNA < 50 copies/mL. Of importance, there was only a single additional virologic failure in this second 48-week period. The injections were generally well tolerated with injection-site reactions (ISRs) experienced by 20% and 23% of participants at Week 48 and 12% and 16% of participants at Week 96 in the 4-week dosing and 8-week dosing arms, respectively. Therefore, ISRs tended to decrease during the second 48 weeks of follow-up in both dosing arms. There were very few grade 3 and no grade 4 ISRs, and of importance, only 18 participants withdrew from the study because of ISRs.

It is exciting to see these additional data on LA injectable therapy, which may serve to modify the indications for injectable LA CAB to include every-8-week dosing in the United States. It will be interesting to see the extent of patient uptake and what the performance of this regimen will be in a real-world clinical setting.

CAPELLA Trial: Antiviral Activity of Capsid Inhibitor Lenacapavir in Heavily ART–Experienced Patients with HIV
Data on newer LA drugs were also presented at CROI 2021. Lenacapavir is an investigational first-in-class capsid inhibitor. It binds to subunits of capsid in a way that interferes with capsid function at 2 points in the virus life cycle—capsid assembly during virus production and capsid disassembly after transport of reverse transcription products into the nucleus. It is an extraordinarily potent agent with an EC50 of 50 picomolar. The CAPELLA study presented at CROI 2021 investigated the role of lenacapavir as a salvage therapy agent. The study followed the design for salvage therapy studies proposed by the FDA to best demonstrate salvage agent activity without the risk of sacrificing remaining active drugs and without prolonging exposure to the novel agent as a single new drug. This eliminates “virtual monotherapy” and minimizes the risk of emergence of resistance to the new drug. This design is similar to the study design used for the approval of ibalizumab and fostemsavir as a salvage therapy agents.

In CAPELLA, patients who were viremic on their current regimen and had documented drug resistance to multiple antiretroviral classes but with 1 or 2 fully active antiretrovirals available for use in their optimized background regimen (OBR) were randomized to receive oral lenacapavir or placebo for a 14-day period while they continued on their failing regimen. Subsequently, all participants received lenacapavir subcutaneously every 6 months plus an OBR. The potential for twice-yearly injections is quite extraordinary. The primary endpoints were the reduction in HIV-1 RNA at Day 14 and the proportion of participants who achieved at least a 0.5 log10 copies/mL decline in HIV-1 RNA. Nearly 90% of the participants who received lenacapavir in that initial 2-week period had ≥0.5 log10 reduction in HIV-1 RNA compared with 17% in the placebo group (P <.0001). In fact, the lenacapavir group had a mean 1.93 log10 reduction in viremia, demonstrating its potency. Lenacapavir resistance with an M66I capsid mutation was observed in virus from 2 participants who experienced virologic rebound after initial suppression. One participant re-suppressed without any change in the OBR, and the other participant suppressed after a change to the OBR.

Lenacapavir resulted in rapid, clinically significant declines in HIV-1 RNA in patients who were failing an existing regimen in this highly treatment–experienced population and led to high rates of virologic suppression when combined with an optimized background regimen. The drug was generally safe and well tolerated, and no participant discontinued due to adverse events (AEs). There were some ISRs with the subcutaneous injections, but all were grade 1 and resolved within a few days. There are ongoing trials with lenacapavir for initial HIV treatment and for HIV prevention.

Novel, Next-Generation HIV Maturation Inhibitor GSK3640254 Demonstrates Dose-Dependent Antiviral Response in Treatment-Naive Patients With HIV Infection
GSK3640254 is an investigational next-generation HIV maturation inhibitor that prevents the proper processing of the Gag-Pol polyprotein by preventing the proteolytic cleavage of specific portions of the Gag polyprotein. Development of the previously investigated drug in this class, bevirimat, was abandoned because preexisting mutations or polymorphisms at the cleavage sites led to bevirimat resistance. GSK3640254 does not appear to have this resistance problem and is active against a wide range of viruses regardless of mutations or polymorphisms in Gag sequences, including virus with compensatory mutations in the setting of protease inhibitor resistance.

This phase IIa study had 2 parts investigating GSK3640254 in ART-naive patients with HIV—participants in part 1 received 200-mg GSK3640254, 10-mg GSK3640254, or placebo daily for 10 days (N = 14) and participants in part 2 received 1 of 3 nested GSK3640254 doses (140 mg, 80 mg, and 40 mg) or placebo daily for 7 days (N = 20). In part 1, the 200-mg dose resulted in nearly a 2 log10 mean reduction in HIV-1 RNA during the 10-day dosing period. However, 4 of the 6 patients who received the 200-mg dose developed evidence of resistance with the A364A/V mutation. Of these 4 patients, 1 developed full resistance to the drug. The participants were receiving monotherapy and did not start standard-of-care ART until Day 18, providing an opportunity for resistance and rebound during declining drug levels.

In part 2, the dosing period was shortened to 7 days, and participants immediately started standard-of-care ART on Day 8 to minimize the potential for resistance and rebound. The 140-mg dose resulted in substantial reductions in HIV-1 RNA, reaching an approximately 2.5 log10 reduction. The 140-mg and 200-mg doses had very similar pharmacokinetic profiles, suggesting a plateau effect and that higher doses would not be beneficial. There were some mild AEs, but no grade 3/4 AEs. Common AEs across all doses included headache (12%) and some mild gastrointestinal AEs (9% with diarrhea), but no AEs resulted in discontinuation.

These data are very promising and certainly support the continued development of this novel agent. There are now studies underway looking at 100-mg, 150-mg, and 200-mg GSK3640254 in combination with 2 nucleos(t)ide reverse transcriptase inhibitors.

Future Drug Development
Despite having more than 30 different drugs and even more drug combinations, there is always more to be discovered to improve HIV treatment, including new delivery methods and new classes of drugs with new mechanisms of action. We are fortunate that the drug discovery effort persists so patients continue to have suitable options in the event of resistance or poor tolerability.

Your Thoughts
Which new antiretroviral data presented at CROI 2021 did you find most intriguing? What is your experience with LA CAB plus RPV so far? Join the discussion by posting a comment sharing your experiences.

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