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LA ART and LA PrEP
Safeguarding the Future of HIV Care at CROI 2025: Advances in LA ART and LA PrEP

Released: May 07, 2025

Expiration: May 06, 2026

Sharon R. Lewin
Sharon R. Lewin, AO, FRACP, PhD, FAA, FAHMS
Activity Information

Activity

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1
Course Completed
Key Takeaways
  • Supplementing lenacapavir with long-acting bNAbs could provide another option for long-acting HIV treatment, but additional work is needed to devise regimens that may be suitable for a broader range of people.
  • Long-acting bNAbs are being studied for their potential role in ART-free viral control by boosting HIV-specific immunity

The Conference on Retroviruses and Opportunistic Infections (CROI) 2025 was held in San Francisco this March, during a time of dramatic changes in the US funding landscape for HIV research and care and, more broadly, across all areas of science. CROI attendees were reminded of this in a powerful opening ceremony where Chris Beyrer, previous President of the International AIDS Society and now Professor of Global Health at Duke University, highlighted the 3 most important words in the HIV response: diversity, equity, and inclusion.

He went on to explain the impact of dismantling the Unites States Agency for International Development (USAID). The effects of this are far reaching, including in my own Asia Pacific region. He explained that even if funding for PEPFAR was maintained or reduced minimally, it was USAID who were responsible for implementation of policies. Without  USAID, the ability to maintain access to both HIV treatment and prevention would be dramatically reduced worldwide. This will result in alarming increases in new HIV infections and AIDS-related deaths, with a disproportionate impact on countries that remain highly dependent on US funding, which in my region includes Myanmar, Laos, and Vietnam.

New Options for Long-Acting ART
Fortunately, the news was not all dire at this meeting. I observed a great deal of excitement around new HIV antivirals and the potential to achieve treatment dosing every 6 months. The results from the phase II clinical trial of half-yearly lenacapavir (LEN) with 2 long-acting broadly neutralizing antibodies (bNAbs), teropavimab plus zinlirvimab, or “TAB and ZAB,” showed very promising results.

However, to be eligible for this trial, participants’ virus needed to be susceptible to both bNAbs. This was found in only 99 out of 200 of those screened for the study, and only 53 participants were enrolled. A key issue for Australia and neighboring countries in the Asia Pacific region is that 1 of these 2 antibodieshas minimal neutralization activity against the AE viral subtype, the dominant circulating strain in parts of South East Asia, which currently accounts for close to 20% of new HIV diagnoses in Australia. Therefore, there will be a significant number of people in Australia and the region who may not meet the eligibility criteria for this treatment should it be approved.

Another small study also assessed ‘longer-acting’ options for antiretroviral therapy (ART). The combination of LEN plus TAB plus ZAB for people living with HIV and whose virus was susceptible to either TAB or ZAB were enrolled. Four people received LEN plus TAB plus low-dose ZAB, and 6 people received LEN plus TAB plus high-dose ZAB. Although this study only enrolled 11 participants, a single dose maintained virologic suppression in 6 of 6 people receiving the high-dose ZAB regimen, and 2 of 4 people receiving the low-dose ZAB regimen. Based on these results, investigators concluded that future treatment studies of this regimen could utilize broader bNAb susceptibility criteria, potentially opening this regimen to more people.

Developments in Long-Acting PrEP
Investigators also presented an exciting development using yearly lenacapavir for HIV prevention. This was a phase I study in participants aged 18 to 55 years without HIV, evaluating the pharmacokinetics, safety, and tolerability of 2 lenacapavir-free acid formulations administered as a single 5000 mg dose by ventrogluteal intramuscular injection (formulation 1 with 5% w/w ethanol, formulation 2 with 10% w/w ethanol). Each group included 20 participants, and drugs levels were monitored out to Week 56. The data demonstrated that median plasma concentrations exceeded those associated with efficacy in phase III studies of twice-yearly subcutaneous lenacapavir for pre-exposure prophylaxis (PrEP). The most common adverse events were injection-site reactions. The presentation was recently published.

ART-Free Control of Viral Replication
Finally, a few studies reporting progress towards ART-free viral control (previously called remission or ‘cure’) by boosting HIV-specific immunity were met with great enthusiasm. The first study was a phase I/II dose escalation trial of 16 people living with HIV who were on stable ART regimens. Three sequential cohorts evaluated weekly IV infusions of an investigational product called IMC-M113V up to doses of 60 μg (n = 5), 120 μg (n = 5), and 300 μg (n = 6) administered over 12 weeks, followed by analytical treatment interruption (ATI) for up to 12 weeks. Control of viremia after viral rebound during ATI was observed in 0 of 5 people at 60 μg, 1 of 5 people at 120 μg, and 2 of 2 people at 300 μg, with 3 people in the 300 μg group still to undergo ATI. 

Two other studies investigated the effect of bNAb administration at ART interruption. The FRESH trial was a single-arm study of 2 bNAbs (VRC07-523LS and CAP256V2LS) with a TLR7 agonist called vesotolimod. The study was performed in South Africa in women living with virologically suppressed HIV who had started ART within days of infection and whose virus was sensitive to at least 1 of the 2 bNAbs. Rebound kinetics of the virus were slow and atypical in about one third of participants, and 2 participants remained off ART after 48 weeks of follow-up.

Finally, the RIO trial was a double-blind, placebo-controlled phase IIa trial of long-acting bNAbs. Participants received either 2 antibodies (3BNC117-LS and 10-1074-LS) or placebo at the time of ART cessation and again after 20 weeks off ART. Approximately 1 in 3 participants  were able to stay off ART for 72 weeks. However, given the very long half-life of these antibodies, longer follow-up will be needed to determine if the antibodies truly induced viral control off ART. In addition, 1 of the 2 bNABs used in the RIO trial is not active against AE virus. Additional studies will be needed with different antibodies to determine if similar results can be achieved in people with HIV from the Asia Pacific region.

Your Thoughts
How do these studies affect your perspective on long-acting HIV treatment and prevention? Are long-acting drugs the solution to HIV care barriers? Leave a comment to join the discussion!