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LA PrEP at CROI 2026
Long-Acting Antiretroviral Agents for PrEP: Insights From CROI 2026

Released: March 25, 2026

Daniel R. Kuritzkes
Daniel R. Kuritzkes, MD
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Key Takeaways
  • Long-acting CAB and LEN for PrEP provide near-complete protection against HIV acquisition and have been shown in clinical trials to be more effective than daily oral PrEP.
  • Very few participants discontinued receiving either drug because of ISRs, and both are generally well tolerated with no other significant safety concerns.
  • The most recent clinical trial data show that although the risk of breakthrough infections and development of resistance for either CAB or LEN is not zero, it is very small.

The age of long-acting (LA) regimens for pre-exposure prophylaxis (PrEP) to prevent acquisition of HIV has arrived! In many countries, people at risk of acquiring HIV now have 2 LA PrEP options available: bimonthly intramuscular injection of the integrase strand transfer inhibitor (INSTI) cabotegravir (CAB) or twice-yearly subcutaneous injection of the capsid inhibitor lenacapavir (LEN).

Both options provide near-complete protection against HIV acquisition and have been shown in clinical trials to be more effective than daily oral PrEP with a fixed-dose combination of tenofovir plus emtricitabine.

Many abstracts at CROI 2026 reported key data in support of these 2 LA agents, as well as drugs in earlier stages of the development pipeline that may someday offer an even greater breadth of LA PrEP options.

Frequency and Severity of Injection-Site Reactions
Each LA PrEP option has benefits and limitations. Because they are delivered by injection, administration of both CAB and LEN can result in injection-site reactions (ISRs).

In the case of CAB, which must be administered more frequently, pain at the injection site was the most common ISR but generally resolved in a few days; in the case of LEN, which must be administered less frequently, subcutaneous nodules were a common ISR that may take weeks to months to resolve in some people.

The good news is that in phase III studies, very few participants discontinued either agent because of ISRs, and both agents were very well tolerated with no other significant safety concerns.

Development of Resistance
A fundamental concern with LA PrEP is the potential for drug resistance if exposure to PrEP continues after HIV acquisition, such as in cases of delayed diagnosis. As previously reported, HIV acquisition in people receiving CAB for PrEP can result in selection of CAB resistance. Extended analysis of the HPTN 083 trial—conducted in men who have sex with men and in transgender women—reported HIV acquisition in 34 of the 2282 participants randomized to the CAB arm, with delayed detection in 32 of those 34 individuals. Major INSTI resistance associated mutations were detected in 10 of the 32 participants with delayed diagnosis. In HPTN 084, conducted in participants assigned female sex at birth, acquisition of HIV occurred in only 4 of 1614 participants randomized to CAB (1 baseline infection and 3 incident infections), none of whom showed evidence of CAB resistance. 

The PURPOSE 1 study of LEN for HIV PrEP in cisgender adolescent girls initially reported no HIV acquisition after baseline among LEN recipients, but 2 of 2134 participants in the LEN group acquired HIV by the end of the randomized blinded phase. In PURPOSE 2, conducted in men and gender-diverse people, an updated analysis reported HIV acquisition in 3 of 2179 persons randomized to LEN. Among all 5 individuals who acquired HIV while receiving LEN in both PURPOSE 1 and 2, capsid mutations associated with LEN were identified in 4 participants.

Taken together, these results suggest that the risk of breakthrough infections and development of resistance for either CAB or LEN—although not zero—nevertheless is very small.

LA Agents in Development
CROI 2026 also included presentations of newer LA PrEP agents in development. The first of these is MK-8527, a nucleoside reverse transcriptase translocation inhibitor, the same class as islatravir.

MK-8527 is being developed as a monthly oral PrEP agent, with no apparent effect on total lymphocyte or CD4+ cell count at the doses tested. Pharmacokinetic modeling based on data from phase I and II studies of this drug have led to selection of 11 mg once monthly as the dose that will move forward in phase III studies.

Early-phase data were also presented for 3 additional LA agents: the INSTIs GS-3242 and VH4524184 (VH-184) and the capsid inhibitor VHVH4011499 (VH-499).

  • Pharmacokinetic data from the phase Ia study of GS-3242 support intramuscular dosing every 3 months; data from the phase Ib study showed that an oral dose of 450 mg given on Days 1 and 2 resulted in a 2.3 log10 reduction in HIV-1 RNA by Day 11.
  • Pharmacokinetic data from a phase I study of 2 formulations of VH-184 given subcutaneously or intramuscularly showed an extended half-life for this drug, supporting LA dosing.
  • A phase I single ascending dose study of VH-499 given subcutaneously or intramuscularly generated pharmacokinetic data that support twice-yearly dosing of this drug.

All 3 drugs were well tolerated with no clinically significant drug-related serious adverse events. Whether these drugs move forward as LA injectable antiretrovirals for prevention or treatment of HIV remains to be seen and will depend on the results of expanded phase II trials.

In summary, several highly effective, safe, and generally well-tolerated options for LA PrEP are now approved for clinical use, with several more in various stages of development. Together with daily or on-demand oral PrEP, these LA agents provide a broad range of options for people at risk for HIV. Ensuring that those most at risk for HIV are aware of and have access to these PrEP regimens remains a global challenge.

Your Thoughts
How has the advent of LA PrEP changed your approach to HIV prevention? How has it facilitated conversations about PrEP? Leave a comment to join the discussion!

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