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LA ART at CROI 2024
LA ART for HIV Treatment and Prevention: CROI 2024 Update

Released: April 02, 2024

Expiration: April 01, 2025

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Key Takeaways
  • LA CAB + RPV was found to be effective in populations not previously evaluated, including adults and adolescents in low- and middle-income countries and those with adherence challenges and viremia.
  • Future LA ART modalities, including oral weekly ISL + LEN and ultralong-acting CAB, show promise for providing an even greater number of options for HIV treatment and prevention.
  • Offering choice of HIV prevention modality between LA PrEP, oral PrEP, or oral PEP significantly increased biomedical coverage time in East Africa.

I really think that the major updates from the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) were on long-acting (LA) therapies for both HIV treatment and prevention. Results on LA cabotegravir (CAB) + rilpivirine (RPV) in populations who had not previously been studied will be important for increasing access globally and for those who have had adherence challenges. I also want to highlight some future LA therapies in the pipeline and discuss the importance of LA pre-exposure prophylaxis (PrEP) availability to increase PrEP coverage. 

LA Antiretroviral Therapy (ART) in Low- and Middle-Income Countries
The CARES trial was the first time that therapy with LA CAB + RPV was studied in low- and middle-income countries using a sparse viral load monitoring approach. There were study sites in Uganda, Kenya, and South Africa and 512 participants in this randomized trial. One half of participants were randomized to stay on their current oral therapy, and one half were randomized to switch to LA CAB + RPV every 8 weeks. All of the participants were virologically suppressed on their current therapy, with the majority receiving dolutegravir (DTG)/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF). At 48 weeks, 97% of participants maintained virologic suppression on each arm, and treatment satisfaction improved among participants switched to LA CAB + RPV. 

Of importance, this was done using a public health approach of monitoring HIV-1 RNA only every 24 weeks. There was no ability to do HIV-1 RNA genotyping prior to the study because all participants were suppressed. The investigators collected peripheral blood mononuclear cell (PBMC) samples at baseline, and after the study was completed, they received the results of the baseline archived DNA analysis. Among the participants enrolled on this study, there was a high percentage of archived DNA recovering RPV resistance mutations—14.7% of those on the oral ART arm and 12.5% of those on the LA CAB + RPV arm. There was also a high rate of CAB resistance mutations—approximately 16% for participants on both arms. Ultimately, we do not know what those resistance mutations mean because the mutations were from archived DNA, and the patients did very well clinically at 48 weeks.

There has been a lot of discussion in the HIV community about what archived DNA resistance to RPV and CAB may mean clinically and which specific mutations may have been found—that information was not revealed in the study presentation. I think a lot more discussion will ensue. But overall, the message of the study is that LA CAB + RPV works well in low- and middle-income countries and really should be made more widely accessible to the world.

Another study using LA CAB + RPV in low- and middle-income countries was the IMPAACT 2017, or MOCHA, study, which evaluated LA CAB + RPV in adolescents in Botswana, South Africa, Thailand, Uganda, and the United States. The most notable characteristic of this study was that, although LA CAB + RPV is approved down to a weight of 35 kg and down to 12 years of age, this is the first study specifically in adolescents. This was a small switch study, not randomized, of only 144 participants who switched to LA CAB + RPV from oral ART. Maintenance of virologic suppression was 96.5% at 24 weeks, and the pharmacokinetics of these drugs in adolescents looked relatively similar to adults. 

LA ART With Adherence Challenges and Viremia
The biggest study from high-income countries on the use of LA CAB + RPV was the late-breaker oral abstract of ACTG A5359, or the LATITUDE study. The results were announced in a press release prior to CROI 2024, which led to a lot of buzz. This study evaluated LA CAB + RPV in people with prior adherence challenges. Although we have been very interested in using LA CAB + RPV in this group, the FDA has not approved the use of these drugs in those with adherence challenges because the registrational trials for LA CAB + RPV were performed in those with virologic suppression doing well on oral ART.

The LATITUDE study took those individuals with adherence challenges, as evidenced by viremia on oral ART in the past, and with the use of conditional economic incentives first tried to get them virologically suppressed prior to randomization. One half of the participants were randomized to switch to LA CAB + RPV every 4 weeks, and one half were randomized to stay on their standard-of-care oral ART. Of importance, although the design of the study asked for those with adherence challenges to try to get suppressed on oral therapy, 17% (24) participants on the LA CAB + RPV arm were viremic upon randomization.

On February 12, 2024, the data and safety monitoring board stopped randomization and said all those remaining on oral ART should be offered LA CAB + RPV because LA CAB + RPV demonstrated superiority to standard-of-care oral ART based on the secondary endpoints of virologic failure and treatment-related failure, which occurred more often in the standard-of-care oral ART arm.

This study showed that something that seems plausible is true—that those who have difficulty taking oral ART to maintain virologic suppression do better when they have an option of getting an injectable for the maintenance of virologic suppression. This, along with some other evidence, led the International Antiviral Society‒USA guidelines committee to recommend LA CAB + RPV on March 1, 2024, for those with viremia when no other treatment options are effective due to an inability to take oral ART.

One other piece of evidence that added to this recommendation on the use of LA CAB + RPV in those with adherence challenges was the 48-week data from the Ward 86 demonstration project; these results were presented at CROI 2024. In the Ward 86 cohort of 59 individuals with viremia who initiated LA CAB + RPV, there was good maintenance of virologic suppression, with 93% of participants having HIV-1 RNA <50 copies/mL and 95% having HIV-1 RNA <200 copies/mL on LA CAB + RPV.

Future LA ART Formulations for Treatment and Prevention
Data on LA options in the pipeline also were presented. There was a phase II study of islatravir (ISL) + lenacapavir (LEN) given orally once weekly. In this small study of 106 people suppressed on bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) once daily who were randomized to remain on their daily oral ART or switch to ISL + LEN orally once weekly, maintenance of virologic suppression after switching was high—94.2% at 24 weeks—paving the way for the phase III study of this combination. There were no significant differences between the arms in CD4 cell count or absolute lymphocyte count changes. This is of importance given the concerns of lymphopenia arising on higher doses of ISL in previous studies. 

LA PrEP Expands Biomedical Prevention Coverage
Going back to the idea of how to use LA agents in low- and middle-income countries, useful data on LA CAB for PrEP were presented from the SEARCH study. SEARCH was a large, randomized trial conducted in East Africa. Participants randomized to dynamic choice HIV prevention were offered LA CAB PrEP or oral FTC/TDF PrEP or DTG/3TC/TDF postexposure prophylaxis (PEP), whereas those randomized to receive standard of care were offered only oral FTC/TDF PrEP or DTG/3TC/TDF PEP. Average biomedical prevention covered time was increased 69.7% when LA CAB PrEP was offered in addition to standard-of-care oral prevention options. Incidence of HIV with LA CAB availability was 0% vs 1.8% with oral prevention options only. These were impressive data, showing that giving people a choice does increase biomedical prevention coverage.

Taken together, all of the LA data presented at CROI 2024 fueled discussions about the need for better global access to the LA options currently available for HIV treatment and prevention and the need to set precedence for products that will become available in the future.

Your Thoughts?
What key questions remain when it comes to expanding LA ART and PrEP? Get involved with the conversation by posting a comment below.