Monthly oral PrEP pill advances to phase III trials
A once-monthly oral HIV prevention pill has shown promising results in a phase II trial and will advance to efficacy studies, offering potential for a more convenient PrEP option than daily pills or clinic-based injections. The investigational drug MK-8527, developed by Merck, demonstrated favourable safety and pharmacokinetics in a study of 350 adults, with protective drug levels achieved within 24 hours and maintained for longer than 28 days. Professor Kenneth Mayer from Fenway Health and Harvard Medical School presented results from the phase II trial at the 13th International AIDS Society Conference on HIV Science (IAS 2025) in Kigali, Rwanda, on Wednesday.
Much of the enthusiasm at the conference has focused on the recent US approval of twice-yearly lenacapavir PrEP. However, monthly oral PrEP could offer advantages including appeal to people who dislike needles, less burden on the health system, and potential delivery in diverse settings beyond medical clinics. Research among men who have sex with men in the US found that oral monthly PrEP was the preferred prevention method compared to currently available options.
The researchers enrolled 350 adults at low risk of being exposed to HIV in the United States, Israel, and South Africa. Nearly 60% were women, about half were White, and 40% were Black, with a median age of 28 years. Participants received MK-8527 at doses of 3mg, 6mg, or 12mg, or placebo, every four weeks for up to six months.
The study found MK-8527 was well tolerated across all dose levels with a safety profile similar to placebo. The most common side effects were headache, nausea, and fatigue, which were mostly mild to moderate. Only one serious adverse event was deemed potentially drug-related, and there were no HIV infections during the study.
Importantly, the drug did not show the lymphocyte toxicity that halted development of its predecessor, islatravir. While some participants experienced minor decreases in CD4 or lymphocyte counts, these were uncommon and resolved quickly. "The lymphocyte counts bounced around but were really not substantially different from baseline," Mayer noted.
MK-8527 belongs to a new class called nucleoside reverse transcriptase translocation inhibitors (NRTTIs), which work differently from existing HIV drugs by both stopping enzyme movement and acting as defective building blocks during viral replication. The drug achieved protective levels within 24 hours and maintained them for slightly longer than 28 days, providing a "cushion of forgiveness" of about a week for late doses.
Based on these results, Merck will launch two phase III trials. EXPrESSIVE-10 will enrol nearly 4600 sexually active young women and adolescent girls in Kenya, South Africa, and Uganda, starting in the second half of this year. EXPrESSIVE-11 will recruit about 4400 sexually active people, including gay men, transgender individuals and non-binary people in 16 diverse countries, beginning in August. Both trials will compare MK-8527 with daily oral PrEP.
"Until now, long-acting PrEP has been synonymous with injectable formulations, and the oral alternative of monthly MK-8527 could represent a paradigm shift," said Dr Rebeca Plank from MSD Research Laboratories. "We hope that this option will provide a user-friendly, systems-friendly option that can be broadly available in a variety of settings."
Injectable HIV treatment effective for people with adherence challenges in Africa
Injectable HIV treatment was as effective as oral medication for people with poor treatment adherence in sub-Saharan Africa, according to new research presented at the conference. The IMPALA trial found that long-acting cabotegravir and rilpivirine injections matched the effectiveness of standard oral treatment, potentially providing an alternative for up to one million people in eastern and southern Africa with unsuppressed HIV despite taking antiretroviral treatment.
Dr Fiona Cresswell of the London School of Hygiene and Tropical Medicine led the three-country study, which enrolled 540 participants in Kenya, Uganda, and South Africa. All participants had a history of suboptimal HIV control, defined as either recent viral loads above 1000 copies/ml, periods of being lost to follow-up, or gaps in care after diagnosis. However, participants needed to achieve viral suppression below 200 copies/ml during a three-month screening phase before being randomised to continue oral treatment or switch to bi-monthly injections.
The study excluded people on second-line treatment, pregnant or breastfeeding women, and those with active hepatitis B infection. The 540 participants were 60% female, had been taking antiretroviral treatment for a median of 7.8 years, and 78% had previously taken non-nucleoside reverse transcriptase inhibitors (NNRTIs), which could affect rilpivirine effectiveness due to potential cross-resistance.
Results showed that injectable treatment was non-inferior to oral medication, with 91% of those receiving injections achieving viral suppression below 50 copies/ml at 48 weeks, compared to 89% on oral treatment. The injectable regimen remained effective even in people with higher body mass index, where efficacy might have been compromised. Five confirmed treatment failures occurred, all in the injectable arm, but all participants successfully resuppressed their viral load when switched back to oral treatment.
The injectable regimen poses challenges for people with hepatitis B, as unlike oral treatments containing tenofovir, it does not have any activity against hepatitis B. Ten per cent of potential participants were excluded due to active hepatitis B infection or lack of immunity. One participant in the injectable arm acquired hepatitis B during the study, though there were no cases of hepatitis B reactivation. This prompted recommendations for hepatitis B vaccination in all injectable recipients.
Participants overwhelmingly preferred injectable treatment because it offered privacy and reduced stigma. The World Health Organization has already recommended long-acting injectable treatment as an alternative for stable patients, and this week ViiV Healthcare expanded licensing agreements to enable generic access. However, generic versions may take at least two years to reach low- and middle-income countries.
A separate study from a wide range of real-world settings in the US showed similar promise, with 85% of 368 people with detectable viral loads achieving suppression after switching to injectable treatment, though 12% never achieved viral suppression after the switch.
HIV treatment switches don't reduce weight, studies show
Two major studies presented at IAS 2025 challenge common assumptions about HIV medication-related weight gain. A randomised trial and large observational study both found that switching from treatments thought to cause weight gain does not lead to meaningful weight reduction, suggesting that broader health interventions rather than medication changes are needed to address weight management in people with HIV.
The first study, the DO-IT trial led by Dr John Koethe from Vanderbilt University, was a randomised controlled trial examining whether switching from medications associated with weight gain would help people lose weight. The study recruited 145 people with obesity who were virally suppressed on regimens containing an integrase inhibitor and tenofovir alafenamide (TAF). Participants were randomised to either continue existing treatment, switch to doravirine and tenofovir disoproxil (TDF), or switch to doravirine whilst continuing TAF. Doravirine is an NNRTI not previously associated with weight changes.
The study found that all three groups lost small amounts of weight over 48 weeks, but there were no statistically significant differences between switching strategies and continuing existing treatment. Those remaining on existing treatment lost 1.84kg, compared to 2.73kg for those switching to doravirine and TDF, and 0.47kg for those switching to doravirine and TAF. Factors such as race, sex, age, and type of integrase inhibitor did not affect weight change outcomes.
"I was reassured that all three arms lost weight," Koethe noted, suggesting that study participation itself may have encouraged healthier behaviours. He concluded that treatment changes are not effective for reducing weight in obese people with HIV, and other interventions are needed to address weight-related health complications.
The second study, led by Dr Rick Elion from Trio Health, examined weight patterns in 10,413 people with HIV receiving care in the United States between 2015 and 2023. This large observational study focused on those with the greatest weight gain (at least 10% of body weight) over three years of treatment. The research found that substantial weight gain was associated with being Black, female, or having a low CD4 count before starting treatment, but not with current treatment regimen or with treatment switches during the follow-up period.
Interestingly, the study found that people who had switched from TAF to TDF at least 12 months before the study period were less likely to experience significant weight gain, though the researchers could not explain why earlier treatment changes had more impact than current medications.
Dr Graeme Moyle from Chelsea and Westminster Hospital emphasised that clinicians should "stop chasing switching as a way of trying to manage weight" and instead focus on comprehensive interventions including diet and exercise when starting or changing HIV treatment.
PEPFAR cuts leave thousands without PrEP
A modelling study revealed that US government funding cuts to PEPFAR will leave over 700,000 people without HIV prevention medication and cause up to 6700 new infections within one year across sub-Saharan Africa. The research, presented at IAS 2025, highlights the devastating impact of removing PrEP funding from the President's Emergency Plan for AIDS Relief, which previously supported 90% of PrEP provision globally.
Dr Jack Stone from the University of Bristol conducted the modelling study using PEPFAR's own coverage figures across 28 African countries. The research examined how many people would lose access to PrEP following the funding withdrawal and calculated the resulting HIV infections based on efficacy rates from research studies. The model considered key affected populations alongside cisgender men and women not in key populations.
The study found that 742,000 people received PEPFAR-funded PrEP in 2024, with 719,000 (96.9%) losing access after the cuts. Only pregnant and breastfeeding women retain funding to prevent vertical transmission. Of those affected, 28% were from key populations, with female sex workers comprising the largest group at 18.4%, followed by gay and bisexual men (7.1%), people who inject drugs (1.7%), and transgender women (0.5%).
The research revealed that even with PEPFAR support, PrEP was reaching only small proportions of those who could benefit – for example, just 5% of female sex workers across the 28 countries.
The model predicts 6700 new HIV infections in the first year, with 85% occurring among key populations. The highest impact will be in Tanzania, Nigeria, Zambia, Zimbabwe, and Uganda. When accounting for secondary infections over five years, the total could exceed 10,000 cases.
"We need to ensure stable funding for PrEP that is not influenced by political shifts and new priorities among funders," Stone emphasised, highlighting the urgent need for sustainable prevention financing.
Intermittent HIV treatment shows promise in adults but fails in adolescents
Intermittent HIV treatment schedules appear effective for adults with well-controlled HIV but are unsuitable for adolescents in African settings, according to two studies presented at the conference. The research comes as severe funding cuts threaten antiretroviral drug supplies, with 46% of surveyed countries experiencing supply chain disruptions and 14% having less than six months' stock of at least one HIV drug.
Dr Cassandra Fairhead from the Royal Free Hospital, London, led a systematic review and pooled analysis of eight randomised trials comparing continuous treatment to intermittent schedules taken on at least three days per week. The studies evaluated various patterns including five days on and two days off treatment, alternate days, four days on and three days off, and three days on and four days off. Four studies used NNRTI-based regimens, two used bictegravir-based combinations, and one evaluated any three-drug regimen.
The pooled analysis included 1346 participants who were virologically suppressed at baseline, with most studies excluding pregnant women and people with hepatitis B. Results showed no difference in viral suppression between intermittent and daily treatment strategies. Only 3% of participants in each group experienced viral rebound above 50 copies/ml. Intent-to-treat analysis at 48 weeks found no significant difference in viral suppression below 50 copies/ml between treatment approaches, even when using highly sensitive viral load tests with thresholds as low as 1 copy/ml.
Treatment-emergent resistance rates were similar between intermittent and continuous treatment (1.9% versus 2.1%). However, Dr Fairhead cautioned that in settings with less frequent viral load monitoring or resistance testing, switching after treatment failure may be less rapid, potentially leading to higher rates of viral rebound and resistance.
The BREATHER Plus study, led by Dr Adeodata Kekitiinwa, tested intermittent treatment in adolescents across Kenya, South Africa, Uganda, and Zimbabwe. The study randomised 470 participants with a median age of 16.5 years to continue their existing tenofovir disoproxil, lamivudine, and dolutegravir regimen or switch to taking the same combination five days on and two days off. Ninety-seven per cent had been living with HIV since infancy and had been on antiretroviral therapy for a median of 11.8 years.
The 96-week results showed that intermittent treatment was inferior to continuous treatment in this population. Ten per cent of participants on continuous treatment and 5% on intermittent treatment experienced viral rebound, representing a significantly higher rate of viral rebound in the intermittent arm. Adolescents receiving intermittent treatment were more than twice as likely to experience viral rebound after 96 weeks compared to those on continuous treatment.
Among the 33 participants who experienced viral rebound, 8 of 11 in the continuous arm and 19 of 23 in the intermittent arm achieved resuppression. Resistance testing revealed three participants in the intermittent arm had developed major NNRTI mutations, while in the continuous arm, one developed dolutegravir and lamivudine resistance and two developed NNRTI resistance.
The study investigators concluded that intermittent treatment cannot be recommended for adolescents with HIV taking this widely used oral regimen whilst receiving viral load tests every six to 12 months.
Long-acting PrEP safe to use in pregnancy and breastfeeding
New studies presented at the IAS 2025 conference support the use of long-acting injectable PrEP – lenacapavir and cabotegravir – during pregnancy and breastfeeding. Both drugs were found to be safe and effective, with minimal transfer to infants through breast milk and no increase in adverse pregnancy outcomes. These findings offer reassurance for pregnant and lactating people, who have historically been excluded from HIV prevention trials.
The PURPOSE 1 study, led by Professor Linda-Gail Bekker of the Desmond Tutu Health Foundation, is the first phase III PrEP trial to enrol pregnant and breastfeeding participants. It found that lenacapavir maintained consistent blood levels during pregnancy, with no need for dose adjustment. Among over 2000 women receiving lenacapavir, pregnancy and birth outcomes were similar to those seen with oral PrEP or in the general population. A pharmacokinetic substudy showed that lenacapavir passes into breast milk at about half the maternal concentration, but only 2% of this reaches the infant’s bloodstream. No participants using lenacapavir acquired HIV.
Two additional studies reinforced the safety of cabotegravir. The Tshireletso study in Botswana found that postpartum cabotegravir remained effective and resulted in low drug levels in breastfed infants. An open-label extension of the HPTN 084 study reported no increase in serious pregnancy complications or adverse birth outcomes. Most births in the study were full-term, with healthy birth weights and no maternal deaths.
Based on these findings, both the US Food and Drug Administration and World Health Organization (WHO) now support the use of lenacapavir during pregnancy. WHO’s updated 2025 guidelines advise that PrEP should not be discontinued during pregnancy or breastfeeding for women at risk of HIV, and that decisions should be made jointly by the individual and their healthcare provider.