Quicknews

By Marcus Low and Elri Voigt

A new antiretroviral combination pill that is taken only once a week appears to work as well as daily pills at treating HIV. This is according to interim study findings to be presented next week at the AIDS 2026 conference in Rio de Janeiro, Brazil.

Almost all of the over six million people in South Africa who are currently taking HIV treatment are taking it in the form of one tablet taken once a day. These tablets contain a combination of three different antiretrovirals, most commonly dolutegravir, lamivudine or emtricitabine, and tenofovir.

Now researchers have found that a new once-weekly antiretroviral formulation appears to be as effective as the daily pills. The new pill contains only two antiretrovirals, islatravir and lenacapavir. A different formulation of lenacapavir is used in the six-monthly HIV prevention injections being rolled out at around 10% of public sector clinics in South Africa.

“I think this is the next treatment blockbuster,” Professor Francois Venter told Spotlight this week when asked about the new once-weekly pill. Venter is the Executive Director of the Ezintsha Research Centre at the University of the Witwatersrand. He was not involved in the studies of the once-weekly pill.

“Patients are crying out for less frequent dosing, and it does not have the fiddliness and complexity, the supply line, healthcare worker training, or resistance issues of the current or immediate next generation of injectables. Imagine dispensing the same number of tablets for 6 months as previously for a month. It looks cheap to make. Low- and middle-income countries really should be taking note,” he said.

Two studies

The findings to be presented in Rio are from the first 48 weeks of two relatively large, multi-country, phase 3 studies called ISLEND-1 and ISLEND-2. Both studies will continue for another 48 weeks. The final study findings will only be reported after the full 96 weeks are completed.

The two studies have similar designs. Both started out with people who were already on antiretroviral therapy and doing well on treatment (607 people in ISLEND-1 and 624 in ISLEND-2). The researchers then switched roughly half of the people in each study over to the weekly islatravir/lenacapavir pill. The outcomes of those who switched to the weekly pill were then compared to those who didn’t switch and simply kept taking the treatment they had been taking before.

A key difference between the studies is in the control groups. In ISLEND-1, the researchers specifically recruited just people who were taking the antiretroviral combination of bictegravir, emtricitabine, and tenofovir alafenamide. In ISLEND-2, they recruited people who were taking whatever the local standard of care was (which often differs between countries). Some of the many ISLEND-2 clinical trial sites are in South Africa where the standard of care is dolutegravir, lamivudine or emtricitabine, and tenofovir.

Another notable difference between the studies is that ISLEND-1 is double-blinded, whereas ISLEND-2 is an open label study. This means that in ISLEND-1 neither study participants or their doctors know which study arm they are on – this is achieved by also giving people on the weekly arm daily placebo pills and people on the daily arm pills that look like the weekly placebo. In ISLEND-2, people know what study arm they are on and there is no need for placebos.

Both studies have a non-inferiority design, which is to say their main aim is to establish whether the weekly pill is roughly as safe and effective as existing treatments. Such designs are commonly used in HIV treatment trials given that existing treatments are already very safe and effective. The potential step forward in this research is the weekly dosing, not improved safety or efficacy against HIV.

“Developing new antiviral HIV medications remains important in order to address pill fatigue, adherence challenges, broaden treatment, with the goal of ending the HIV epidemic,” Professor Jürgen Rockstroh, lead author of the presentation of the ISLEND-1 results at AIDS 2026, told Spotlight by e-mail.

What the researchers found

The short version, as described in a conference media release, is that in both studies the weekly pill was found to be “efficacious and well tolerated and statistically non-inferior” to the controls it was measured against. In other words, based on the 48-week data, the weekly pill is passing the test so far. The findings have also been summarised in a media statement by pharmaceutical company Gilead Sciences.

The key indicator that the researchers looked at was the proportion of people whose HIV viral load was not suppressed at 48 weeks (they used a cut-off of 50 copies per millilitre of blood). If antiretroviral treatment is working well in someone’s body, one’s viral load is typically suppressed below this level.

In ISLEND-1, zero of the people on the weekly pill had a viral load above the cut-off, while one person on the bictegravir, emtricitabine, and tenofovir alafenamide study arm was above the cut-off. In ISLEND-2, one person taking the weekly pill had a viral load above the cut-off, while four people on the standard of care arm were above the threshold. Given that outcomes on the weekly pill were technically better than for the controls, it should come as no surprise that the non-inferiority thresholds were met.

Though the once-weekly pill was well-tolerated, there are some interesting nuances in the safety data. In ISLEND-1, treatment-related adverse events were very similar between the two study arms. In ISLEND-2, however, treatment-related adverse events were reported in 18% of participants treated with the once-weekly pill compared to less than 1% receiving standard of care antiretroviral regimens. Among those receiving the weekly pill in ISLEND-2, the most common treatment-related adverse events reported were headache (5%), nausea (3%) and diarrhoea (3%). There were no red flags regarding more serious treatment-related adverse events.

“It is not uncommon to see a higher rate of treatment related adverse events in the experimental arm of an open label switch study due to reporting bias. That is, when someone knows they are on a new drug, they may be more apt to believe that any new symptoms are caused by the new drug,” Dr Amy Colson, a principal investigator for both ISLEND studies at a study site in Boston in the United States, explained to Spotlight. “Of note, all treatment related adverse events in ISLEND-2 were grade 1 or grade 2.  And importantly, the rate of treatment related adverse events in the ISLEND 1 study – which was a double-blind study – was nearly identical in the islatravir/lenacapavir and bictegravir/emtricitabine/tenofovir alafenamide arms which further supports that the discrepancy in ISLEND 2 may indeed be due in part to reporting bias in the open label study.” (Adverse events are graded from 1 to 4, with 1 being the least severe. Only grade 3 and 4 adverse events are considered severe.)

“It is too early to comment on how any safety signals from the ISLEND 1 and ISLEND 2 trials will impact eligibility for future studies or eligibility for treatment outside of clinical trials.  However, safety data at week 48 from both trials was reassuring.  The overall rates of adverse events, grade 3 adverse events, serious adverse events and discontinuations due to adverse events was highly comparable between islatravir/lenacapavir and comparator groups in both trials,” Colson said.

The early data from ISLEND-2 suggests that people who switched to the once-weekly pill prefer it to the daily treatments they were taking before. According to Colson, 78% reported that they were more or much more satisfied with the weekly pill relative to their prior daily treatment and 64% reported that their prior daily treatment was more of a burden than the weekly pill. More extensive data on people’s self-reported experience of the treatment will be reported on at a future conference.

The new weekly pill is not the first long-acting form of HIV treatment, although it is the first long-acting HIV treatment in pill form. HIV treatment injections administered every two months have been available in the United States for around four years. Spotlight has previously explored in depth why we do not have these HIV treatment injections in South Africa.

Next steps

In a media statement released early in June, pharmaceutical companies Gilead Sciences and Merck (called MSD outside of the United States and Canada) indicated that they plan to file the once-weekly pill with medicines regulators “globally”. Spotlight asked both companies whether this will include filing with the South African Health Products Regulatory Authority, but neither company answered this question. Gilead has the patent on lenacapavir and Merck on islatravir. ISLEND-1 and ISLEND-2 were sponsored by Gilead. Gilead has already filed a weekly lenacapavir pill, used for HIV prevention rather than treatment, for registration with the United States Food and Drug Administration.

The companies didn’t provide details in response to Spotlight’s questions on their pricing plans and whether they would license other companies, directly or through the Geneva-based Medicines Patent Pool, to produce generic versions of the pill.

“Merck and Gilead are committed to supporting global efforts to reduce the incidence and burden of HIV by bringing forward new treatments. This includes our joint investigational long-acting oral treatment option, ISL/LEN. The single-tablet regimen represents a potential step-change in HIV treatment by offering a once-weekly oral regimen that may broaden choice for people living with HIV,” a Merck spokesperson told Spotlight by e-mail. “We remain focused on advancing the development program. If approved, our decades of experience collaborating with a range of stakeholders will help us explore pathways with the goal of facilitating rapid uptake and broad access around the world.”

Republished from Spotlight under a Creative Commons licence.

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