What if you only had to take your HIV meds once a week? That’s the potential of ISL/LEN, a long-acting combination antiretroviral (ARV) pill now in Phase 3 clinical trials called ISLEND-2.

To understand how groundbreaking this is, it helps to look back at how far HIV treatment has come. In the 80s and 90s, treatments were largely ineffective. Then came protease inhibitors in 1996. They saved millions of lives but meant taking multiple pills a day, and the side effects were often horrendous.

Today, many people with HIV take just one daily pill — a safe, powerful combination of two or three antiretrovirals (ARVs), often with minimal or no side effects. For some, it feels like a functional cure enabling them to live full, productive and healthy lives. But not everyone finds daily pills easy to remember or without side-effects, while others who have had HIV for decades, have been on multiple regimes and over time have developed resistance to many of the ARVs presently available.

Injectable long-acting ARVs, such as Cabotegravir and Rilpivirine may soon be available as four-monthly injections following clinical trials. But injectables aren’t for everyone.

Now, another major advance is on the horizon: a once-weekly oral ARV pill.

Three such weekly orals are currently in development, with the ISL/LEN weekly in phase 3 clinical trials in several international sites including Melbourne, Australia.

The ISLEND-2 trial experience

ISLEND-2 is a 96-week Phase 3 trial of weekly oral Islatravir/Lenacapavir. Results from the earlier Phase 2 trial showed that 94% of participants achieved an undetectable viral load (less than 50 copies/mL) after 48 weeks. Side effects were minimal: 3.3% experienced diarrhoea and fewer than 2% reported fatigue. And there was no significant weight gain reported by trial participants.

Emily, a peer support worker with Positive Women Victoria and a passionate HIV advocate, joined the ISLEND-2 trial in December 2024.

“When I heard about the trial, I didn’t hesitate. I want to help science find better treatments and, hopefully, a cure. This is how I can contribute,” Emily says.

The ISLEND-2 study includes 11 clinic visits over two years, involving blood and urine tests, full body checks, blood pressure monitoring, and detailed discussions on health changes. While the schedule is demanding, Emily said the frequent medical support is a major benefit.

“The first three months of visits were monthly, and now they are every three months. It might sound inconvenient, but it’s worth it,” says Emily. “I get excellent medical care and can raise concerns, like menopause. My doctor even referred me to a menopause clinic.”

While some positive people see a weekly ARV pill as more convenient, especially for travel, others welcome it for reducing pill burden and side effects.

When daily pills aren’t tolerated

Sebastian migrated from Chile to Australia in 2018 and was diagnosed with HIV later that year. Since then, he’s struggled with side effects from daily oral ARVs.

“I was healthy with no symptoms, but once I started HIV meds, I was constantly nauseous. I lost my appetite, lost weight, and had constant stomach pain and bloody stools. I felt fatigued, confused, cognitively impaired and depressed all the time. I tried many combinations, but nothing stopped these horrendous side effects,” he explains.

Sebastian advised that his HIV includes a particular type that is multi-drug resistant, making him ineligible for long-acting injectable cabotegravir/rilpivirine. And while his viral load was undetectable on the various combinations of ARVs he tried, he had no quality of life and couldn’t work due to being intermittently bedridden.

“As soon as I stopped the meds, the stomach pain went, and I could eat again. I put on weight, but my viral load spiked so I had to go back on the meds, and the side effects returned,” he says.

When his doctor mentioned the ISLEND-2 trial, Sebastian immediately agreed.

“I didn’t care what it was — I just wanted to try something new. I was desperate.”

Although he experienced some nausea, dry mouth, and fatigue for a couple of days after his first dose, the daily stomach pain disappeared.

“Now I can eat every day. My focus is better. There’s no more brain fog.”

Sebastian acknowledges that many people tolerate daily pills well. “But these medications don’t work for everyone. People like me are suffering, and too often doctors don’t believe the side effects exist, despite them being reported in research,” he says.

“We need to be talked about, so we’re validated. Long-acting treatments like the weekly oral can reduce pill burden and toxicity

A pill that makes life easier

For Emily, the weekly pill is a breakthrough.

“I don’t have to think about HIV every single day. I’m a mother of three young children and the weekly pill makes life so much easier, especially when we travel. I don’t have to pack pills for every trip, which is a relief.”

Many people with HIV, especially those who haven’t disclosed their status, find it difficult to take pills discreetly. Emily hasn’t yet disclosed her HIV status to her children, but as she takes other medications daily, they don’t question her about what she is taking.

However, Emily has found that it is easy to forget taking a medication when it’s only once a week and sets a reminder on her phone which helps.

Sebastian says he’s also organised with taking pills. “But if I forget to take it on the right day, I can take it the next day and it’s not that bad.”

With data presented from the Phase 2 trial for the ISL/LEN weekly oral showing it had a one-week forgiveness window if a dose was missed, Sebastian says it’s great to know there is this flexibility. However, researchers have expressed concern that if people missed their weekly pill dose too often, resistance could develop.

Sebastian also values the freedom of the weekly pill and says the recent advances in HIV treatments and PrEP is exciting.

“Lenacapavir changes everything! It will help reduce stigma. Imagine a future with people with HIV suffering less chronic inflammation from the metabolic burden of their treatment so they are more like an HIV negative person. And some are taking the same compound as PrEP twice a year. People would be less afraid of HIV, because they wouldn’t feel it affecting their health. It would be a new transitional phase before the final cure comes,’ he says.

What is Islatravir and Lenacapavir?

Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) developed by Merck.  It blocks the HIV reverse transcriptase enzyme and disrupts the virus’s replication process. Earlier in the history of HIV treatments, much higher doses of Islatravir were prescribed and this was linked to decreased lymphocytes (a type of white blood cell), but in this new weekly oral, Islatravir is used at a low 2mg dose.

Lenacapavir is in a class of its own — a capsid inhibitor. It was discovered by US biochemist Wesley Sundquist about 25 years ago and later developed by Gilead Sciences. Lenacapavir targets the HIV capsid — the protein shell essential for replication. Lenacapavir has gained global attention as a six-monthly PrEP injection to prevent HIV transmission and is now in trials for once-yearly PrEP. Researchers and HIV advocates agree that Lenacapavir has the potential to effectively end new HIV transmissions globally if made widely and cheaply available.

As an HIV treatment, Lenacapavir is currently only available as a six month long-acting injection taken with a daily ARV for people with multi-drug resistance in Australia. Alone, Lenacapavir is not effective at controlling HIV, so must be taken with another HIV antiretroviral; such as a daily pill.

Sebastian, who studied a university degree in biochemistry, and is also a dietitian, is also passionate about HIV science.

“I’ve learned more about biochemistry since my diagnosis than I did at university. The research is exciting, but we need to focus on more than just becoming undetectable and trying to support the immune dysfunction and chronic inflammation to decrease patient suffering. We also need a real cure— urgently — what would be an excision of the virus out of the genome or to really make our bodies be able to battle the virus effectively to eradicate it.”

The importance of women in HIV trials

Historically, HIV clinical trials have enrolled more men than women, despite women accounting for over half of the 38 million people living with HIV globally. Hormonal changes, body composition, and other factors can affect how women respond to treatment, making their inclusion essential.

“The more women who enrol, the better,” Emily says. “If we can help science understand how treatments work for women, that’s a step toward a better future for all of us.”

Emily learned about ISLEND-2 through her healthcare team at the Monash HIV Clinic.

‘They thought I’d be a good candidate and were specifically looking for women. If they hadn’t contacted me, I wouldn’t have known about it,’ she says.

Emily has since joined the Victorian HIV Cure Volunteer database to stay informed about upcoming trials. With Melbourne a global hub for HIV cure and treatment research, participants for these trials need to live there to attend the regular clinic visits.

“If you’re living with HIV and interested in trials, it’s a way to give back — to help shape a future with longer-acting treatments and, one day, a cure,” she says.

Next steps for ISL/LEN weekly ARV oral

After the ISLEND-2 trial ends in 2026, participants like Emily and Sebastian can remain on the weekly oral for another year. The ISL/LEN weekly oral pill is hoped to be available as an HIV treatment option for people with HIV in Australia sometime in late 2027. For more information speak to your HIV doctor.

This weekly ARV pill could transform HIV treatment — making it easier to manage and less disruptive. For participants in ISLEND-2, it’s already changing lives. 

Learn more

For information about HIV treatment and cure trials in Australia, visit the HIV cure website.

To join the Victorian HIV Cure Volunteer database and receive updates about trials, visit: Join the Database.