Trials of long-acting islatravir for HIV treatment and prevention placed on hold


On December 13, the US Food and Drug Administration (FDA) placed a clinical hold on islatravir, a long-acting experimental antiretroviral from Merck that is being developed for HIV treatment and prevention.

The move came after HIV-positive participants in treatment trials and HIV-negative volunteers in pre-exposure prophylaxis (PrEP) studies experienced declining CD4 cell or total lymphocyte counts. The reason for the apparent side effect is not well understood at this time, nor is the fate of islatravir going forward.

"We don't have a full explanation right now," Dr Michael Robertson, executive director of Merck Research Laboratories, said during a December 16 virtual meeting with HIV community advocates. "The CD4 count is concerning, but the overall safety profile [of islatravir] has been really excellent, so we don't want to throw the baby out with the bathwater…. We're going to do everything we can to understand that and see if there's a path forward, but it's going to take some time."

Studies of long-acting pills, implants and injections

Islatravir (formerly known as MK-8591 or EFdA), a first-in-class nucleoside reverse transcriptase translocation inhibitor with multiple mechanisms of action, has a long half-life in the body and has potential for both long-acting HIV treatment and prevention.

Islatravir has shown good activity in a once-daily combination with Merck's approved NNRTI doravirine (Pifeltro). At the recent European AIDS Conference, researchers reported that the regimen led to sustained viral suppression for 144 weeks in people new to treatment. In addition, data from the phase III ILLUMINATE SWITCH trials showed than the combination maintained viral suppression for 48 weeks in people who switched from their current regimen to islatravir plus doravirine. However, doravirine is not suitable for long-acting therapy, so Merck paired islatravir with its experimental long-acting NNRTI MK-8507 in a once-weekly regimen evaluated in the phase II IMAGINE-DR trial.

But a couple weeks after the conference, Merck announced that it was halting IMAGINE-DR after participants randomised to receive once-weekly islatravir plus MK-8507 experienced a decline in CD4 cells. An independent data and safety monitoring committee recommended that dosing be stopped and participants continue to be monitored.

At the time, Merck said that while it had paused development of MK-8507, it "remains confident in islatravir’s overall profile." But an internal review of other studies revealed more bad news for islatravir.

In the same November 18 press release, Merck noted that small, treatment-related decreases in CD4 counts were observed in the ILLUMINATE SWITCH trials, in which islatravir was used with doravirine, not MK-8507.

On October 26, Merck and Gilead Sciences announced that they were pausing enrolment in a phase II trial evaluating a once-weekly oral regimen of islatravir plus lenacapavir, Gilead's long-acting HIV capsid inhibitor, "out of an abundance of caution."

Islatravir is also being evaluated for PrEP, both as a once-monthly pill and as an implant, which early studies suggest could provide protection against HIV for a year. Merck's trial review found a dose-dependent decrease in total lymphocyte counts in an on-going phase 2 trial of monthly islatravir for PrEP. This led to the company's December 6 announcement that it would pause enrolment in two phase III PrEP trials, IMPOWER 22 and IMPOWER 24.



In pharmacology, a medication which maintains its effects over a long period of time, such as an injection or implant.


A type of white blood cell that is important in the immune system. Includes B cells (B lymphocytes, which produce circulating antibodies) and T cells (T lymphocytes, which are responsible for cell-mediated immunity).

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.


Something (such as a graft or device) implanted in a body tissue. In a context of prevention (such as contraception), the word refers to a device that will deliver an active agent slowly, over several months or years. This technique might be used one day to deliver antiretrovirals in the body for HIV prevention (PrEP) or treatment. 

On December 13, Merck announced that the FDA had gone further, placing a full clinical hold on five trials of oral and implant formulations of islatravir for PrEP as well as a study of injectable islatravir. No new studies of the drug may be initiated. Participants will no longer receive islatravir, but investigators will continue to monitor their CD4 cell and total lymphocyte counts to see if they recover.

The agency also placed a partial clinical hold on seven trials of once-daily islatravir plus doravirine for HIV treatment, including studies of treatment-naive and treatment-experienced adults and paediatric patients. Participants in trials that are now underway will continue to receive the medication with more frequent CD4 monitoring, but no new participants will be randomized. The studies will add stopping rules for participants who fall below a certain CD4 threshold.

Finding a path forward

Researchers do not yet understand what might be causing the decline in CD4 cells and other types of white blood cell, Robertson told community representatives. "What's the mechanism? This is a big unknown. We have hypotheses but we don't really have a good understand of what's causing this." Merck did extensive animal studies prior to human trials and saw no signal of this adverse effect, but the drug is metabolized very differently in animals and people, he explained. Once the mechanism and its relation to drug levels becomes clearer, it may be possible to resume development of islatravir, perhaps with different dosing.

While islatravir plus MK-8507 had an additive effect on CD4 counts, with the greatest decreases seen in those who received the highest doses of MK-8507, declines were also seen when islatravir was used in combination with doravirine or alone. So far, an additive effect has not been seen with lenacapavir.

Robertson noted that declines in CD4 counts were very small and subtle in trials of once-daily islatravir but larger in studies of monthly dosing. Starting treatment for the first time typically leads to a gain in CD4 cells, which could mask a small drug-related decline in treatment-naive people.

The best data come from participants with well-controlled HIV in switch studies, in which people taking daily islatravir plus doravirine experienced about a 40-cell decrease while those in the control group saw about a 30-cell increase. But in an individual with around 700 CD4 cells, that change initially didn't look clinically meaningful, Robertson said.

"Once the mechanism and its relation to drug levels becomes clearer, it may be possible to resume development of islatravir, perhaps with different dosing."

Among those who received higher doses of islatravir once weekly, the effect was larger and more apparent, with some study participants seeing a 50% drop in their CD4 cells and some falling below the 200 cells/mm3 threshold. However, there have been no cases of virological failure, and aside from one case of shingles in a person receiving once-weekly islatravir plus MK-8507, there have been no conditions that are sometimes associated with immunosuppression.

In the PrEP programme, lymphocyte counts fell by about 20%, but levels remained within the normal range. Robertson noted that CD4 cell levels specifically are not usually measured in healthy HIV-negative study participants. The islatravir implant releases a daily drug level below that of once-daily dosing, and he said he's hopeful its development can continue.

Regarding demographics, Robertson said lymphocyte changes appeared to be similar in men and women and in Africans, African-Americans and White people. He acknowledged that highly treatment-experienced patients with initially low CD4 counts stand to gain the most benefit from treatment, they also have the least room for additional CD4 cell losses. "We have to be very careful with those people," he said.

Researchers are continuing to follow study participants to see whether CD4 and total lymphocyte decreases are reversible and, if so, how long this takes.

Robertson said the FDA has provided little information about what it wants to see in order to lift the clinical holds on islatravir. He noted that so far the FDA is the only regulatory agency that has provided strong feedback, but the studies are currently on hold in all countries. Merck looks forward to hearing from health authorities in other countries, which may have differing opinions about the balance of risks versus benefits of islatravir.

"If we feel that there's a path forward, we will certainly talk with the FDA, other stakeholders, people like yourselves and our scientific leaders," he said. "I can't give a timeframe for when that might occur…This is not going to happen in just a few weeks."

Robertson also said that while studies of MK-8507 are now on hold, that drug, too, has a lot of good features, and Merck is investigating whether it could go forward, possibly in combination with something other than islatravir.