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Alimatravir, a once-monthly oral HIV prevention pill, moves forward in clinical trials
November 10, 2026
CATIE News
- A second phase trial of HIV prevention pill alimatravir included people at low risk
- Results with 350 people so far suggest that it is generally safe and well tolerated
- A once-monthly pill could offer more options for long-acting PrEP without injections
There are several highly effective options for preventing HIV, including:
- tenofovir DF + FTC (emtricitabine) – a pill sold as Truvada and available in generic formulations
- TAF (tenofovir alafenamide) + FTC – a pill sold as Descovy
- a long-acting formulation of cabotegravir – a liquid for injection sold as Apretude
- a long-acting formulation of lenacapavir – a liquid for injection sold as Yeytuo.
While each of these are highly effective, they may not be suitable for some people because of their adherence requirements (tenofovir-containing pills are generally taken daily; in some cases, they may also be taken for shortly before and for several consecutive days after sex in an “on-demand” schedule). In the case of cabotegravir and lenacapavir for prevention, some people may not tolerate the injections.
Enter alimatravir
Alimatravir (formerly called MK-8527) is being developed by the pharmaceutical company Merck. It belongs to a relatively new class of drugs called nucleoside reverse transcriptase translocation inhibitors (NRTTIs). These drugs have multiple ways of interfering with HIV infection.
In experiments with cells and HIV in laboratory studies, alimatravir protects cells from the virus. In experiments with monkeys, some of which were treated with alimatravir, it protected them from infection with the hybrid virus that scientists call SHIV. This hybrid virus is a combination of SIV (simian immunodeficiency virus), which causes an AIDS-like disease in susceptible monkeys, and HIV. The hybrid virus causes disease relatively quickly compared to HIV and is used by some research labs when testing anti-HIV drugs in monkeys.
Alimatravir in people
In a short study involving people with HIV, scientists confirmed that alimatravir’s anti-HIV activity, previously observed in the laboratory, was also seen in people. This finding is important because it confirms that the drug has anti-HIV activity in the body—a crucial step before alimatravir is evaluated in future trials for HIV prevention.
Alimatravir is being tested as a prevention pill taken once monthly for people without HIV. This population will be the focus of the rest of this CATIE News bulletin.
In a phase 1 clinical trial to assess preliminary safety, alimatravir was found to be generally safe in people without HIV.
Phase 2 – a study with 350 people
Merck has completed a phase 2 study of alimatravir. In this study, researchers tested different doses of alimatravir given once monthly for several months. Participants were randomly assigned different doses of either alimatravir or placebo. The trial was designed so that most participants (301) received alimatravir, while 49 participants received placebo. In this study, the use of placebo helped scientists determine more information about the safety of alimatravir. Participants were at low risk of HIV; this was an essential characteristic at the time of recruitment because a placebo was being used.
Participants were recruited from Israel, South Africa and the U.S. Most of them were between 18 and 35 years old and were cisgender male or female. There were 12 transgender men, one transgender woman, and seven people who were either non-binary or gender nonconforming.
Participants were randomly assigned to receive different doses of alimatravir (3, 6 or 12 mg per pill) or placebo that looked like alimatravir.
Results
As participants were selected because they were at low risk of HIV, no one became HIV positive during the study.
Safety
Only 1% of participants (three out of 301) who received alimatravir and 4% (two out of 49) who received placebo left the study prematurely because of an adverse effect. The reasons for premature study departure are discussed later.
Among the people who received alimatravir and left the study prematurely, one was receiving the 12-mg dose and developed numbness in their cheeks beginning on the day they took their third dose. This was graded as moderate in severity, and it resolved without intervention 12 days later.
In general, the most common side effects reported in the study were distributed as follow:
Headache
- alimatravir – 4%
- placebo – 2%
Nausea
- alimatravir – 3%
- placebo – 2%
Most cases of headache and nausea were temporary and graded as mild or moderate. Such side effects are relatively common in clinical trials of HIV drugs.
In less than 0.7% of participants (two people) who received alimatravir and 2% (one person) who received placebo, side effects were graded as more serious. One person on the 12-mg dose of alimatravir developed a very high level of the enzyme lipase in their blood. This enzyme is produced by the pancreas and could suggest inflammation in that organ. This was not linked to any symptoms, and it resolved without treatment about a month after their last dose.
Another person, who was on the 3-mg dose of alimatravir, had a miscarriage at the sixth week of pregnancy, about a month and a half after their last dose. This person had been pregnant eight times before, and in seven of those cases had an abortion. In the remaining case they carried the fetus to term. The miscarriage may have been related to the use of alimatravir, though when it occurred alimatravir levels would have been very low.
Among people who took placebo, one developed severe bone/joint pain.
A note about miscarriages, and plans for pregnancy monitoring
Most miscarriages typically occur in the general population in the first trimester of pregnancy. Studies on cells and experiments with animals have not detected any concerns about the effect of alimatravir on pregnancy or its safety to the fetus.
However, Merck plans to collect extensive data on participants who become pregnant when taking alimatravir. Also, any infants born to participants who took alimatravir will be monitored up to their first year of life.
Focus on lymphocytes
Clinical trials of high doses of islatravir (by Merck) and of long-acting experimental drugs (by Gilead Sciences) have found that some long-acting drugs can reduce levels of lymphocytes—T-cells and B-cells—that are necessary for fighting infections. In particular, there was a decline in a subset of T-cells called CD4+ cells. However, after cessation of the study medicines, lymphocyte counts, including CD4+ cells, returned to normal. Today much lower doses of islatravir are used and have been found to be safe for lymphocytes.
In the current study, decreased lymphocyte and/or CD4+ cell counts were distributed as follows:
Reduced lymphocyte counts
- alimatravir – 2% (seven out of 301 people)
- placebo – 2% (one out of 49 people)
Reduced CD4+ cell counts
- alimatravir – 4% (12 out of 301 people)
- placebo – 4% (two out of 49 people)
The distribution of these reduced lymphocyte counts and CD4+ T-cells was similar between alimatravir and placebo. More importantly, the decline in lymphocytes and CD4+ cells was generally mild or, at worst, moderate. No complications arose in participants from these mild decreases. The decline in lymphocytes and/or CD4+ T-cells was not considered severe.
In total, less than 1% of people (two) taking alimatravir met the pre-specified criteria in the study protocol for discontinuation due to adverse changes to lymphocytes and CD4+ cells. These declines resolved within two to three months after alimatravir cessation.
Additional focus on two people
Two participants who received alimatravir (one in the 6-mg group and one in the 12-mg group) left the study prematurely.
Merck provided the following details about their changes to lymphocytes and CD4+ counts:
- In the person taking the 6-mg dose – lymphocyte levels declined by 37% and CD4+ count decreased by 51% to 313 cells/mm3. These decreases began on the day that they took the third dose of alimatravir. Lymphocyte and CD4+ cell counts normalized 48 days after they last took alimatravir.
- In the person taking the 12-mg dose – lymphocytes declined by 54% after their third dose. This problem resolved 77 days after their last dose.
In both participants, the decline in lymphocyte and CD4+ counts were considered mild by study scientists.
Drug levels
Alimatravir is absorbed when swallowed. Once inside cells, particularly lymphocytes, it is converted into its active, or antiviral, state. This state is called alimatravir-TP (triphosphate). Blood samples revealed that alimatravir is well absorbed. Furthermore, the level of alimatravir-TP inside cells was sufficiently high to block HIV infection if the cell was exposed to the virus in people who took the 6-mg and 12-mg doses of alimatravir.
Also, in people taking the 12-mg dose, the concentration of alimatravir-TP remained sufficiently high to block HIV infection for six weeks after the last dose of the drug. This finding confirms that alimatravir taken once monthly should lead to drug levels that block HIV infection.
For the future
A phase 3 clinical trial to assess the ability of alimatravir to prevent HIV infection is planned and underway. Merck is using a dose of 11 mg taken once monthly.
Resources
Long-acting injectable PrEP: Evidence and implications for practice — CATIE evidence brief
Lenacapavir (Yeytuo) injected every six months approved for HIV prevention in Canada — CATIE News
PrEP pharmacist and navigation services at a sexually transmitted infection clinic — CATIE evidence brief
Canadian guideline on HIV pre- and postexposure prophylaxis: 2025 update — CIHR Pan-Canadian Network for HIV and STBBI Clinical Trials Research (CTN+)
REFERENCES:
- Mayer KH, Kotze PH, Lombaard J, et al. Alimatravir oral once monthly in adults with low likelihood of HIV exposure: A randomized, double-blind, placebo-controlled study. Journal of Infectious Diseases. 2026; in press.
- Carstens RP, Kapoor Y, Vargo RC, et al. Antiretroviral activity, pharmacokinetics, and safety of MK-8527, an oral nucleoside reverse transcriptase translocation inhibitor, in adults with HIV-1 who had not previously taken antiretroviral agents: Results from 2 open-label, phase 1 studies. Clinical Infectious Diseases. 2026 May 20;82(5):e984-e991.
- Diamond TL, Kapoor Y, Li F, et al. Weekly oral prophylaxis with MK-8527 protects rhesus macaques rrom intrarectal challenge with simian-human immunodeficiency virus. Journal of Infectious Diseases. 2026 Apr 29;233(4):e923-e931.
- Daly MB, Kim D, Inusah S, et al. Oral islatravir in macaques decreases lymphocytes and monocytes and is associated with immune alterations. Pharmaceutics. 2026 Mar 20;18(3):381.
- Hillier SL, Bekker LG, Riddler SA, et al. Safety, tolerability, and pharmacokinetics of once-monthly oral islatravir: A phase 2a study in participants at low risk for acquiring human immunodeficiency virus type 1. Journal of Infectious Diseases. 2025 Nov 14;232(5):1050-1060.
- Gilead Sciences. Gilead provides update on clinical studies evaluating GS-1720 and/or GS-4182 for the treatment of HIV-1 infection. Press release. 10 June 2025.
- Michailidis E, Marchand B, Kodama EN, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by 4'-Ethynyl-2-fluoro-2'-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. Journal of Biological Chemistry. 2009 Dec 18;284(51):35681-91.
From Canadian AIDS Treatment Information Exchange (CATIE).
This content was originally published by CATIE, Canada’s source for HIV and hepatitis C information.
Source: CATIE:
https://www.catie.ca/catie-news/alimatravir-a-once-monthly-oral-hiv-prevention-pill-moves-forward-in-clinical-trials
For more information visit CATIE's Information Network at www.catie.ca
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