Each year on TheBodyPro, we review the latest research and the most important events of the past year, looking for those with the greatest impact on how we provide HIV care and services in the U.S. This article is part of a series examining the 10 most significant developments in 2024.
The future of HIV therapy is long-acting treatment. But at present, the only practical option other than orally downing an antiretroviral with each of Earth's rotations is to receive cabotegravir/rilpivirine administered intramuscularly every eight weeks.
Lenacapavir, as two subcutaneous injections every six months, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of drug-resistant HIV infection. While this is exciting as an exhibition of HIV therapeutics minimalism, it must be taken with other antiretrovirals—and there are no other antiretrovirals taken twice a year with which it can partner.
Lenacapavir is versatile, though. Not only can it be injected, but when taken in oral form, the results can be long-ish acting. The same is true for islatravir, a novel investigational nucleoside reverse transcriptase translocation inhibitor that studies suggest can be dosed orally, once weekly. A swipe right moment for lenacapavir?
At the 2024 HIV Drug Therapy Glasgow conference the drug duo was blessed in a 48-week 48-week Phase 2 trial that compared once-a-week oral islatravir plus once-a-week oral lenacapavir to co-formulated bictegravir, emtricitabine, and tenofovir fumarate (B/F/TAF) in people with suppressed viremia. The trial randomized 104 people 1:1 to the once weekly regimen or continued daily B/F/TAF.
At one year of follow-up, more than 90% of the participants in both groups had plasma HIV RNA <50 copies/mL and there were no drug-related treatment discontinuations.
Islatravir development had previously been stymied by lymphocyte cytotoxicity—a problem that has been resolved by tweaking the dosing of the drug, though it is no longer being pursued as an HIV prevention option. In this study of islatravir and lenacapavir, changes in CD4 and absolute lymphocyte counts were not significantly different and were quite stable over the course of follow-up. Weight also was largely unchanged in both study groups.
The Bottom Line: A Welcome Duo
Weekly oral dosing of HIV medications may not be exactly what some have in mind when thinking of long-acting therapy. But for many people with HIV, taking two pills 52 times a year may be substantially more preferrable than taking one pill 365 times a year.
It is hard to get a fix on how many daily pill-takers will be interested in a switch to once-a-week timing but my guess is at least a third would. Experienced (i.e., old) HIV providers may be having flashbacks to weekly azithromycin for prophylaxis of mycobacterium avium complex, where adherence and gastrointestinal side effects challenged efficacy. Motivation for adherence to HIV therapy is different, though, and creative types can take advantage of technology to develop interventions to support dosing reminders. In this trial, more than 98% of participants had on-time dosing.
Speaking of creativity: This trial could also be interpreted to support weekly oral islatravir plus every-six-month lenacapavir injections.
The resistance barrier of the islatravir-plus-lenacapavir regimen is lower than we are used to with regimens like B/F/TAF; however, the same is true for injectable cabotegravir/rilpivirine, and compared to cabotegravir/rilpivirine, it is arguably less consequential for a regimen containing lenacapavir plus islatravir to fail and lead to resistance. (There were no virological failures in this small trial.)
While we wait patiently for the perfect long-acting antiretroviral match, this is a duo that, if it endures through the already launched next phase trials, will be welcomed with open arms.
Read All of the Top 10 HIV Clinical Developments of 2024
#5: Thinking Twice About Causes of Weight Gain on HIV Therapy
#6: It Is Time for Donor HIV+/Recipient HIV+ Kidney Transplantation
#7: We Need to Start Paying Attention to Dolutegravir Resistance