LIMA, Peru – The infection-prevention potential of Lenacapavir,  the long-acting anti-HIV injectable administered just twice a year, took centre stage at the fifth HIV Research for Prevention Conference (HIVR4P) held last week.

However, several other important studies were also unveiled, including an injectable that combines contraception and HIV protection, results from a three-month vaginal ring, and real-world findings from Zambia’s rollout of long-acting injectable cabotegravir. 

Lenacapavir in diverse populations

Lenacapavir reduced HIV infections by 96% in a gender-diverse population, according to results from the PURPOSE 2 trial, which enrolled over 3,200 participants from Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the US between June 2021 and December 2023. 

Participants were randomly assigned to one of two groups: one receiving lenacapavir injections every six months and the other taking daily oral pills for pre-exposure prophylaxis (PrEP) with matched placebos.

The average age of participants was 28, with over one-third under the age of 25. Around 70% identified as non-white, and the gender breakdown featured cisgender men, transgender men, transgender women, and non-binary individuals who have sex with partners assigned male at birth.

At 39 weeks, only two HIV cases occurred in the lenacapavir group of 2,179 individuals, translating to a 96% reduction in HIV incidence, according to Dr Colleen Kelley from Emory University. 

In contrast, there were nine new HIV cases among the 1,087 participants taking daily oral TDF pills (comprising tenofovir disoproxil fumarate and emtricitabine and marketed as Truvada). This makes lenacapavir 89% more effective than oral PrEP.

The findings echoed earlier results from the PURPOSE 1 trial, which showed 100% efficacy in preventing HIV among cisgender women in Africa. With regulatory filings expected to begin globally by the end of 2024, lenacapavir has the potential to be a transformative HIV prevention tool. Future phases of the study will focus on other groups, including women in the US (PURPOSE 3) and people who inject drugs (PURPOSE 4).

Injectable contraceptive and HIV prevention in one 

For millions of young women worldwide, two major health concerns often intersect: HIV acquisition and unintended pregnancy. 

Many have expressed a preference for a method that protects against both. At the conference, Melissa Peet from CONRAD presented results from a promising solution—a silica-based hydrogel injectable that combines HIV antiretroviral drugs with contraception in a single shot.

In designing this dual-purpose method, researchers selected long-acting cabotegravir (CAB-LA) as the HIV prevention drug and levonorgestrel (LNG) as the contraceptive. 

The hydrogel injectable they developed is a silica-biodegradable material comprising two compartments, one for each medication. The injectable is capable of delivering both drugs with a single injection offering dual protection for three months.

Preclinical tests in rats showed sustained drug levels in the bloodstream without significant interactions or safety concerns, and the researchers are now conducting additional studies in non-human primates to fine-tune dosing and asses the duration of protective drug concentration.

No interactions between Cabotegravir and contraceptives

One concern with combining HIV prevention and contraception has been the potential for drug interactions, particularly between long-acting HIV medications like cabotegravir (CAB-LA) and commonly used contraceptives. 

To address this, Dr. Mark Marzinke from Johns Hopkins University presented results from a sub-study within the HPTN 084 trial to explore any potential interactions.

The study included 170 participants from South Africa with a median age of 23. A total of 80 women were randomised to the CAB-LA arm and 90 in the oral PrEP arm. Participants used three types of hormonal contraceptives: etonogestrel implants, injectable norethindrone, or medroxyprogesterone acetate (MPA), alongside either CAB-LA or oral PrEP. 

Researchers measured drug concentrations at enrolment and again at weeks 25, 49, and 73 to determine if there were any drug interactions. The results were reassuring: plasma concentrations of the contraceptives remained high enough to prevent pregnancy in both the CAB-LA and oral PrEP groups. 

CAB-LA concentrations were also consistent across contraceptive types, indicating that CAB-LA does not interfere with contraceptive effectiveness. However, tenofovir concentrations were unquantifiable for most participants, regardless of contraceptive type, due to low adherence to oral PrEP.

New data on the three-month vaginal ring

For women seeking long-term HIV prevention, the dapivirine vaginal ring, sometimes called the PrEP ring, has been a promising option. This is a flexible silicone ring that is placed in the vagina that releases the anti-HIV drug, dapivirine, over a month.

Delegates at the conference heard results from a South African study comparing the bioavailability of the standard one-month dapivirine ring with a new three-month version.

The study enrolled 124 women, but only 104 completed the trial. This was a crossover trial with two treatment phases: half the group started with the one-month ring (containing 25 mg of dapivirine) and then switched to the three-month ring, containing 100 mg of dapivirine. The other group followed the reverse order; they began with the three-month ring and later switched to the one-month ring.

The three-month ring was identical to the one-month version in silicone, dimensions, and appearance. Plasma and vaginal fluid samples were collected throughout the study to measure drug levels.

Based on dapivirine concentrations in plasma, results showed that the three-month ring provided greater overall drug exposure than the one-month version, indicating equal or possibly higher efficacy in preventing HIV.

Jeremy Nuttall from the Population Council’s Center for Biomedical Research, who presented the findings, noted that the reduced frequency of ring changes might increase acceptability and adherence, potentially improving overall effectiveness. 

He also highlighted that the estimated cost of the three-month ring is $16, making it a potentially more affordable option, projecting that the three-month ring could become available on the market by 2026.

Real-world results from Zambia’s CAB-LA rollout

Zambia became the first country in sub-Saharan Africa to roll out long-acting injectable PrEP (CAB-LA) beyond clinical trials, sharing results from their first three months (February to April 2024) in real-world settings. 

A total of 609 individuals with a median age of 24 were enrolled across six health facilities in two districts. Among the clients, 55% were female, 20% were adolescent boys and young men, 7% identified as key populations, and 40% as other high-risk populations.

Adamson Ndhlovu from Zambia’s JSI USAID DISCOVER-Health Project shared that over 90% of participants due for their second injection received it on time. 

A total of 24 participants (about 4%) discontinued CAB-LA. Most discontinuations were due to hepatitis B (20 cases), with two participants stopping due to pregnancy, one due to a severe rash, and one because of severe pain at the injection site. Those who discontinued were switched to oral PrEP.

During a press briefing at the conference, Professor Lloyd Mulenga from Zambia’s Ministry of Health stated that four of those enrolled had acquired HIV, explaining that they likely had undetected HIV at the time they started PrEP.

The real-world implementation of CAB-LA is anticipated to expand, as ViiV Healthcare, the manufacturer, announced at the conference its plans to triple the supply of cabotegravir that will be available for low- and middle-income countries in 2025-2026 to at least two million doses.

Image Credits: Nicole Bergman / IAS, Gilead, Nicole Bergman / IAS.