A study presented at the 2024 HIV Drug Therapeutics Conference in Glasgow suggests that two broadly neutralizing antibodies (bnAbs), teropavimab and zinlirvimab, could be effective partners alongside lenacapavir in long-acting HIV treatments. The results emphasize the significance of screening for antibody sensitivity in HIV, while also proposing that people with partial resistance might still benefit from this combination if the dosing is sufficient.
Lenacapavir (Sunlenca), administered as an injection every six months, is approved for people with multidrug-resistant HIV who have undergone extensive treatment. However, there is currently no other durable partner for lenacapavir to form a full six-month regimen, meaning it must be combined with daily oral antiretrovirals.
Broadly neutralizing antibodies (bnAbs) show potential in fulfilling this role. While most individuals with HIV produce antibodies targeting highly variable parts of the virus (which can’t handle new mutations), a small group of individuals naturally produce bnAbs. These bnAbs target stable regions of the virus, making them more effective in neutralizing the virus across different strains. Research indicates that bnAbs are promising for HIV prevention, treatment (especially in children), and functional cures, though viral resistance can limit their use.
Dr. Paul Cook and colleagues from East Carolina University tested a combination of lenacapavir with two bnAbs, teropavimab and zinlirvimab, both developed by Gilead Sciences.
Lenacapavir is the first approved HIV capsid inhibitor. Teropavimab (GS-5423), derived from the bnAb 3BNC117, targets the CD4 binding site on the gp120 protein of HIV, which is a critical entry point for the virus into cells. Zinlirvimab (GS-2872), derived from the bnAb 10-1074, binds to the V3 loop of the HIV envelope. Both bnAbs have been modified for longer half-lives, allowing for less frequent dosing. Prior studies indicate that about half of individuals with HIV subtype B (common in the U.S. and Europe) are highly sensitive to these two antibodies, and approximately 90% are sensitive to at least one of them.
In a phase 1b trial (NCT04811040), 32 participants who had been on standard oral antiretroviral therapy with an undetectable viral load for at least 18 months and a CD4 T-cell count of at least 500 were enrolled. Participants were divided into two cohorts: the main cohort (sensitive to both bnAbs) and a pilot cohort (sensitive to only one bnAb).
At the beginning of the study, participants received an oral loading dose of lenacapavir, a subcutaneous injection of lenacapavir, and an intravenous infusion of teropavimab (30 mg per kg of body weight) after discontinuing oral antiretrovirals. They were also randomly assigned to either a 10 mg/kg or 30 mg/kg infusion of zinlirvimab. The trial, initially planned for a year, was shortened to six months due to a temporary clinical hold on lenacapavir.
In the main cohort, 21 participants received full treatment, with 10 from each dosing group. More than 80% were male, and the majority were white. At 26 weeks, 90% of participants in both zinlirvimab dose groups maintained an undetectable viral load, as reported at the 2023 Conference on Retroviruses and Opportunistic Infections and in The Lancet HIV. However, one individual in the low-dose group experienced viral rebound, and another withdrew from the study.
A pilot cohort of 11 participants with high sensitivity to either teropavimab or zinlirvimab, but not both, was also assessed. This cohort was more diverse, with about a quarter being women, more than a third black, and 27% Latino. One person, diagnosed with hepatitis B, was excluded from analysis. At week 26, 80% of the remaining participants (eight out of 10) maintained viral suppression, with responses varying by zinlirvimab dose. All six participants in the high-dose group maintained undetectable viral loads, while two out of four in the low-dose group did the same.
Cook shared results from a combined analysis of all 32 participants, including those sensitive to one or both bnAbs. By week 26, 81% of the participants (26 out of 32) sustained viral suppression. Three people in the low-dose zinlirvimab group had detectable viral loads, but no one in the high-dose group experienced viral rebound.
In the low-dose group, one person with detectable viral load despite being sensitive to both bnAbs regained viral suppression after resuming oral treatment but developed a lenacapavir resistance mutation. Another person, insensitive to teropavimab, also resumed oral treatment and regained suppression. The third participant, who was insensitive to zinlirvimab, experienced viral rebound after a COVID-19 infection, but the viral load remained detectable after resuming oral treatment.
The combination regimen was safe and well tolerated, with no serious drug-related adverse events or withdrawals due to side effects. The most common adverse effects were mild to moderate injection site reactions from lenacapavir, such as pain, swelling, or nodules. No significant differences in safety or tolerability were observed between the two zinlirvimab dose groups.
The researchers concluded that these early-stage results suggest that a long-acting combination of lenacapavir, teropavimab, and high-dose zinlirvimab could be highly effective for individuals with HIV highly susceptible to one or both bnAbs. Based on these findings, a larger phase 2 trial (NCT05729568) is now underway, testing the triple-combination regimen with high doses of zinlirvimab.
