Broadly neutralising antibodies may be partners for long-acting antiretrovirals

Two long-acting antiretrovirals, lenacapavir (Sunlenca) and cabotegravir (Vocabria), may pair well with broadly neutralising antibodies for HIV treatment, according to two presentations yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2024).

Monoclonal antibodies are manufactured proteins that work like natural antibodies made by the immune system. People living with HIV normally produce HIV-specific antibodies, but these mostly target parts of the virus that are hidden or highly variable. However, a small proportion of people make broadly neutralising antibodies (bnAbs) that target conserved parts of the virus that don’t change much. These specialised antibodies are being explored for HIV prevention, treatment and cure research. As with antiretroviral drugs, though, the virus can develop resistance to bnAbs, so they are best used in combination therapy.

Lenacapavir plus two bnAbs

Professor Joseph Eron of the University of North Carolina at Chapel Hill presented new results from a study of lenacapavir plus teropavimab and zinlirvimab, two antibodies being developed by Gilead Sciences.

Lenacapavir is an HIV capsid inhibitor approved for treatment-experienced people with multidrug-resistant virus. It is administered by injection every six months, but it currently does not have equally durable partners to build a complete twice-yearly regimen; bnAbs could potentially fill this role.

Teropavimab (GS-5423) is derived from a bnAb called 3BNC117 that targets the CD4 binding site on HIV’s gp120 protein, which the virus uses to enter cells. Zinlirvimab (GS-2872) is derived from a bnAb called 10-1074 that binds to the V3 loop of HIV’s envelope. Both bnAbs were modified to extend their half-life and enable less frequent dosing. More than half of HIV subtype B (the most common type in western Europe and North America) is highly susceptible to both antibodies and more than 90% is susceptible to one or the other, according to Eron.

At CROI 2023, Eron reported results from a phase Ib trial (NCT04811040) that enrolled people on antiretroviral therapy (ART) with an undetectable viral load; the findings were later published in The Lancet HIV.

At the outset, participants were tested to ensure that their HIV was sensitive to both teropavimab and zinlirvimab. Of the 124 people initially screened, only 44% met the susceptibility criteria. Others were unable to enrol due to a temporary clinical hold on lenacapavir or for other reasons, leaving 20 people for the analysis. Most were White men and their median age was 44 years.

At the start of the study, after discontinuing their existing antiretrovirals, all participants received an oral loading dose of lenacapavir, two subcutaneous injections of lenacapavir and an intravenous infusion of teropavimab (30mg/kg). In addition, they were randomly assigned to receive either 10mg/kg or 30mg/kg infusions of zinlirvimab.

Lenacapavir, teropavimab and zinlirvimab remained well above therapeutic levels, and 90% of participants in both dose groups maintained viral suppression for six months. Treatment was safe and generally well tolerated.

These findings set the stage for a new cohort of 11 people with high-level sensitivity to either teropavimab or zinlirvimab – but not both.

Again, they were on stable ART with an undetectable viral load, had a current CD4 count above 500 and had never fallen below 350. This cohort was more diverse; about a quarter were women, more than a third were Black and 27% were Latino. The median age was 49 and they had been diagnosed with HIV for a median of 16 years. One person was found to have hepatitis B and was excluded from the analysis.

The 10 remaining participants were randomly assigned to the same two regimens as the first cohort. At 26 weeks, they restarted their baseline ART. At that point, eight of the 10 (80%) maintained viral suppression. But the response differed in the two zinlirvimab dose groups. Only two of the four people who received the lower dose still had an undetectable viral load, compared with all six of those who received the higher dose. No risk factors for viral rebound were identified other than a lower zinlirvimab dose.

One participant in the lower dose group who was sensitive to teropavimab was diagnosed with COVID at the time of viral rebound and regained suppression after resuming oral ART. The other was sensitive to zinlirvimab and continued to have a low-level detectable viral load after resuming oral treatment. No treatment-emergent resistance was detected.

Again, treatment was well tolerated and no one stopped therapy due to side effects. The only treatment-related adverse events were mild injection site reactions related to lenacapavir, such as pain, itching, swelling or nodules. None experienced infusion reactions from the antibodies.

All participants in the higher zinlirvimab dose group maintained viral suppression for six months, suggesting that “more inclusive bnAb sensitivity criteria may be appropriate for treatment studies with [lenacapavir+teropavimab+zinlirvimab] when higher bnAb concentrations are maintained,” the researchers concluded.

Based on these findings, this combination has advanced to a phase II trial (NCT05729568), according to Gilead. The study will assess the safety and efficacy of multiple doses of the regimen in people with viral suppression.

Cabotegravir plus bnAb

In the second study, Professor Babafemi Taiwo of Northwestern University in Chicago and colleagues evaluated the safety and efficacy of long-acting cabotegravir plus a bnAb called VRC07-523LS that targets HIV’s CD4 binding site. Like the Gilead antibodies, it was modified to extend its durability.

The combination of injectable cabotegravir and rilpivirine administered once monthly or every other month is currently the longest-acting complete antiretroviral regimen. But other durable partners would be welcome, especially for people whose HIV is resistant to NNRTIs like rilpivirine.

The phase II ACTG A5357 trial (NCT03739996) enrolled adults with viral suppression for at least two years, no prior treatment switches due to virological failure and a current CD4 count of at least 350. Among the 142 people screened, 36 did not meet the criteria for sensitivity to VRC07-523LS and 31 were excluded for other reasons. The remaining 75 people had a median age of 54. About three-quarters were men, half were White, a third were Black and 11% were Latino.

In step 1, the participants in this open-label study first took oral cabotegravir plus two NRTIs for four weeks. Those who maintained viral suppression proceeded to step 2 and received long-acting cabotegravir injections every four weeks and 40 mg/kg infusions of VRC07-523LS every eight weeks. After 48 weeks, they resumed a standard oral ART regimen. A total of 71 people started and 60 finished step 2.

All but five participants (7%) maintained viral suppression, defined as 200 copies or less at 48 weeks. Those five all had cabotegravir and VRC07-523LS levels within the therapeutic range. Three people experienced virological failure after receiving a COVID or mpox vaccine. Two regained viral suppression while staying on the same regimen, but one continued to have a low-level viral load after resuming an oral regimen. One person had an integrase resistance mutation (R263K). None developed antibodies against VRC07-523LS.

Treatment was generally safe and well tolerated. Twelve participants had severe (grade 3) adverse events or stopped therapy due to events deemed possibly related to treatment. Most of them experienced chills, fatigue, muscle pain or other symptoms possibly related to VRC07-523LS. One person discontinued treatment due to a mild infusion reaction.

The combination of a single long-acting bnAb plus injectable cabotegravir “has potential for maintenance of HIV-1 suppression, but will require a better understanding of the mechanisms underlying breakthroughs,” the researchers concluded.

While these findings are interesting, injectable cabotegravir and rilpivirine is highly effective, well tolerated and does not require IV infusions. Cabotegravir plus VRC07-523LS given on an every-other-month schedule does not appear to offer an advantage, except, perhaps, for people with NNRTI resistance (a frequent concern in sub-Saharan Africa). For those individuals, a small case series presented by Professor Monica Gandhi of the University of San Francisco and colleagues suggests that cabotegravir plus lenacapavir could be a feasible option. However, clinical development of that would require co-operation between Gilead Sciences and ViiV Healthcare.