Two new long-acting antiretroviral drugs, VH-184 and VH-499, have demonstrated similar potency to the best available antiretrovirals currently in use in phase 2a proof-of-concept trials, according to findings presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco this week.
Although modern antiretroviral therapy is highly effective and well tolerated, new drugs are needed for people who develop resistance or rare side effects. Drug companies are competing to develop long-acting treatments so that people with HIV do not have to take pills every day and the new drugs presented this week at CROI 2025 each have the potential to be given as long-acting, injectable treatments.
VH-184
VH-184 is a third-generation integrase inhibitor chosen for its activity against HIV resistant to the second-generation integrase inhibitors dolutegravir and bictegravir. VH-184 is being developed as a medication that can be given by injection, potentially every six months. ViiV Healthcare is also developing two broadly neutralising antibodies that could be dosed every six months and a capsid inhibitor, VH-499, suitable for long-acting treatment.
The phase 2a trial assessed the efficacy, safety, and tolerability of VH-184 in people living with HIV-1.
The randomised, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults with HIV-1 who had not previously received antiretroviral therapy (ART) and had viral loads of at least 3000 copies/ml. A total of 22 participants were enrolled and randomised to receive VH-184 at doses of 10 mg (n=6), 50 mg (n=6), or 300 mg (n=7), or placebo (n=3). Participants took oral VH-184 or placebo on days 1, 4, and 7, followed by initiation of standard ART after the monotherapy phase.
The study population was predominantly male (86%), 68% were White, 14% were Black or African American and 59% were of Hispanic or Latin American ethnicity. Participants had a median age of 32 years.
The primary endpoint of the study was the maximum change in viral load from baseline to day 10. Results showed that VH-184 led to a rapid and potent decline in HIV-1 RNA levels. The mean maximum reduction in viral load was -1.17 log10 copies/ml for the 10mg dose, -2.15 log10 copies/ml for the 50mg dose and -2.31 log10 copies/ml for the 300mg dose.
Importantly, the maximum viral load reductions seen in this study are similar to those recorded in the phase 2a proof-of-concept trial for dolutegravir (-1.51 to -2.46 log10 copies/ml), confirming that VH-184 has similar potency to dolutegravir.
No participants developed genotypic or phenotypic resistance to VH-184 by day 10.
VH-184 was well tolerated, with no serious adverse events or discontinuations due to side effects. All adverse events were classified as mild (grade 1 or 2).
Although this study tested an oral formulation to assess short-term efficacy, VH-184 will be developed in a long-acting injectable formulation. A phase 1 safety and pharmacokinetic study of an injectable version of VH-184 is recruiting HIV-negative people in the United States.
VH-499
VH-499 is an investigational HIV-1 capsid inhibitor. Lenacapavir (Sunlenca), the first capsid inhibitor to be approved for HIV treatment, is dosed by injection every six months in a clinic. Drug developer ViiV Healthcare hopes that VH-499 can be developed as a long-acting injectable drug too.
The phase 2a study of VH-499 tested oral doses of the drug to evaluate its safety and effectiveness in previously untreated adults with HIV. The study recruited people with viral loads above 3000 copies/ml.
A total of 23 participants were enrolled and randomised to receive VH-499 at doses of 25mg (n=7), 100 mg (n=6), or 250 mg (n=7) or placebo (n=3) on days 1 and 6.
The study population was predominantly male (83%), 65% were White, 17% Black or African American and 65% were of Hispanic or Latin American ethnicity. The median age was 31 years.
The primary endpoint of the study was the maximum change from baseline in viral load to day 10. Results showed that VH-499 led to a rapid and potent decline in HIV-1 RNA levels. The mean maximum reduction in viral load was -1.83 log10 copies/ml for the 25mg dose, -1.8 log10 copies/ml for the 100mg dose and -2.17 log10 copies/ml for the 250mg dose. Higher drug concentrations at day 11 were associated with greater viral load reductions.
One participant receiving the 25mg dose developed a resistance mutation associated with capsid inhibitor resistance (Q67Q/H). This participant subsequently achieved a suppressed viral load on an antiretroviral regimen of dolutegravir / lamivudine.
VH-499 was well tolerated, with no serious adverse events, deaths, or treatment discontinuations due to side effects. Reported adverse events were all mild (grade 1 or 2), with no consistent patterns in type or frequency. No significant changes were observed in laboratory parameters, electrocardiograms, or vital signs.
Two phase 1 clinical trials are investigating the safety and pharmacokinetics of subcutaneous and intramuscular dosing of VH-499 in HIV-negative volunteers.
Rogg L et al. Proof-of-concept trial of VH4524184 (VH-184), a third-generation integrase strand transfer inhibitor. Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 152, 2025.
View the abstract on the conference website.
Griesel R et al. Proof-of-concept trial of oral VH4011499 (VH-499), a new HIV-1 capsid inhibitor. Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 153, 2025.