With an HIV vaccine still elusive (but still possible), research continues for longer-acting, effective regimens that are less susceptible to resistance and easier to take. Here are a few ongoing treatment trials to watch in 2024.
PHASE 1b
Long-acting injectable regimen
Gilead Sciences
Twice-yearly injections of lenacapavir and bNAbs considered safe
At the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), key findings were presented from a study evaluating the safety and efficacy of Gilead’s lenacapavir (LEN) with broadly neutralizing antibodies (bNAbs) in a twice-yearly injection.
A phase 1b study published in The Lancet HIV demonstrated that a combo of LEN+two broadly neutralizing antibodies (bNAbs), teropavimab (GS-5423, TAB) and zinlirvimab (GS-2872, ZAB), both under development by Gilead, maintained virologic suppression for six months with twice-yearly dosing. Following up on these results, an additional cohort was added to evaluate the regimen in an expanded population of virologically suppressed PWH who were on ARV therapy for at least 18 months and who had high sensitivity to either TAB or ZAB. The goal was to determine whether either bNAb would impact the safety profile or efficacy of the combined therapy.
Eleven participants (ages 28–63 years) were randomized and treated, and at 26 weeks 8 out of 10 remaining participants maintained viral suppression (HIV viral load ≤50 copies/mL). Of two participants who had virologic rebound, one had sensitivity to TAB and was diagnosed with acute COVID-19 at the time of rebound, and the other had sensitivity to ZAB; both had HIV RNA below 100 copies at week 26.
“The long-acting combination of LEN+TAB+ZAB was well tolerated, with a favorable safety profile,” the authors wrote. “All participants in the higher ZAB dose group maintained viral suppression for 6 months, which suggests that more inclusive sensitivity criteria may be appropriate for treatment studies of LEN+TAB+ZAB when higher bNAb levels are maintained.”
Study of the lenacapavir+TAB+ZAB combination now advances to a phase 2 trial (NCT05729568), which will continue evaluating the combination’s safety and efficacy in virologically suppressed participants.
PHASE 2
Long-acting injectable
ViiV Healthcare
CAB-LA+bNAbs safe for ART maintenance
In a growing wave of research into combining bNAbs with traditional antiretroviral therapy, a phase 2 study pairing a bNAb infusion every two months with a monthly cabotegravir injection shows that the combination is safe, researchers presenting the data at CROI said. The trial, studying the combination of VRC07-523LS, a bNAb targeting the HIV CD4-binding site, and long-acting cabotegravir (CAB-LA) for maintenance ART, showed that most participants maintained viral suppression; however, 14% prematurely discontinued the regimen, including 5 virologic failures and 1 death (unrelated to the study).
PHASE 2
Weekly oral regimen
Gilead Sciences
Islatravir+lenacapavir: effective, but adverse events common
Researchers at CROI presented 24-week data evaluating a once-weekly oral combination of islatravir (ISL) and lenacapavir (LEN), both made by Gilead, another investigative compound that could help decrease pill burden and increase adherence. (SEE “Two pills a week or two shots a month” in the MAY+JUNE 2024 PA.)
In the study, 104 virologically suppressed adults with a median age of 40 years on bictegravir/emtricitabine/tenofovir alafenamide fumarate (B/F/TAF, brand name Biktarvy) were randomized to one of two groups: weekly oral ISL 2 mg+LEN 300 mg, or continuing the daily B/F/TAF regimen. The study found that at week 24, ISL+LEN maintained viral suppression and was well tolerated. “The ISL 2 mg dose showed no clinically significant decreases in CD4+ T cell counts as were seen previously with higher daily, weekly, and monthly doses of ISL,” researchers wrote. Comparing the two groups of participants, 49 (94.2%) on ISL+LEN and 48 (92.3%) taking B/F/TAF maintained viral suppression at week 24. However, two (3.8%) and four (7.7%) participants, respectively, had no data due to discontinuation or missing visits, and adverse events occurred in 39 participants (75.0%, the most common, 13.5%, being diarrhea) taking ISL+LEN and 38 (73.1%) on the B/F/TAF regimen. No serious (Grade 3 or 4) adverse events related to study drug were reported.
PHASE 2
Daily oral regimen
ST Pharm Co. Ltd.
ALLINIs may be longer-lasting therapy
Allosteric integrase inhibitors (ALLINIs) target the noncatalytic sites of the viral integrase and interfere with integrase-viral RNA interaction during viral maturation, an approach that, if effective, could be longer lasting than current therapies that could improve the quality of life for people living with HIV. The study, now in phase 2a (NCT05869643), is assessing the antiviral effect, safety, tolerability, and pharmacokinetics of one ALLINI, pirmitegravir, which was developed by ST Pharm Co. Ltd., in treatment-naïve adults. Phase I data showed a once-daily dose of pirmitegravir to be well tolerated. Phase 2 data are expected this year.
PHASE 2/3
Daily oral regimen
Gilead Sciences
Bictegravir and lenacapavir once-daily combo
Nearly 10 percent of people with HIV (PWH) on treatment take two or more pills per day. The ARTISTRY-1 trial (NCT05502341) has been studying the effect of combining bictegravir (BIC) and lenacapavir (LEN) in a once-daily tablet, which could reduce the pill burden for them. Although single-tablet regimens for HIV have been available for more than a decade, some people cannot take those regimens.
In the study, 128 virally-suppressed PWH on multi-tablet regimens were randomly selected to either receive once-daily tablets of bictegravir 75 mg+lenacapavir 25 mg or remain on their current treatment. In the 24-week data presented at CROI, people who switched to daily oral BIC+LEN still had undetectable levels of HIV in their blood and had few, and mild, side effects.
“These data support the continued evaluation of a combination of BIC and LEN to optimize treatment in [virally suppressed] PWH who are receiving complex regimens,” the authors wrote. This single-tablet regimen will be further evaluated in the Phase 3 portion of the ARTISTRY-1 study.
Bictegravir and lenacapavir are manufactured by Gilead Sciences.
PHASE 3
Daily oral regimen
Gilead Sciences
Biktarvy for PWH with comorbidities
A study evaluating the efficacy and safety of Gilead’s Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, B/F/TAF) shows promise as long-term treatment option for PWH who may also have common comorbidities or other health needs, according to researchers presenting phase 3 data at CROI. PWH with hepatitis B (HBV) and tuberculosis (TB) coinfection have complex and changing treatment needs. ALLIANCE (NCT03547908) is the first randomized clinical trial of TAF- versus TDF-based regimens in treatment-naïve adults with HIV and HBV. Previously reported week 96 results demonstrated the efficacy of both antiretroviral regimens. Data presented at CROI further investigated the factors associated with the HBV treatment response observed with Biktarvy compared to DTG+F/TDF. This subgroup analysis showed that “TAFversus TDF-based therapy for many HBV treatment outcomes may be greater for certain subgroups, supporting the continued evaluation of Biktarvy in this population.” Subgroups showing a favorable response to Biktarvy included younger people and “those with certain levels or types of HBV DNA/genotypes and those with higher-than-normal liver enzymes, among others.”
In addition, researchers at CROI also presented week 24 data from the INSIGHT (NCT04734652) trial evaluating Biktarvy in people with HIV and tuberculosis, which is significant because TB is the leading cause of death globally for PWH. In a subgroup analysis comparing participants on Biktarvy compared to individuals on DTG+F/TDF showed that 97% percent of participants treated with Biktarvy achieved viral suppression as did 97% of individuals treated with the DTG-based regimen. “Serious adverse events (AEs) were common in this population with advanced HIV disease and TB, however, none of the reported AEs were deemed related to the study drug.”