Back Back
Novel ART at AIDS 2024
State of the ART: Novel Antiretrovirals at AIDS 2024

Released: August 22, 2024

Expiration: August 21, 2025

Daniel R Kuritzkes
Daniel R Kuritzkes, MD
Activity Information

Activity

Progress
1
Course Completed
Key Takeaways
  • Several novel capsid inhibitors are in development in phase I and phase IIa studies, with candidates for weekly dosing as well as long-acting ART.
  • Novel integrase inhibitors are in phase I and phase IIa studies for daily and weekly dosing, with one candidate for long-acting ART in phase I studies.

The potency and tolerability of modern antiretroviral therapy (ART) has enabled healthcare professionals to focus on treatment optimization and individual quality of life more than ever before. However, despite the advantages of highly effective, once-daily, single-tablet regimens and injectable, long-acting ART for the treatment of HIV, additional options would provide better opportunities to help each person find a regimen that suits their individual needs. In addition, novel drugs are always needed to combat resistance, particularly for people who are treatment experienced or who have had HIV for longer periods of time. To this end, several studies presented at the AIDS 2024 conference highlighted novel antiretroviral drugs in development, including novel integrase strand transfer inhibitors (INSTIs) and capsid inhibitors.

Novel Capsid Inhibitors
Two poster presentations reported on the safety and pharmacokinetic profile of single and multiple ascending doses of GS‑4182, an oral prodrug of the capsid inhibitor lenacapavir, in participants without HIV. This novel oral prodrug, which does not enter cells, is stable at low pH in the stomach but dissolves and undergoes hydrolysis at alkaline pH in the gastrointestinal tract, releasing lenacapavir and an inactive metabolite.

Pharmacokinetic data showed that weekly dosing of GS-4182 maintains concentrations of lenacapavir at above the target inhibitory quotient of 4—that is, a plasma concentration of lenacapavir 4 times above the protein-adjusted effective concentration to inhibit viral replication by 95%. GS-4182 was also well tolerated, with no discontinuations because of drug adverse effects. These data support once-weekly dosing of this prodrug, which could be an attractive option for some patients if combined with other once-weekly oral drugs currently in development.

Also of interest are VH-280 and VH-499, novel capsid inhibitors currently in development. In preclinical studies, both of these investigational compounds demonstrated inhibition of HIV in vitro at picomolar concentrations. X-ray crystallography data suggest that these agents bind the HIV capsid in a manner similar to lenacapavir, and in vitro resistance selection experiments show that the same single amino acid substitutions convey resistance to VH-280, VH-499, and other capsid inhibitors, suggesting cross-resistance between current capsid inhibitors and these drug candidates. In preliminary phase I studies, both candidate drugs were well tolerated, and the half-lives of each drug support their development as long-acting ART. Both are now under investigation in a phase IIa proof-of-concept study.

Novel INSTI
Next, VH-184 is a third-generation INSTI with in vitro antiviral potency comparable to the second-generation INSTIs dolutegravir and cabotegravir. Of note, investigators report that VH-184 has a distinct in vitro resistance profile compared with second-generation INSTIs, retaining potent antiviral activity against INSTI-resistant clinical isolates. In addition, in vitro isolation studies of VH-184, conducted up to Day 112, did not identify any resistance mutations, suggesting that VH-184 has a high barrier to resistance, similar to that of second-generation INSTIs. Results from a preliminary phase I study in adults without HIV show that VH-184 is safe and well tolerated and support its continued development for HIV treatment. Currently, VH-184 is under evaluation in a phase IIa study of ART-naive people with HIV, and a long-acting injectable formulation is being studied in a phase I trial of people without HIV.

Finally, the last drug I want to discuss is GS-1720, a novel INSTI with strong in vitro potency and potential for once-weekly oral administration. Preclinical studies showed that in vitro selection of resistance to GS-1720 proceeded at a similar rate as selection of bictegravir resistance, and GS-1720 maintained in vitro antiviral activity against a panel of HIV-1 mutants that are resistant to other antiretroviral classes.

In phase Ia studies, GS-1720 was well tolerated and had pharmacokinetics compatible with once-weekly oral dosing. Of importance, a phase Ib trial of this drug in people with HIV demonstrated robust antiviral activity, supporting once-weekly dosing. After a loading dose on Day 1 and a single dose on Day 2, participants experienced a mean decline in HIV-1 RNA of 2.0 log10 copies/mL by Day 8.

Altogether, these studies from the AIDS 2024 conference demonstrate the field’s ongoing commitment to improving and optimizing HIV care. ART has come a long way since the early days of the HIV epidemic, but “good enough” is no longer good enough. Treatment optimization for each individual is our new goal.

Your Thoughts?
Do you think any of these novel drugs will become the new standard of care? Leave a comment to join the discussion!