Though Gilead Sciences made waves last June with a landmark FDA approval for its twice-yearly HIV preventive Yeztugo (lenacapavir), the first-in-class drug had previously been used as a long-acting treatment for the viral infection. Now, Gilead has conducted an analysis of a phenomenon that can undermine all infectious disease therapies, including lenacapavir—HIV’s ability to evolve resistance to the breakthrough antiviral.
After exposure to lenacapavir, HIV was able to shift the structure of its protein coating to avoid the drug’s effects, but this often came at a cost to the virus’s reproduction. The results, published in Science Translational Medicine on Jan. 7, suggest that while it may be difficult for lenacapavir-resistant strains of HIV to spread, surveillance for drug resistance and the pairing of lenacapavir with other antivirals could help prevent the virus from evolving resistance to the groundbreaking treatment.
The new study adds to existing evidence that “resistances are rare” in HIV treated with lenacapavir, Jared Baeten, M.D., Ph.D., senior vice president and virology head at Gilead, told Fierce Biotech. “That has been the most reassuring thing,” he added.
Before its headline-grabbing 100% efficacy rate in an HIV prevention trial and subsequent long-acting prophylactic approval, lenacapavir was approved in 2022 as Sunlenca for the treatment of HIV that resisted other antiviral therapies. The drug is the only approved HIV med that targets the virus’s protein capsid, which acts as a shield for the pathogen’s genetic material.
“All drugs for HIV have the potential for the development of resistance,” Baeten said. Because lenacapavir uses a novel mechanism to target the virus, the goal of the new study was to establish whether and how HIV may evolve to evade the drug and, potentially, other future capsid inhibitors.
To attack that question, Gilead scientists analyzed HIV samples taken during lenacapavir’s phase 3 Capella and phase 2 Calibrate trials, which studied the molecule’s use as an HIV treatment. In 40 samples, the team identified three primary changes to the virus’s capsid that enabled it to escape lenacapavir binding, the most common of which was a methionine amino acid that was swapped to an isoleucine.
Though this change “resulted in high-level resistance” to lenacapavir, it also led to “extreme fitness cost, reducing replication capacity to below 20%” that of normal HIV, Manish Choudhary, Ph.D., and Jonathan Li, M.D., virologists at Brigham and Women’s Hospital and Harvard Medical School, noted in a Jan. 7 commentary on the new study.
The mutation, called M66I, primarily arose in the Capella study, in which lenacapavir was given as a monotherapy to patients whose HIV didn’t respond to other treatments. But, even in some of these patients, the virus was still effectively suppressed because of the trade-off between drug resistance and virus replication, Baeten noted. And lenacapavir resistance didn’t translate to resistance to other classes of antivirals.
Allison Agwu, M.D., an infectious disease specialist at Johns Hopkins University and former chair of the HIV Medicine Association, found it interesting that “the evolution of resistance can come at a fitness cost” to the virus, but she noted that HIV was able to tack on other mutations to compensate for those negative effects, she told Fierce Biotech. “It is important to continue to interrogate the evolution and consequences of resistance mutations” to lenacapavir, she added.
Overall, the results will help “construct a fully active regimen” for patients with drug-resistant forms of HIV, Baeten said. For patients with less complicated forms of the virus, it’s important to avoid lenacapavir resistance in the first place, he said, which comes down to “maintaining adherence to the medicines.”
“These findings highlight the importance of maintaining fully active companion drugs during HIV treatment, improving access to resistance testing and surveillance and accelerating development of next-generation capsid inhibitors,” Choudhary and Li wrote.
Agwu agreed, highlighting that “infrastructure to support consistent and sustained drug access to avoid lapses” is critical for avoiding drug resistance.
Gilead is trying to turn lenacapavir into a pipeline gift that keeps on giving, while also developing new capsid inhibitors and probing why exactly lenacapavir resistance hampers HIV’s ability to replicate, Baeten said.
“We're not going to be done with HIV until the virus is done,” Baeten added, pointing to his video call background featuring Gilead’s pledge to end the HIV epidemic. “We are constantly thinking about how to stay further ahead.”