In February, the U.S. Food and Drug Administration (FDA) approved an expanded indication (usage) for Biktarvy to include people living with HIV (PLWH) with suppressed viral loads and resistance to M184V/I, one of the most common forms of drug resistance. According to manufacturer Giliead Sciences, the new indication makes Biktarvy (a three-drug combination of bictegravir, emtricitabine and tenofovir alafenamide) the first and only integrase strand transfer inhibitor (INSTI)-based regimen approved for PLWH whose virus has this mutation.
But it’s not the only approved drug that can help PLWH with single- or multi-drug resistance (MDR), a serious condition where meds that should work simply don’t. There are no clear data on how many people with HIV have MDR, which is defined as resistance to two or more drug classes and is more perilous than resistance to only one drug class. But according to Dr. Daniel Kuritzkes, professor of medicine at Harvard Medical School and chief of the Division of Infectious Diseases at Brigham and Women’s Hospital, there is good news for this hard-to-treat population: the range of options for suppressing HIV has never been greater.
“What we are concerned about clinically is when people are resistant to numerous classes of drugs, where it becomes challenging to find an acceptable and effective regimen to establish viral resistance,” Kuritzkes said. “That’s less of an issue today, because therapy is better and we have more classes of drugs. In the late ’90s and 2000s we did a lot of serial monotherapy when each new protease inhibitor [the first drug class of effective antiretroviral therapy] came out. But since the advent of integrase inhibitors and the second generation INSTIs—dolutegravir and bictegravir, along with boosted darunavir—there are small numbers of people for whom it’s challenging to find a tolerable and effective regimen.”
PLWH most likely to have MDR were on very early treatment that did not achieve complete viral suppression. As a result, they may have developed selective drug resistance to one or more regimens. People who acquired HIV at birth before effective therapies became available may also face MDR.
Kuritzkes said that in his practice in recent years he has seen only a handful of patients who truly meet the definition of MDR.
PLWH most likely to have MDR were on very early treatment that did not achieve complete viral suppression.
“In most cases we have found a regimen through these new generations like lenacapavir (LEN) and fostemsavir. There could be people resistant to at least one nucleoside and non-nucleoside and one PI but may be highly responsive to a regimen that includes a second-generation integrase inhibitor like dolutegravir or bictegravir and a boosted PI or other third agent.” LEN is a capsid inhibitor and can be given as a shot every six months. It’s highly effective because it’s a novel drug class, so there should be no pre-existing resistance.
Kuritzkes added that physicians must also try to understand why a patient’s regimen is failing, whether it’s due to drug resistance, or if there is another explanation, such as lack of adherence or drug-drug interactions (other meds are interfering with the HIV drugs). A drug resistance test could confirm or rule out resistance, and asking the patient about adherence (and offering counseling if necessary) could provide more insight into a failing regimen.
More options for people with multi-drug resistant HIV
There is another HIV drug approved for PWH with MDR: ibalizumab (brand name Trogarzo), a monoclonal antibody given as an injection every other week, was approved in 2018. Beyond ibalizumab, fostemsavir (brand name Rukobia), an oral drug that binds to the HIV envelope and prevents virus entry, has been successful when paired with other meds.
In the future, PLWH with MDR may find new treatment options from broadly neutralizing antibodies (bNAbs) which can recognize and prevent a broad range of HIV strains from entering healthy cells. Gilead is studying LEN with a two bNAb combination, and presented phase two study findings at CROI last year. ViiV is looking at combining cabotegravir with bNAb combinations for treating virally-suppressed PLWH, and the company presented the most recent data at CROI 2024.
When combined with other drugs with higher barriers to resistance, like LEN or fostemsavir, there might be a role for bNAbs in those highly treatment experienced with MDR, Kuritzkes said
“I think we’re several years from bNAbs being approved for use in treatment,” he added, noting that the viral envelope that bNAbs target is highly variable and much larger than other proteins. “So it’s harder to predict susceptibility or resistance based on genotype and therefore harder to sequence.”