Studies confirm non-inferiority of doravirine / islatravir to standard HIV treatment

Two clinical trials presented last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco show that a two-drug regimen of doravirine / islatravir is non-inferior to commonly prescribed HIV drug combinations in maintaining viral suppression in adults with HIV.

Islatravir is a new type of antiretroviral drug, a nucleoside reverse transcriptase translocation inhibitor, which works in a different way from previous drugs of the nucleoside reverse transcriptase inhibitor class.

Islatravir development has been complicated by the discovery that doses of the drug of 2.25mg or higher cause lymphocyte suppression. Previous phase 3 studies of doravirine / islatravir in previously untreated people used an islatravir dose of 0.75mg a day. This did not cause lymphocyte reductions but nor did lymphocyte levels increase, as would be expected after starting antiretroviral treatment. New phase 3 studies, using an islatravir dose of 0.25mg a day, were launched in 2023 to determine whether a lower dose of the drug could be used without an increased risk of treatment failure.

At CROI 2025, researchers presented the results of the two phase 3 studies using the lower islatravir dose, in which people with HIV on stable and suppressive regimens were randomised to switch to doravirine / islatravir or continue taking their existing treatment.

Switching from Biktarvy

In the first study, presented by Dr Amy Colson of Community Research Initiative, Boston, people with HIV taking one of the most commonly prescribed regimens, Biktarvy (bictegravir / emtricitabine / tenofovir alafenamide) were randomised to continue taking their existing treatment or switch to doravirine / islatravir (100mg/0.25mg) once daily.

The phase 3, double-blind study enrolled 513 participants who had maintained virologic suppression for at least three months on Biktarvy. They were randomised 2:1 to either switch to doravarine / islatravir or continue their current regimen.

Study participants had a median age of 47 years, 30% were Black or African American, 60% were White, and 21% were female. Participants had been diagnosed with HIV for a median of 11 years. A quarter of participants were positive for hepatitis B core antibody.

At week 48, 1.5% of those on doravarine / islatravir had viral load above 50 copies/ml compared to 0.6% in the Biktarvy group, a non-significant difference. Two of the five people taking doravarine / islatravir with viral loads above 50 copies/ml had viral loads above 200 copies/ml. None developed resistance to doravirine or islatravir.

Most participants maintained viral suppression, with 91.5% in the doravarine / islatravir group and 94.2% in the Biktarvy group achieving viral load below <50 copies/ml. Data were missing at the week 48 visit for 7% of the doravarine / islatravir group and 5.3% of the Biktarvy group.  Drug-related adverse event rates were comparable (10.2% vs. 9.4%), with 1.2% discontinuing due to side effects in each study arm.

There were no significant differences in changes in total lymphocyte or CD4 lymphocytes at week 48 between study arms.

No cases of clinical hepatitis B reactivation were observed in the doravarine / islatravir arm but two people developed low-level hepatitis B viraemia (HBV DNA <50 copies/ml) without antigenemia or elevated liver enzymes. Two people in the doravarine / islatravir arm who were negative for hepatitis B core antibody and surface antibody were diagnosed with acute hepatitis B virus infection during the study.

Switching from 3-drug or 2-drug regimens

In the second study, presented by Professor Chloe Orkin of Queen Mary University of London, people with HIV with suppressed viral load taking three- or two-drug antiretroviral regimens were randomised to continue taking their existing treatment or switch to doravarine / islatravir  (100mg/0.25 mg).

The phase 3 trial enrolled 551 participants who had been virally suppressed for at least three months. They were randomised 2:1 to either switch to doravarine / islatravir (100mg/0.25 mg) or continue their existing treatment.

Study participants had a median age of 51 years, 45% were Black or African American, 30% were White, and 39% were female. Participants had been diagnosed with HIV for a median of 13 years. Twenty-nine per cent of participants were positive for hepatitis B core antibody.

Approximately two-thirds (64%) had been taking an integrase inhibitor and 30% had been taking a non-nucleoside reverse transcriptase inhibitor prior to enrolment.

At week 48, 1.4% of those on doravarine / islatravir had HIV-1 RNA ≥50 copies/ml compared to 4.9% in the baseline ART group, a non-significant difference. Viral suppression (<50 copies/ml) was achieved in 95.6% of those on doravarine / islatravir and 91.9% of those on pre-existing treatment.

Two participants who discontinued doravarine / islatravir due to viraemia were found to have pre-existing drug resistance mutations in proviral DNA, dating back to early HIV treatment, though these did not affect integrase inhibitors. Three participants discontinued after the week 48 visit, one with the NNRTI resistance mutation V90I (present in baseline proviral DNA sample) and one with the T215T/I mutation associated with nucleoside reverse transcriptase inhibitors, but with no effect on susceptibility to islatravir.

Drug-related adverse events were more common with doravarine / islatravir (12.0% vs. 4.9%), but only one participant discontinued, due to diarrhoea.

There were no significant differences in changes in total lymphocyte or CD4 lymphocytes at week 48 between study arms.

One person receiving doravarine / islatravir who was positive for hepatitis B core and surface antibody developed low-level hepatitis B viraemia without antigenemia or elevated liver enzymes during the study.

Twenty-eight per cent of people randomised to doravarine / islatravir had been taking tenofovir disoproxil (TDF) in their previous regimen and an unspecified proportion had been taking efavirenz. TDF and efavirenz are mildly weight suppressive and by week 48, participants assigned to doravarine / islatravir had gained over 2kg more than people continuing an existing regimen that contained TDF and/or efavirenz. But if TDF and/or efavirenz had not been part of the previous or current regimen, the weight gain at week 48 was similar (approximately 0.3kg).

These results support doravarine / islatravir as an alternative to traditional multi-drug regimens, offering a simplified option for people with HIV who have no history of treatment failure or resistance, Professor Orkin concluded.