Doravirine/islatravir non-inferior to Biktarvy as first-line treatment

A once-daily combination of doravirine and islatravir was non-inferior to the three-drug combination of bictegravir, emtricitabine and tenofovir alafenamide (Biktarvy) as a first-line antiretroviral regimen in an international trial, Professor Jürgen Rockstroh of the University of Bonn reported last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) in Denver.

Islatravir is a new type of antiretroviral drug, a nucleoside reverse transcriptase translocation inhibitor, which works differently from previous nucleoside reverse transcriptase inhibitors (NRTI).

Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI), already licensed as Pifeltro.

Merck began human studies of islatravir over 10 years ago, but the US Food and Drug Administration froze development of the drug in 2021 after a study showed that participants taking a once-weekly dose of 2.25mg islatravir experienced declines in CD4 counts. Studies of daily treatment with doravirine/islatravir at an islatravir dose of 0.75mg suggested that islatravir suppressed lymphocyte production. Eventually, studies of doravirine/islatravir resumed, using a 0.25mg islatravir dose that does not suppress lymphocyte production.

At CROI 2026, Rockstroh presented results of a phase 3 study comparing daily doravirine/islatravir (DOR/ISL) to daily bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF).

The study excluded people with previous HIV treatment experience and people who had acquired HIV with either major NNRTI or NRTI resistance mutations. People with active hepatitis B were also ineligible to join the study.

The study randomised 536 participants to receive a once-daily regimen consisting of either doravirine 100mg/islatravir 0.25mg, or BIC/F/TAF.

Study participants had a median age of 32 years, 25% were female, 31% were Black or African American, 10% were Asian and 39% had Hispanic or Latin ethnicity. The median CD4 cell count of participants was 370 (17% had a count below 200). The median viral load at study entry was 55,000; 36% of participants had a viral load above 100,000 and 10% had a viral load above 500,000.

The study recruited participants in 20 countries; 20% participated at sites in Africa, 25% in Latin America, 21% in the United States, 18% in Europe, and 13% in Asia.

The primary outcome of the study was the proportion of participants in each study arm with viral load below 50 at week 48.

At week 48, 91.8% of the DOR/ISL group and 90.6% of the BIC/F/TAF group had viral load below 50; 2.2% in the DOR/ISL group and 3.4% in the BIC/F/TAF group had viral load above 50. In the remaining cases, participants did not attend the week 48 clinic visit.

Two participants in the DOR/ISL study arm developed resistance mutations associated with the study drugs. Both developed high-level resistance to doravirine (Y188L and V106A mutations, respectively) and mild resistance to islatravir (M184V/I mutations). No one in the BIC/F/TAF arm developed resistance.

Both participants who developed resistance had viral loads above 1 million and CD4 counts below 200 on study entry. In one, viral load declined to 300,000 but rebounded to 951,000 by week 16. Testing showed low blood levels of doravirine and islatravir at week 8, suggesting non-adherence to study medication between weeks 4 and 8. In the other participant, viral load was suppressed to 500 but rebounded to 224,000 at week 24 despite adequate concentrations of both study drugs. Rockstroh said it was impossible to rule out the presence of drug resistance mutations at undetectable levels.

There was no significant difference in virological response between the study arms by baseline viral load or CD4 count. The presence of minor NNRTI or NRTI resistance mutations did not affect virological response.

Participants in each study arm experienced similar increases in CD4 count (+218 in the DOR/ISL arm vs +226 in the BIC/F/TAF arm), indicating that islatravir at a dose of 0.25mg does not restrict lymphocyte production.

Both study regimens were well tolerated, with few drug-related serious adverse events occurring in participants. One participant in the DOR/ISL study group experienced a drug reaction with systemic symptoms, while another participant experienced drug-induced liver injury. The most common drug-related adverse events were weight gain (2.6% vs 3.4%, DOR/ISL vs BIC/F/TAF), headache (2.2% vs 3.4%), reduced kidney function (decreased eGFR) (0.7% vs 3.0%) and abdominal distention (0.4% vs 2.2%), each occurring in less than 3% of participants.

There was no significant difference in weight gain at week 48 between participants receiving DOR/ISL (+3.6kg) and BIC/F/TAF (+3.9kg).

Three participants in the DOR/ISL study group acquired hepatitis B during the trial. In two cases, hepatitis B core antibody was detected after liver enzyme (ALT) elevations and DOR/ISL treatment continued. In the third case, HBV DNA was detected, and the participant switched to BIC/F/TAF, as TAF is active against hepatitis B.

Commenting on hepatitis B acquisition in study participants, Professor Anton Pozniak of London’s Chelsea and Westminster Hospital said that trial protocols should mandate hepatitis B vaccination in any study evaluating an antiretroviral regimen that doesn’t contain tenofovir.

Concluding the presentation of the results, Rockstroh said that doravirine/islatravir offered a two-drug, integrase inhibitor-sparing option for first-line treatment. The combination had proved highly effective in people with high viral load and low CD4 counts, he pointed out.

But during a discussion on the conference highlights, Professor Paul Sax of Harvard Medical School questioned whether the study results showed any unique advantage to the doravirine/islatravir combination. “It was non-inferior, but there was no advantage found, in fact, there were some disadvantages. There was a tiny bit of resistance, M184V emerged, there were some hepatitis B issues, there was certainly no metabolic benefit.”

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