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Doravirine + low-dose islatravir in a single pill

Doravirine (Pifeltro) is an anti-HIV drug that is approved for combination HIV treatment. Doravirine is available in pill form and is taken once daily in the following medication:

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  • Delstrigo (containing doravirine + TDF + 3TC)

The pharmaceutical company Merck (also known as MSD in some countries) is developing a new doravirine-based medicine that contains two drugs: doravirine + islatravir (nick-named “dora-isla” by some researchers). 

Doravirine belongs to a class of HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs or non-nukes). 

Islatravir belongs to a new class of HIV medicines called translocation inhibitors. It interferes with HIV-infected cells at several points in the viral life cycle. In particular, islatravir interferes with HIV’s ability to use a viral enzyme called reverse transcriptase.

In previous clinical trials with relatively high doses (0.75 mg/day) of islatravir, this drug was found to depress levels of lymphocytes (T and B cells) in the blood as well as CD4+ cells in people with and without HIV. However, subsequent studies with lower doses of islatravir have found it to be safe. We will now focus on the lower doses (0.25 mg/day) of islatravir.

When islatravir is combined with doravirine, the combination has powerful anti-HIV activity in lab experiments with cells and HIV. 

Two recent clinical trials of doravirine (100 mg/day) and islatravir (0.25 mg/day) have been completed in people with HIV. In one of these studies, participants who had been virally suppressed with daily Biktarvy (bictegravir + TAF + FTC) were randomly assigned to receive either continued Biktarvy or once-daily doravirine-islatravir. In this trial, the combination was safe and highly effective. We will mention details about the other trial later.

Study details

Researchers enrolled 513 participants with HIV who were randomly assigned in a 2:1 ratio to receive doravirine-islatravir or Biktarvy for 48 weeks.

The average profile of participants upon study entry was as follows:

  • age – 47 years
  • 78% assigned male at birth; 22% assigned female at birth
  • main ethno-racial groups – White – 61%; Black – 31%; Asian – 6%
  • time since HIV diagnosis – 11 years
  • CD4+ count – 700 cells/mm3
  • all participants had a viral load less than 50 copies/mL

Results

After 48 weeks, the proportion of participants who continued to have a suppressed viral load was distributed as follows:

  • doravirine-islatravir – 92%
  • Biktarvy – 94%

This difference was not statistically significant.

Five people on doravirine-islatravir and one on Biktarvy had a viral load of 50 copies/mL or greater. In two of these people, viral loads were 200 copies/mL or greater. No resistance by HIV to doravirine or islatravir was detected in blood samples from these two people.

No data were available on the remaining participants.

Lab and other tests

Throughout the study, lymphocyte levels continued to rise modestly in participants regardless of which regimen they were taking. On average, CD4+ cell counts rose in participants regardless of study regimen.

One participant taking doravirine-islatravir had a significant decrease in the level of platelets in their blood (needed for clotting). They were withdrawn from the study as a precaution.

Neither doravirine-islatravir nor Biktarvy appeared to cause noticeable and significant side effects. A small proportion of participants on both study medicines had mild and temporary bone pain and fatigue. It is not clear if these were caused by the study medicines or COVID-19.

People who used doravirine-islatravir had, on average, virtually no change in weight or a slight decrease. People who used Biktarvy had a slight increase in weight. This difference between regimens was not meaningful. 

Focus on hepatitis B virus 

Some people with HIV are also chronically coinfected with hepatitis B virus (HBV). In many such cases, doctors prescribe regimens containing drugs that have activity against HIV and HBV to keep both viruses suppressed. Examples of such drugs include:

  • TAF + FTC
  • TDF + FTC
  • TDF + 3TC

Doravirine and islatravir do not have anti-HBV activity; they are only active against HIV. Nevertheless, researchers found that none of the study participants with HIV and HBV who used doravirine-islatravir had their HBV reactivate and cause symptoms of HBV-related illness.

In two people with HBV coinfection who were taking doravirine-islatravir, researchers detected low levels of HBV-infected cells in their blood but no HBV-related proteins or increases in liver enzymes (suggestive of liver inflammation caused by HBV).

Two other people on the same combination who did not have HBV coinfection at the start of the study subsequently developed HBV coinfection. 

No participants on Biktarvy developed low-level HBV coinfection or new HBV co-infection. This is not surprising, as Biktarvy contains TAF + FTC, which have activity against both HIV and HBV.

Bear in mind

The present study found that the combination of doravirine-islatravir was safe and effective for people who were virally suppressed on a regimen of Biktarvy and who were switched to doravirine-islatravir.

There were only two cases of reactivated HBV, which is reassuring. However, the study underscores the need for physicians to screen potential users of doravirine-islatravir to be sure that they do not have active HBV. 

The study also raises the issue of the future role of doravirine-islatravir. While the combination is generally safe and effective, what do doctors do for patients at risk of HBV? 

This is a question that will become increasingly important in the future as more people and their healthcare providers contemplate the use of two-drug regimens for HIV treatment. 

A pill containing doravirine-islatravir meant for once-daily use will hopefully be approved in Canada in 2026. It will provide another treatment option. However, the ideal population that could benefit from doravirine-islatravir is not yet clear.

A second study

In another study, researchers randomly assigned 551 participants on an oral ART regimen in a 2:1 ratio to receive doravirine-islatravir (at the same once-daily dose previously mentioned). After one year, results were broadly similar to the trial discussed in this article. That is, 96% of people on doravirine-islatravir and 92% of those continuing their pre-study regimen had a suppressed viral load. This difference was not statistically significant.

—Sean R. Hosein

REFERENCES:

  1. Colson AE, Mills AM, Ramgopal M, et al. Switch to doravirine/islatravir (100 mg/0.25 mg) once daily from bictegravir/FTC/TAF: a blinded phase 3 study in adults with HIV-1. Program and abstracts of the 32nd Conference on Retroviruses and Opportunistic Infections, March 9-12, 2025, San Francisco. Abstract 204A.
  2. Orkin C, Mngqibisa R, Diego Velez J, et al. Switch to doravirine/islatravir (100 mg/0.25 mg) once daily from oral ART: an open label phase 3 study in adults with HIV-1. Program and abstracts of the 32nd Conference on Retroviruses and Opportunistic Infections, March 9-12, 2025, San Francisco. Abstract 204B.