Doravirine is an experimental non-nuke that is undergoing phase III clinical trials. It is designed to be effective against most strains of HIV that are resistant to other non-nukes, such as the following:

• efavirenz (Sustiva, Stocrin and in Atripla)
• nevirapine
• rilpivirine (Edurant and in Complera)

Doravirine can be dosed once daily with or without food. In addition to being developed in a 100-mg pill, doravirine is also being developed as a fixed-dose formulation with the following two drugs:

• tenofovir DF (Viread and in Truvada and many other combinations)
• 3TC (lamivudine and in Triumeq and many other combinations)

Merck, the developer of doravirine, recently conducted a randomized, placebo-controlled study comparing regimens based on doravirine to regimens based on darunavir (Prezista and Prezcobix). Darunavir is the leading protease inhibitor used in high-income countries today. It has to be taken with a small dose of another drug, ritonavir (Norvir), which helps to boost or maintain levels of darunavir in the blood so that it can be taken only once daily. In its clinical trial Merck found that doravirine was roughly equivalent in potency to darunavir-based regimens.

Study details

Upon entering the study the average profile of participants was as follows:

• no participants had previously used HIV drugs  and no participants were infected with HIV that was resistant to doravirine or darunavir
• age – 35 years
• 84% men, 16% women
• 10% had symptoms of AIDS in the past
• 70% had the strain of HIV that is most common in North America and Western Europe – subtype B
• viral load – 25,000 copies/mL
• 20% of participants had a viral load greater than 100,000 copies/mL
• CD4+ count – 422 cells/mm³
• 14% of participants had a CD4+ count of 200 cells/mm³ or less

The nukes used in this study were as follows:

• tenofovir DF + FTC
• abacavir + 3TC

Data were released on study participants after one year. Their distribution was as follows:

• doravirine-based regimen – 327 people
• darunavir-based regimen – 312 people

The study will continue for two years.

Results—Changes in viral load and CD4+ cell counts

Overall, after one year, the proportions of participants who had a viral load less than 50 copies/mL were distributed as follows:

• doravirine-based regimens – 84%
• darunavir-based regimens – 80%

Statistical analysis found that both regimens are roughly equivalent (the technical term for this is non-inferior).

The following proportions of participants were unable to keep their viral load suppressed:

• doravirine-based regimens – 11%
• darunavir-based regimens – 13%

Data from the remaining participants was not yet available.

Among participants who entered the study with a viral load greater than 100,000 copies/mL, the proportions with a suppressed viral load at week 48 were as follows:

• doravirine-based regimens – 81%
• darunavir-based regimens – 76%

Among participants who entered the study with a CD4+ count greater than 200 cells/mm³, the proportions that were virologically suppressed at week 48 were as follows:

• doravirine-based regimens – 89%
• darunavir-based regimens – 89%

Among participants who entered the study with a CD4+ count between 51 and 200 cells/mm³, the proportions with a suppressed viral load at week 48 were as follows:

• doravirine-based regimens – 83%
• darunavir-based regimens – 74%

Among participants who entered the study with a CD4+ count of 50 or less cells/mm³, the proportions with a suppressed viral load at week 48 were as follows:

• doravirine-based regimens – 83%
• darunavir-based regimens – 67%

CD4+ cell counts increased over the course of the study. Below are the average increases in e cell counts for each regimen by week 48:

• doravirine-based regimens – 193 cells/mm³
• darunavir-based regimens – 186 cells/mm³

This difference in CD4+ cell counts was not statistically significant.

Side effects

About 30% of all participants experienced side effects; this is relatively common when people begin HIV treatment in or out of clinical trials. In most cases, side effects should fade after a few weeks. However, 2% of participants on doravirine and 3% on darunavir had to quit the study due to side effects.

Common side effects were distributed as follows:

Diarrhea

• doravirine-based regimens – 14%
• darunavir-based regimens – 22%

Nausea

• doravirine-based regimens – 11%
• darunavir-based regimens – 12%

Headache

• doravirine-based regimens – 11%
• darunavir-based regimens – 14%

Rash

• doravirine-based regimens – 7%
• darunavir-based regimens – 8%

Focus on the brain

All non-nukes are based on a chemical structure distantly related to Valium-type drugs. This means that they can get inside the brain, which is a sanctuary for HIV. However, it also means non-nukes have the potential to cause brain-related side effects (also called neuropsychiatric side effects). As an example, efavirenz was a first-generation non-nuke that is notorious for causing brain-related side effects. Examples of brain-related side effects include the following:

• concentration problems
• confusion
• dizziness
• difficulty falling asleep and/or staying asleep
• vivid dreams
• in rare cases depressive illness

We do not have detailed information about brain-related side effects from this study.

The overall distribution of brain-related side effects was as follows:

• doravirine-based regimens – 11%
• darunavir-based regimens – 13%

No participant left the study because of these side effects.

Abnormal lab test results

Analysis of blood samples from participants detected few severe abnormalities. If abnormal test results did occur, for the most part they were generally of mild to moderate intensity.

Here is the distribution of severely abnormal elevated blood test results:

LDL-C (“bad cholesterol”)

• doravirine-based regimens – less than 1%
• darunavir-based regimens – 3%

Blood sugar

• doravirine-based regimens – 1%
• darunavir-based regimens – less than 1%

AST (a liver enzyme)

• doravirine-based regimens – 1%
• darunavir-based regimens – 3%

ALT (a liver enzyme)

• doravirine-based regimens – 1%
• darunavir-based regimens – 2%

Creatinine (used to assess kidney health)

• doravirine-based regimens – 1%
• darunavir-based regimens – 3%

Creatine kinase (sometimes called creatinine phosphokinase)

Elevated levels of creatine kinase indicate that muscle inflammation and injury may be occurring. However, given the low levels of this issue found in this study (regardless of the regimen used) and that there were no complaints about muscle pain, it is unlikely that this was a problem.

• doravirine-based regimens – 2%
• darunavir-based regimens – 2%

More about cholesterol and triglycerides

Over the long-term, elevated levels of LDL-C are associated with an increased risk for cardiovascular disease. In the present study, when analyses were done on blood samples for their lipid (cholesterol and triglyceride) levels, researchers asked participants to fast before the samples were collected. As a result of deeper analysis of lipid levels, researchers found that there was a small but significant increase in LDL-C levels among participants taking darunavir. In contrast LDL-C levels fell modestly in doravirine users. Triglycerides also rose among darunavir users but declined in doravirine users.

Levels of HDL-C (“good cholesterol”) rose modestly in participants regardless of which study drug they used.

Summary

Overall, the study shows that doravirine is not inferior to darunavir and is a potent and highly effective treatment, particularly for people who are initiating HIV therapy, with only some participants experiencing side effects.

—Sean R. Hosein

REFERENCE:

Molina J-M, Squires K, Sax P, et al. Doravirine is non-inferior to darunavir + ritonavir in a phase 3 treatment-naïve trial at week 48. Conference on Retroviruses and Opportunistic Infections. 13-16 February 2017, Seattle. Abstract 45 LB.