Dolutegravir in Women

In a study called Aria, researchers tested the following two regimens with nearly 500 HIV-positive women:

• Triumeq -- one pill that contains dolutegravir + abacavir + 3TC
• atazanavir (Reyataz) + ritonavir + tenofovir DF + FTC

Women who entered the study had not previously used anti-HIV drugs.

After 48 weeks, 82% of Triumeq users and 71% of women taking an atazanavir-based regimen had a viral load less than 50 copies/mL. This difference gave Triumeq statistical superiority over the atazanavir-containing regimen. This was driven in part by more participants who took atazanavir dropping out for reasons due to side effects.

Study Details

Researchers from many countries, including Canada, Spain, South Africa, Russia, Thailand, the U.S. and elsewhere, screened 705 volunteers but found only 495 who were suitable for the study. They then randomly assigned these 495 women to receive one of the study regimens as follows:

• Triumeq
• an atazanavir-based regimen

Participants knew which treatment they received, as there were no placebos used.

The average profile of participants upon entering the study was as follows:

• age -- 37 years
• main ethno-racial groups: white -- 44%; black -- 42%; Asian -- 9%
• 85% of participants had no symptoms of HIV disease
• HIV viral load -- 32,000 copies/mL
• CD4+ count -- 375 cells/mm³
• 7% had been exposed to hepatitis C virus

The main part of the study lasted for 48 weeks. After this time, participants who were already taking Triumeq continued to receive the drug from the study sponsor, ViiV Healthcare (which also makes Triumeq), until Triumeq was approved in their country. We will report on the results up to the 48th week of the study.

Results -- Effectiveness

As mentioned earlier, at week 48 of the study 82% of the women taking Triumeq and 71% of those taking an atazanavir-based regimen had a viral load less than 50 copies/mL.

Here is what happened to the remaining participants:

Virological non-response (these participants either did not get their viral load below the 50 copy mark and/or they did but were unable to keep it there):

• Triumeq -- 6%
• atazanavir-based regimen -- 14%

There was no virological data (usually because participants left the study prematurely) for the following participants:

• Triumeq -- 12%
• atazanavir-based regimen -- 15%

High Viral Loads at Baseline

Among participants who entered the study with a high viral load (more than 100,000 copies/mL), here are the proportions with a suppressed viral load (less than 50 copies/mL) at week 48:

• Triumeq -- 80%
• atazanavir-based regimen -- 64%

Among participants who entered the study with a low CD4+ count (350 or fewer cells), here are the proportions with a suppressed viral load at week 48:

• Triumeq -- 85%
• atazanavir-based regimen -- 72%

Adverse Events

The term adverse events covers a broad range of unfortunate health-related incidents that can occur during a clinical trial. Some of these incidents may be related to drug side effects. However, some adverse events could be related to the underlying infection, disease process or even, in some cases, events outside the clinical trial, such as an accident.

Overall adverse events of moderate, severe or very severe intensity were distributed as follows:

Nausea

• Triumeq -- 13%
• atazanavir-based regimen -- 14%

Diarrhea

• Triumeq -- 5%
• atazanavir-based regimen -- 7%

Indigestion

• Triumeq -- 2%
• atazanavir-based regimen -- 6%

Headache

• Triumeq -- 2%
• atazanavir-based regimen -- 6%

Yellowing of the whites of the eyes (ocular icterus)

• Triumeq -- 0%
• atazanavir-based regimen -- 7%

Yellowing of the skin (Jaundice)

• Triumeq -- 0%
• atazanavir-based regimen -- 5%

The proportion of participants who left the study because of side effects was distributed as follows:

• Triumeq -- 4%
• atazanavir-based regimen -- 7%

One woman who was taking Triumeq died and investigation revealed that her death was not related to the study medicines.

Focus on Mental Health

Dolutegravir belongs to a class of anti-HIV drugs called integrase inhibitors. All integrase inhibitors have been associated with reports of mental health issues (usually sleeping problems, anxiety and/or depression) in a small proportion of patients who use them. Researchers are not sure why some people develop this side effect.

In previous clinical trials, rates of neuro-psychiatric side effects among dolutegravir users were relatively low, usually between 2% and 4%. Since the licensure of dolutegravir several years ago (in Trivicay and Triumeq) there have been reports of mental health issues in a minority of participants who used this drug. Unfortunately, many of these reports arise from studies that were not robustly designed, so drawing firm conclusions from them about the use of dolutegravir and possible mental health issues is fraught with difficulty. Also, depression and anxiety are relatively common issues among HIV-positive people regardless of the type of treatment they take.

In Aria, the overall distribution of neuro-psychiatric side effects was as follows:

• Triumeq -- 14%
• atazanavir-based regimen -- 14%

The distribution of specific neuro-psychiatric side effects was as follows:

Difficulty falling asleep or staying asleep

• Triumeq -- 4%
• atazanavir-based regimen -- 4%

Anxiety

• Triumeq -- 2%
• atazanavir-based regimen -- 3%

Depressive illness (includes depression and related problems)

• Triumeq -- 3%
• atazanavir-based regimen -- 4%

Thoughts of suicide

• Triumeq -- 2%
• atazanavir-based regimen -- 1%

Panic attacks

• Triumeq -- less than 1%
• atazanavir-based regimen -- less than 1%

Agitation

• Triumeq -- less than 1%
• atazanavir-based regimen -- 0%

Bipolar illness

• Triumeq -- less than 1%
• atazanavir-based regimen -- 0%

There were no reports of the following neuro-psychiatric issues:

• confusion
• hallucinations
• psychosis
• suicide

Based on the results of Aria, about 14% of women who used Triumeq or an atazanavir-based regimen developed mental health issues, mostly related to problems with sleep, anxiety or depression.

Reference

Orrell C, Hagins D, Belonosova E, et al. Superior efficacy of dolutegravir/abacavir/lamivudine FDC compared with ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate/emtricitabine FDC in treatment-naïve women with HIV-1 infection: Aria study. In: Program and abstracts of the 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa. Abstract THAB0205LB.