Scientists in South Africa and Cameroon conducted two randomized clinical trials of dolutegravir-based regimens. These trials have yielded important safety information as well as data about weight gain. The findings from these studies confirm general trends that we will report on later in this issue of TreatmentUpdate.

The ADVANCE study in South Africa

In South Africa, scientists conducted a randomized 96-week study of the following once-daily regimens used to initiate HIV treatment (ART):

• dolutegravir + TDF (tenofovir disoproxil fumarate) + FTC
• dolutegravir + TAF (tenofovir alafenamide) + FTC
• efavirenz + TDF + FTC

Study coordinators enrolled 1,053 HIV-positive people who initiated ART with one of the above regimens. Notably, nearly 60% of participants in ADVANCE were women and 99% were black.

Results

Not surprisingly, all three regimens worked well. We won’t explore the effects of the medicines on viral load and CD4+ cell count, as such effects have been well established in clinical trials beginning nearly a decade ago for dolutegravir and even longer for efavirenz. Instead, we focus on some safety issues and weight.

Sleep

Overall, dolutegravir-containing regimens were well tolerated. There were generally no significant differences in sleep quality and the time spent sleeping among the different regimens. However, the scientists stated that “there were slightly more reported cases of [severe or very severe] insomnia in the TAF-based group than in the other groups but no discontinuation of the trial regimen due to insomnia.”

Fetal safety

As detailed in TreatmentUpdate issue 233, there have been reports of five babies born to HIV-positive mothers in the southern African country of Botswana who were born with a type of birth defect called neural tube defects. All mothers were taking dolutegravir at the time of conception.

In the ADVANCE study, a total of 78 women became pregnant; 50 of them were taking dolutegravir during pregnancy. None of their babies were born with neural tube defects. Ten percent of the pregnancies are ongoing.

Focus on weight

According to the scientists, “absolute weight gain and the percentage of patients in whom obesity emerged during treatment were highest in the TAF-based group (6 kg, 14% new obesity), but the values in the TDF-based group (3 kg, 7% new obesity) were also higher than those in the standard-care group [efavirenz: 1 kg, 6% new obesity].”

Furthermore, scientists added that “weight gain was significantly higher in female than in male patients across all three groups with no clear plateau in the increase.”

Obesity tended to occur by week 48 and was associated with the following factors upon study entry:

• lower CD4+ cell count
• higher viral load
• older age

ANRS 12313 (NAMSAL)

In Cameroon, another randomized clinical trial called NAMSAL enrolled 613 HIV-positive people, a majority of whom (66%) were women. All participants were initiating ART that consisted of one of the following regimens:

• dolutegravir + TDF + 3TC
• low-dose efavirenz (400 mg) + TDF + 3TC

All medicines were taken once daily and data were reported after 48 weeks.

Results—Focus on weight gain

On average weight gain was observed in more participants who took dolutegravir than low-dose efavirenz, as follows:

• dolutegravir – 5 kg; 12% new obesity
• efavirenz – 3 kg; 5% new obesity

A total of 25 women became pregnant during the study, 13 who were taking dolutegravir and 12 who were taking efavirenz. No birth defects were found in their infants.

Putting it all together

The data from ADVANCE and NAMSAL show that commonly used regimens in parts of sub-Saharan Africa these days are associated with weight gain, in particular, the combination of dolutegravir and TAF. However, other factors also associated with weight gain were as follows:

• lower CD4+ cell count
• higher viral load
• older age

The fact that having a lower CD4+ cell count and a higher viral load were both associated with weight gain suggests that HIV does something to the immune system that increases the risk of weight gain. This finding is yet another reason to initiate ART early in the course of HIV infection.

—Sean R. Hosein

REFERENCES:

1. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to Treat HIV. New England Journal of Medicine. 2019 Aug 29;381(9):803-815.
2. NAMSAL ANRS 12313 Study Group, Kouanfack C, Mpoudi-Etame M, Omgba Bassega P, et al. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1. New England Journal of Medicine. 2019 Aug 29;381(9):816-826.
3. Havlir DV, Doherty MC. Global HIV treatment - Turning headwinds to tailwinds. New England Journal of Medicine. 2019 Aug 29;381(9):873-874.