Weight Gain on INSTI-based HIV Antiretrovirals

Heather Boerner

July 26, 2019

MEXICO CITY — Michelle Moorhouse, MB BCh, from Wits Reproductive Health and HIV Institute, like many other physicians, started to notice that the numbers on the scale kept going up for her patients who were taking integrase inhibitors.

"We need to introduce some lifestyle interventions," she told these patients. But as a researcher at the University of the Witwatersrand in Johannesburg, she also knew that bigger datasets could tell her whether what she was seeing in her own clinic was a larger issue.

As part of the OPTIMIZE consortium, Moorhouse works with a group run by ICAP at Columbia University in New York City that seeks to simplify and make HIV treatments accessible.

The consortium's ADVANCE trial is looking for a universal first-line HIV treatment regimen and was designed to examine three HIV drug combinations (Curr Opin HIV AIDS. 2017;12:351-354).

The medications under evaluation are dolutegravir (Tivicay, GlaxoSmithKline) plus the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead Sciences); dolutegravir plus the combination of emtricitabine and tenofovir disoproxil fumarate (Truvada, Gilead); and efavirenz (Sustiva, Bristol-Myers-Squibb) plus Truvada.

Speaking from the podium here at the International AIDS Society (IAS) 2019 Conference on HIV Science, Moorhouse explained that "a real flurry" of reports started coming in about tenofovir alafenamide and dolutegravir being associated with weight gain.

New data from the ADVANCE trial presented at the meeting showed that both the dolutegravir plus Descovy group and the Descovy plus Truvada group were as effective as the efavirenz group, but with fewer adverse effects than in the efavirenz group.

So the ADVANCE team worked with researchers from the New Antiretroviral and Monitoring Strategies in HIV Infected Adults in Low-income countries (NAMSAL) trial (NCT02777229) to pull together all the weight-gain data accrued from their combined cohort of 1666 participants.

And they found a consistent story.

In NAMSAL, weight gain was higher in the dolutegravir group than in the efavirenz group (5 kg vs 3 kg; P ≤ .001), and the mean increase in body mass index was greater in the dolutegravir group (1.7 vs 1.2 kg/m2; P ≤ .001).

In ADVANCE, weight gain was even more pronounced, but the pattern was the same: participants in the dolutegravir plus Descovy group gained more weight over 96 weeks than those in the dolutegravir plus Truvada group (8 kg vs 5 kg).

Table. Weight Gain in the NAMSAL and ADVANCE Trials
Outcome by Regimen Change in Weight, kg Treatment-Emergent Excess Weight, % Treatment-Emergent Obesity, %
Tenofovir disoproxil fumarate plus lamivudine plus dolutegravir
48 weeks +5 16 12
Tenofovir disoproxil fumarate plus lamivudine plus efavirenz
48 weeks +3 17 5
Descovy plus dolutegravir
48 weeks +6 23 14
96 weeks +8 25 19
Truvada plus dolutegravir
48 weeks +3 14 7
96 weeks +5 13 8
Tenofovir disoproxil fumarate plus emtricitabine plus efavirenz (Atripla, Gilead)
48 weeks +1 9 6
96 weeks +2 11 4

A previous observational study suggested that integrase inhibitors are associated with weight gain (J Virus Erad. 2019;5:41-43), but the data presented by Moorhouse show that weight gain is not spread evenly across the population. All participants gained weight initially, but the women continued to gain and, so far, it hasn't stopped, she reported."There was a statistically significant increase with dolutegravir regimens," Moorhouse reported. And "participants experienced even higher changes in weight," particularly in the tenofovir alafenamide group.

In NAMSAL, men gained at least 10% of their body weight but the change was not significant; however, 44% of women in the dolutegravir groups saw their weight increase by at least 10%, which was significant. Only 34% of women in the efavirenz saw the same thing.

In ADVANCE, men gained about 4 kg or 5 kg, depending on the regimen. "That continued until week 48, after which the increases seem to plateau," Moorhouse explained.

"There was an increase in mean weight and mean body fat in the female participants who received the dolutegravir regimens, and that was particularly high in the tenofovir alafenamide group. Unlike in men, those changes progressed beyond week 48 and seem to be continuing beyond week 96."

By 96 weeks, women had gained a mean of 10 kg, or 22 pounds.

It is too soon to make any decisions about treatment on the basis of these findings, Moorhouse noted.

"The trouble is trying to tease out what it is," she said. "Is there a protective effect of TDF? Is there an aggravating effect of TAF? I think we just don't know enough."

The same questions occurred to Carlos del Rio, MD, from Emory University in Atlanta.

"It's so interesting," he said. "Clearly DTG regimens increase weight gain, more in women than in men, and it is higher when you have TAF with DTG. We need to understand why this is happening metabolically."

But when it comes to his practice, he said he will start sharing with patients that the regimens have been shown to be associated with increased weight gain. "You just need to have that discussion with patients. These data emphasize that communication is key and that patients need to be partners."

Implications for Trial Design

Steven Deeks, MD, from the University of California, San Francisco, said he has always been a traditionalist when it comes to designing clinical trials for HIV. "We always assumed that if it worked in men, it would probably work well in women," he explained.

But the data showing that weight gain was higher and lasted longer in women than in men taking integrase inhibitors and the nucleoside analog tenofovir alafenamide — along with additional data on neural tube defects in women taking dolutegravir at conception — have changed his mind.

"I've never seen such a dramatic series of studies showing that gender, and perhaps ethnicity, has an impact on how these drugs work," Deeks told Medscape Medical News. "My viewpoint changed dramatically at this meeting."

NAMSAL is funded by ANRS. ADVANCE was funded by USAID, Unitaid, and South Africa MRC. Moorhouse reports receiving speaker fees and honoraria from Gilead Sciences, AbbVie, Cipla, Johnson & Johnson, Sanofi, Pfizer, ViiV Healthcare, Milan, and Southern African HIV Clinicians Society. del Rio reports consulting for ViiV Healthcare and InnaVirVax. Deeks has disclosed no relevant financial relationships.

International AIDS Society (IAS) 2019 Conference on HIV Science: Abstract MOAX0102LB. Presented July 22, 2019.

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