A South African clinical trial that compared various combinations of anti-HIV drugs has linked two popular antiretrovirals (ARVs) to massive weight gain in women, at an average of 5 kilograms per year. The unexpected weight gain, which was far less pronounced in male participants, has researchers combing through the trial data to better understand why the drugs caused people to put on weight. What this means for patients outside of the trial is unclear, but some doctors say they’ll be more cautious about prescribing the combo, which is not yet available in South Africa but is a first-line treatment in the United States.

“Some of the people have gained so much weight that doctors have gone into the waiting rooms and not even recognized their patients,” says Andrew Hill, a statistician at the University of Liverpool in the United Kingdom, and one of the study’s lead authors. “The worry we have is there’s no sign of plateau [with the weight gain], and we don’t know where it’s going to end.”

Concerns about weight gain have surrounded many ARVs. It has long been difficult to sort out a drug’s side effects from the “return to health” effect that many people experience as they rebound from uncontrolled HIV infections. The largest weight gain with treatment often accompanies the most dramatic recovery, and it often occurs in people who have suffered the most immune damage and weight loss from HIV.

The new study, which took place in Johannesburg, South Africa, recruited just over 1000 HIV-infected participants—all but two were black, and 59% were women. The study randomly assigned them to one of three treatment regimens with three ARVs each. Women in one group, who were given dolutegravir, emtricitabine (FTC), and tenofovir alafenamide (TAF) gained on average 10 kilograms over 96 weeks, researchers reported at the International AIDS Conference in Mexico City last month. (Results from 48 weeks of data were published on 24 July in The New England Journal of Medicine.) “That’s 10 years of weight gain in 2 years,” Hill says.

Men taking the same drug regimen, in contrast, gained 5 kilograms after 48 weeks and then saw their weight stabilize. “This was a really unexpected side effect,” says Francois Venter, a clinician at the University of the Witwatersrand in Johannesburg who led the study.

A second group replaced TAF with tenofovir, an older formulation that requires far higher dosing and can cause kidney damage and bone loss. Weight gain was modest in that group over the 96 weeks—5 kilograms in women and 4 kilograms in men. The third group used the standard of care in South Africa, which is tenofovir, FTC, and efavirenz. In that group, women gained 3 kilograms and men lost 2 kilograms after 96 weeks. (FTC was not considered a factor in weight gain because it was used in all three arms of the study.)

Dolutegravir and TAF, which cripple different enzymes that HIV uses to copy itself, are considered state-of-the-art ARVs and are first-line treatments in the United States. In South Africa, dolutegravir is widely used, but TAF is not. Venter says that unlike tenofovir, TAF doesn’t require expensive monitoring of kidney function.

The new findings have caused widespread concern, including in the United States, where some doctors say they now will be cautious when prescribing dolutegravir with TAF.  “We need more data on the weight gain issue, given the potential for harm if increasing obesity leads to a large increased risk of other chronic diseases,” such as diabetes, hypertension, and heart disease, says HIV/AIDS clinician Rebecca Zash of Beth Israel Deaconess Medical Center in Boston. Zash, who also works in Botswana, says this is especially true in places where the infrastructure to treat such diseases is lacking.

Researchers are perplexed by what might be causing the weight gain, and there’s no evidence that it has occurred in female populations outside of Africa. In some studies, dolutegravir has been shown to increase appetite, but in others, tenofovir has been linked to weight loss. One possibility, researchers say, is that using TAF instead of tenofovir took away the countereffect of dolutegravir.

Part of the gain could be due to the return-to-health effect, say representatives of the drugmakers, ViiV Healthcare of London and Gilead Sciences, Inc. of Foster City, California. However, ViiV and Gilead spokespeople both told Science that South Africa’s high incidence of female obesity will make it difficult to sort out how much of the weight gain is linked to the drugs, versus other causes.

David Piontkowsky, who heads Gilead’s research into drugs already on the market, says another “huge caveat” is that the 96-week analysis looked at only 25% of the participants because most had not received that many weeks of treatment. “It’s an incomplete picture,” he says.

Venter says he hopes to investigate the kind of weight that patients gained. For example, visceral fat (which collects around the midsection) is strongly associated with heart problems and diabetes. The researchers will analyze fat distribution through bone scans, which the study already has performed. Venter adds that his team needs longer-term data to assess impacts on blood pressure and levels of lipids and glucose in the blood.

But the weight gain, from the patients’ perspectives, is not necessarily a bad thing, Venter says. A survey of 51 women in the study found that 84% were happy with their additional weight. But if weight gain continues and causes health problems, he notes, this perception may well change.