Weight gain and HIV treatment

Starting antiretroviral treatment leads to improved health, suppression of HIV and restoration of the immune system. In recent years, studies have reported that people living with HIV gain weight after starting HIV treatment. Not everyone gains weight and the amount of weight gained varies.

When HIV-related illness was first recognised, one of the most common symptoms was severe weight loss. When people started highly effective antiretroviral treatment, they gained weight. This is called a ‘return to health’ effect of treatment and is still seen today in people with very advanced HIV who lost weight before starting treatment.

In the early years after highly effective antiretroviral treatment became available (1996-2006), fat loss from the limbs and fat gain in the abdomen were common among people taking antiretroviral treatment. These changes in body fat were known as the lipodystrophy syndrome. Fat loss was associated with treatment with the nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine. Fat gain in the abdomen was associated with treatment with a drug from the protease inhibitor class, especially indinavir, nelfinavir or ritonavir. Newer NRTIs and protease inhibitors have not been associated with these body fat changes, and the lipodystrophy syndrome is rare nowadays in people starting treatment.

Recent reports of weight gain in people new to antiretroviral treatment show that they gain weight in several ways:

• A modest increase in lean muscle mass (this varies between drug combinations)
• Increases in subcutaneous fat (fat beneath the skin)
• Increases in visceral fat (fat around the organs in the abdomen).

Subcutaneous and visceral fat are gained to a similar extent.

How much weight gain is being seen?

Several large clinical trials have reported on weight gain after starting treatment:

• The ADVANCE study compared three different drug combinations. People gained between 0.5kg and 6.4kg over 48 weeks. Women gained more weight than men and people taking TAF with dolutegravir tended to gain more weight (Venter 2019, 2022).
• An analysis of eight large clinical trials found that 17% of participants gained at least 10% in body weight over one to two years (Sax).
• The same analysis found that, on average, people gained 2kg during their first two years on treatment, much of it in the first year.

Studies have also looked at what proportion of people progress from a normal weight to overweight or obese after starting treatment. A normal body weight is classified as a body mass index (BMI) below 25, overweight as between 25 and 30, and obese as a BMI of 30 or above.

A large study in North America found that just over one in five people went from a normal weight to overweight after three years of treatment and a similar proportion went from being overweight to obese in the same time frame (Koethe).

Who is more likely to gain weight?

Clinical trials in North America, Europe and sub-Saharan Africa show that people with low CD4 counts and high viral load at the time of starting treatment gained more weight. As CD4 counts went up on treatment, so did body weight.

Studies have also consistently shown that women gained more weight than men after starting treatment. This difference is most pronounced in people with high viral load and/or low CD4 counts at the time they start treatment (Bares).

Black people gained more weight than other ethnic groups.

People with higher baseline weight were more likely to gain weight after starting treatment.

Older people may be at risk of gaining more weight, but this effect has not shown up in all studies.

Weight gain seems less frequent after switching treatment, although more research is needed on this question. Studies of people who switch to a combination that includes an integrase inhibitor have reported that women and Black people gain more weight after switching than White men and that substantial weight gain is more common in people switching to both TAF and the integrase inhibitor dolutegravir (Bansi-Matharu, McComsey, Mugglin, Palella,Verboeket, Verburgh).

Which drugs have been linked to weight gain?

Weight gain has consistently been greater in people taking antiretroviral drugs introduced in the past ten years (integrase inhibitors, TAF). Greater weight gain is seen in people who start treatment with a combination that contains the integrase inhibitors dolutegravir, bictegravir or elvitegravir, or the NRTI tenofovir alafenamide (TAF) (Sax).  People taking raltegravir were more likely to gain weight when compared to people taking a boosted protease inhibitor (Bhagwat). The protease inhibitor darunavir has also been linked to weight gain in one study, but not in others (Ruderman).

Basic information on a healthy weight

The greatest weight gain in both previously untreated people and people who switch treatment has been seen in people taking dolutegravir with TAF (Bansi-Matharu, McComsey, McKann, Palella, Venter 2019, 2022,). Numerous large studies have reported the same pattern in various populations worldwide, with the greatest gains in weight seen during the first year after starting or switching treatment.

Weight gain is normal during pregnancy. However, women taking both TAF and an integrase inhibitor were more likely to experience higher-than-average weight gain during pregnancy than women taking either an integrase inhibitor or TAF as part of their treatment. (Joseph)

Why do people gain weight?

The reasons for weight gain after starting treatment are unclear. Several explanations have been proposed.

One explanation is that weight gain is a result of immune recovery. Long-term viral infection depletes fat stores. When people recover from famine or severe infection, body fat stores are replenished. Weight gain may represent a restoration of weight to what it might have been, had the person not been living with HIV for a number of years (Kumar). However, weight gain may ‘overshoot’ in people more prone to obesity for dietary or genetic reasons. Studies show that people with more advanced HIV disease (low CD4 counts, high viral load) gain more weight, as do people who were underweight before starting treatment.

Another explanation is that some of the drugs most often used in the past – efavirenz and tenofovir disoproxil fumarate (TDF) – suppress weight gain after starting treatment. When these drugs are replaced in first-line treatment by drugs that do not suppress weight gain, the effect of immune recovery on weight after starting treatment might become more obvious. These effects may be more pronounced in Black people, who are more likely to have a gene that results in higher levels of efavirenz, leading to greater suppression of weight gain (Griesel).

Similarly, if people switch from older drugs such as efavirenz to newer drugs such as dolutegravir, this theory might explain weight gain after changing treatment.

Other explanations for weight gain have focused on the impact of integrase inhibitors on the way the body regulates appetite (Domingo, McMahon 2020) or stores fat (Eckard, Gorwood) but neither theory can account for why weight gain is greater in some people or why specific combinations of drugs are linked to greater weight gain.

Other factors contribute to weight gain in people living with HIV, including age, diet and a high prevalence of obesity. In some settings, up to half of people starting antiretroviral treatment are already overweight or obese, and there is some evidence that higher pre-treatment weight and lower physical activity also predict greater weight gain (Guaraldi).

What are the long-term consequences of weight gain?

Weight gain soon after starting treatment in people who were previously underweight reduces the risk of death. This is an example of the ‘return to health’ effect.

However, in the long term, weight gain in people with normal body weight prior to treatment may increase the risk of cardiovascular disease and diabetes (Achhra).

People living with HIV are at increased risk of cardiovascular disease compared to the general population. This increased risk is especially pronounced in women and younger people.

Having a body weight in the ‘overweight’ or ‘obese’ range raises the risk of diabetes, cardiovascular disease, chronic kidney disease and cancer for everyone. Being overweight raises the risk of death for men more than for women.

Abdominal fat gain on antiretroviral treatment raises the risk of diabetes, as does overall weight gain (McMahon 2018, Herrin). A large study of over 49,000 people followed for five years after starting treatment found that those with normal body weight at the time they started treatment had a greater risk of cardiovascular disease the more weight they gained after starting treatment (Acchra). Underweight people did not have a similarly increased risk.

The ADVANCE study found that weight gain was associated with a small projected increase in the risk of developing type 2 diabetes over ten years, but the overall risk remained low (Hill). The same study did not find an increased risk of cardiovascular disease as a result of weight gain.

Obesity and diabetes are risk factors for the development of neurocognitive impairment in people living with HIV.

Obesity also contributes to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD promotes the development of diabetes and cardiovascular disease and is a risk factor for liver cancer.

Weight gain during pregnancy

Excessive weight gain during pregnancy raises the risk of complications of pregnancy including high blood pressure, pre-eclampsia and gestational diabetes. In turn, these maternal complications raise the risk of stillbirth and premature delivery.

Is weight gain reversible if people change treatment?

As the causes of weight gain are unclear, it is uncertain if changing to different antiretrovirals might slow down or reverse weight gain. It is also important to bear in mind that integrase inhibitors are preferred for first-line treatment because they are more reliable in suppressing viral load, are less likely to cause drug resistance and have fewer side effects than other antiretrovirals.

More evidence is needed on whether lifestyle changes such as diet and exercise have benefits for people who have gained weight on antiretroviral treatment.