Weight gain and HIV treatment

A research briefing
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Key points

  • Recent studies have reported that one in six people starting HIV treatment gain at least 10% in body weight over one to two years.
  • Weight gain is more common in women, black people and those who were in poorer health before starting treatment.
  • Weight gain is associated with specific anti-HIV medications, including integrase inhibitors and tenofovir alafenamide.
  • The reasons for weight gain are unclear: several explanations have been proposed.
  • Weight gain associated with HIV treatment may increase the risks of diabetes and cardiovascular disease.

Starting antiretroviral treatment leads to improved health, suppression of HIV and restoration of the immune system. Recently, studies have begun to report 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 there were differences in weight gain between drug combinations (Venter).
  • 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 become 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 become 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 (Mugglin, Verboeket).

Which drugs have been linked to weight gain?

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 greatest weight gain has been seen in people taking dolutegravir with TAF (Venter, McKann). Weight gain has been greater in people taking antiretroviral drugs introduced in the past ten years (integrase inhibitors, TAF).

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 theory is that integrase inhibitors might cause weight gain through effects on the hormonal system which governs appetite regulation, leading to increased food intake (Domingo). But a laboratory study by one of the drug’s manufacturers found that the amount of any integrase inhibitor needed to interfere with the normal activity of this system would be far greater than the drug concentrations achieved from normal doses of integrase inhibitors (McMahon 2020).

Glossary

integrase

HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase (see ‘integrase’). Blocking integrase prevents HIV from replicating.

antiretroviral (ARV)

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

association

An association means that there is a statistical relationship between two variables. For example, when A increases, B increases. An association means that the two variables change together, but it doesn't necessarily mean that A causes B. The relationship isn't necessarily causal.

Furthermore, one study found that people did not eat more after starting treatment nor did they experience a reduction in metabolic rate (Eckard). Another study found that substantial weight gain after four years of treatment was largely attributable to higher pre-treatment weight and lower physical activity, not increased food intake (Guaraldi).

Another variant on this theory is the possibility that integrase inhibitors cause changes to fat cells that lead to increased fat storage. But this research only looked at two integrase inhibitors and can’t explain why people taking TAF with an integrase inhibitor gain more weight than people who take an integrase inhibitor with the older formulation of tenofovir (tenofovir disoproxil fumarate, TDF) (Gorwood).

A third theory is that some of the drugs most often used in the past – efavirenz and 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.

Newer drugs are also less likely to cause diarrhoea, stomach ache or nausea, perhaps leading to improved absorption of food and better appetite.

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.

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.

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.

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.

References

Achhra AC et al. Short-term weight gain after antiretroviral initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study. HIV Medicine, 17: 255-68, 2016.

https://doi.org/10.1111/hiv.12294

You can read more about this study in our news report.

Bares SH et al. HIV-infected women gain more weight than HIV-infected men following the initiation of antiretroviral therapy. Journal of Women’s Health, 27: 1162-9, 2018.

doi: 10.1089/jwh.2017.6717

Bhagwat P et al. Changes in waist circumference in HIV-infected initiating a raltegravir or protease inhibitor regimen: effects of sex and race. Open Forum Infectious Diseases, 5: ofy201, 2018.

doi: 10.1093/ofid/ofy201

Domingo P et al. Possible role of the melanocortin signalling system interference in the excess weight gain associated to some antiretroviral drugs in people living with HIV. International Journal of Obesity, February 2020.

https://doi.org/10.1038/s41366-020-0551-5

Eckard ER et al. Fat gains occur after ART without changes in metabolic rate or caloric intake. Conference on Retroviruses and Opportunistic Infections, abstract 667, 2020.

You can read more about this study in our news report.

Gorwood J et al. Integrase inhibitors dolutegravir and raltegravir exert proadipogenic and profibrotic effects and induce insulin resistance in adipose tissue and adipocytes. 17th European AIDS Conference, Basel, abstract PS3/4, 2019.

You can read more about this study in our news report.

Griesel R et al. CYP2B6 genotype and weight-gain differences between dolutegravir and efavirenz. Conference on Retroviruses and Opportunistic Infections, abstract 82, March 2020.

You can read more about this study in our news report.

Guaraldi G et al. Contribution of INSTI, BMI, physical activity, caloric intake to weight gain in PWH. Conference on Retroviruses and Opportunistic Infections, abstract 675, 2020.

You can read more about this study in our news report.

Herrin M et al. Weight gain and incident diabetes among HIV-infected veterans initiating antiretroviral therapy compared with uninfected individuals. Journal of Acquired Immune Deficiency Syndromes, 73: 228-36, 2016.

doi: 10.1097/QAI.0000000000001071

Hill A et al. Risks of metabolic syndrome, diabetes, and cardiovascular disease in ADVANCE trial. Conference on Retroviruses and Opportunistic Infections, abstract 81, March 2020.

You can read more about this study in our news report.

Koethe JR et al. Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Research and Human Retroviruses, 32: 50-8, 2016.

https://doi.org/10.1089/aid.2015.0147

Kumar S, Samaras K. The impact of weight gain on HIV treatment on the risk of pre-diabetes, diabetes mellitus, cardiovascular disease and mortality. Frontiers in Endocrinology, 9: 705, 2018.

https://doi.org/10.3389/fendo.2018.00705

McCann K et al. The ADVANCE clinical trial: changes from baseline to week 96 in DXA-assessed body composition in TAF/FTC +DTG compared to TDF/FTC+DTG, and TDF/FTC/EFV. 17th European AIDS Conference, Basel, abstract PS3/3, 2019.

You can read more about this study in our news report.

McMahon C et al. High rates of incident diabetes and prediabetes are evident in men with treated HIV followed for 11 years. AIDS, 32: 451-9, 2018.

doi: 10.1097/01.aids.0000546215.40422.5f

McMahon C et al. Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight. PLOS ONE, 15: e0229617, February 2020.

doi: 10.1371/journal.pone.0229617

Mugglin C et al. Changes in weight after switching to dolutegravir containing antiretroviral therapy in the Swiss HIV cohort study. 17th European AIDS Conference, Basel, abstract PS3/5, 2019.

You can read more about this study in our news report.

Sax P et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clinical Infectious Diseases, online ahead of print, 2019.

https://doi-org.ezproxy01.rhul.ac.uk/10.1093/cid/ciz999

You can read more about this study in our news report.

Venter WF et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. New England Journal of Medicine, 281: 803-15, 2019.

doi: 10.1056/NEJMoa1902824

You can read more about this study in our news report.

Verboeket S et al. Switching to an integrase inhibitor containing antiretroviral regimen is not associated with above-average weight gain in middle-aged people living with HIV on long-term suppressive antiretroviral therapy, the AGEhIV cohort study. 17thEuropean AIDS Conference, Basel, abstract PS3/6, 2019.

You can read more about this study in our news report.

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