Older version of tenofovir used as PrEP linked to weight loss

Further studies needed to show if TDF causes weight loss in people with HIV too
Image: Monthira/Shutterstock.com
Image: Monthira/Shutterstock.com

People who took the older formulation of tenofovir during clinical trials of PrEP were more likely to experience substantial weight loss than people taking either a placebo or cabotegravir, an analysis of seven studies has shown. The findings add to evidence that TDF may play a role in the weight changes experienced by people with HIV taking antiretroviral therapy.

The study was presented at the IDWeek 2021 conference (29 September – 3 October) by Shahini Shah of the University of East Anglia.

Numerous studies have shown that a minority of people taking newer antiretroviral regimens containing an integrase inhibitor gain weight after starting treatment or switching to the newer drug. Early interpretations of these findings credited integrase inhibitors – especially dolutegravir – with causing weight gain.



A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

gastrointestinal (GI) symptoms

Relating to or affecting the gut, stomach or bowel. GI symptoms include diarrhoea, abdominal pain (cramps), constipation, gas in the gastrointestinal tract, nausea, vomiting and GI bleeding. Among several possible causes of GI symptoms are infections and antiretroviral medicines.



Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.

However, subsequent research has shown a more complex pattern. Analysis of clinical trials of newer antiretroviral drugs showed that lower CD4 count and /or high viral load before starting treatment was the strongest risk factor for substantial weight gain. Increases in weight may represent a ‘return to health’ effect.

The medications that integrase inhibitors are taken with also affect weight gain. This is the case for tenofovir, of which there are two formulations. Several studies have shown that people are more likely to gain weight when an integrase inhibitor is paired with the new formulation tenofovir alafenamide (TAF) than if used with the older formulation tenofovir disoproxil fumarate (TDF).

Studies have shown that people taking efavirenz or TDF gain less weight after starting treatment, leading some researchers to ask whether these two drugs suppress weight gain after starting treatment.

But it is difficult to disentangle the independent effects of HIV and different antiretroviral drugs on weight. Studies of people taking the same antiretrovirals for prevention purposes are of interest as there is unlikely to be a 'return to health' effect.

To investigate whether taking TDF can affect body weight, Shah and colleagues looked at weight changes in HIV-negative people taking TDF as part of a PrEP regimen in seven clinical trials. This analysis was designed to identify whether people taking TDF were more likely to experience substantial changes in weight than people taking the comparator regimen, and also to investigate whether gastrointestinal side-effects were more common in people taking TDF, as these might affect body weight.

Six of the seven trials compared TDF in combination with emtricitabine, or TDF alone, to a placebo. One study (HPTN 084) compared TDF and emtricitabine to injectable cabotegravir. No studies comparing TDF to TAF were included.

The primary endpoint of this analysis was the number of participants experiencing weight loss of at least 5%, or at least grade 2 abnormal weight loss (for example, a weight loss of at least 3.5kg in a 70kg adult).

"It is difficult to disentangle the independent effects of HIV and different antiretroviral drugs on weight."

The seven clinical trials involved a total of 19,359 participants, 11,054 exposed to TDF, 6691 to placebo and 1614 to cabotegravir.

People taking TDF had significantly greater odds of experiencing substantial weight loss in two of the seven clinical trials.

In iPrEx, which tested TDF/FTC against placebo in 2499 men who have sex with men and transgdender females, people taking TDF were 81% more likely to experience substantial weight loss (95% confidence interval 1.03-3.19).

In TDF-2, which tested TDF/FTC against placebo in 1219 heterosexual men and women, people taking TDF were twice as likely to experience substantial weight loss (OR 2.07, 95% CI 1.52-2.54).

In the remaining studies that compared TDF-containing PrEP to placebo (Bangkok TDF, Partners PrEP, FEM-PrEP, VOICE), people taking TDF did not have higher odds of substantial weight loss.

However, when all studies TDF-containing PrEP to placebo were pooled (370 cases in TDF recipients and 249 cases in placebo recipients), people taking TDF had significantly greater odds of substantial weight loss than the placebo recipients in the six studies (OR 1.48, 95% CI 1.06-2.07).

People taking TDF/FTC did not have greater odds of substantial weight loss than people taking cabotegravir (OR 1.32, 95% CI 0.97-1.79).

When cases in studies comparing TDF to placebo or to cabotegravir were pooled, people taking TDF had significantly greater odds of substantial weight loss (OR 1.44, 95% CI 1.12-1.85).

A separate analysis looked at gastrointestinal adverse events (nausea, vomiting, diarrhoea or loss of appetite). Only one adverse event – vomiting – occurred more frequently in people taking TDF (5% vs 3%, p<0.005). Other events that might affect food intake or absorption and so have an effect on body weight, did not occur more frequently in people receiving TDF – indeed, diarrhoea was somewhat more frequent in placebo recipients.

The findings suggest that TDF use can lead to weight loss in HIV-negative people, and by implication in people with HIV too, although the mechanism is unclear.

The study authors say that investigators of studies of TDF/FTC in people with HIV should publish weight data so that further analyses can be carried out. Longer-term follow-up might also show whether changes in weight are transient. Further investigation of a possible relationship between weight changes and gastrointestinal adverse events might also reveal more about the mechanisms underlying weight changes, they conclude.


Shah S, Pilkington V, Hill A. Use of tenofovir disoproxil fumarate shows weight loss vs placebo: a meta-analysis of 7 clinical trials in 19,359 HIV-negative individuals. ID Week 2021, poster abstract 882.