Switching from TAF to TDF leads to weight loss

Switching from tenofovir alafenamide (TAF) to the older formulation of tenofovir disoproxil (TDF) resulted in modest weight loss in people with HIV in the Swiss HIV Cohort, researchers report in the journal Clinical Infectious Diseases.

Switching from TAF to TDF also brought benefits in the forms of reduced cholesterol and triglycerides.

In contrast, switching from TAF-containing treatment to a two-drug combination of dolutegravir/lamivudine or injectable cabotegravir/rilpivirine did not lead to any changes in weight.

Tenofovir alafenamide is a component of several widely prescribed fixed-dose combinations, including Descovy (TAF and emtricitabine), Biktarvy (bictegravir, TAF and emtricitabine), Symtuza (daruanvir, cobicistat, TAF and emtricitabine) and Odefsey (rilpivirine, TAF and emtricitabine).

Find out more: Switches away from integrase inhibitors do not reverse weight gain, studies find

In the ADVANCE study, people who started treatment with a regimen containing TAF and dolutegravir gained more weight than people taking TDF and emtricitabine with either dolutegravir or efavirenz. But randomised trials which have looked at switching away from TAF have failed to show any effect of the switch on weight, except for post-trial follow-up of participants in the ADVANCE study. In that group, participants who switched from TAF to TDF lost weight.

Swiss HIV Cohort researchers wanted to look at changes in weight and metabolism after switching from TAF in a larger population than the ADVANCE post-trial follow-up. The Swiss HIV Cohort follows approximately 80% of people receiving HIV treatment in Switzerland; between 2016 and 2023, 11,782 people with HIV were included in the cohort.

The researchers identified 6,555 people who took TAF between 2016 and 2023 and had follow-up weight and metabolic data. Of these, 83% continued taking TAF until the end of the study period and 16% (1070 participants) switched from a TAF-containing regimen to another regimen.

Those who switched away from TAF were significantly younger, had been on antiretroviral treatment for less time and were slightly more likely to be virally suppressed. They had significantly higher median weight and body mass index, so that a higher proportion were classifed as either overweight or obese. They had significantly higher total cholesterol and LDL cholesterol levels but were less likely to be taking lipid-lowering drugs or to have diabetes, to smoke or to have a history of cardiovascular disease.

The proportions who were female and/or Black did not differ between the two groups (22% of those who switched were female and 12% were Black).

Of those who switched, 196 (18%) swapped TAF for TDF, 565 (52%) switched to dolutegravir/lamivudine, 115 (10%) to injectable cabotegravir/rilpivirine and 94 (18%) to another antiretroviral combination.

As this was an observational study rather than a randomised trial, the researchers adjusted for confounding factors that might also affect weight (age, sex, Black race, CD4 count and weight at the beginning of follow-up, time on antiretroviral treatment, use of integrase inhibitors, level of physical activity, smoking and use of other medications known to affect weight).

Overall, after adjusting for confounding factors, switching from TAF was associated with a weight loss of 0.60kg after one year, compared to no change in weight in people taking TAF. However, when analysed by the agent to which people switched, it was apparent that participants only lost weight (a median of 1.89kg) if they switched to TDF. Weight remained stable in people who switched to other agents or drug combinations.

Weight loss after switching was greater in women and Black people, and in people who had gained at least 10% in body weight after starting TAF, irrespective of what they switched to.

Switching from TAF was also associated with reductions in total cholesterol, total cholesterol-HDL cholesterol ratio and triglycerides, especially in people who switched to either TDF or dolutegravir/lamivudine.

In this population, almost three-quarters (74%) of those who switched from TAF to TDF also switched from an integrase inhibitor to a non-nucleoside reverse transcriptase inhibitor (predominantly doravirine (61%) or rilpivirine (13%). But when the analysis was restricted to people who were not taking an integrase inhibitor at the beginning of follow-up, switching from TAF to TDF was still associated with a reduction in weight, suggesting that discontinuing TAF is sufficient to reduce weight.

A US AIDS Clinical Trials Group randomised study will provide more information on switching from TAF and an integrase inhibitor in people with excessive weight gain. The ‘Do It’ study is comparing the impact on weight of sticking with the existing regimen or switching to the NNRTI doravirine, combined with either TAF and emtricitabine or TDF and emtricitabine. The study is expected to report results by 2025.

The Swiss HIV Cohort study investigators say that people with HIV taking TAF who are concerned about weight gain should be made aware of these findings but also encouraged to balance them against the improvements in renal function and improved bone mineral density observed in people who take TAF. But in an accompanying commentary, Dr Andrew Hill of Liverpool University points out that two meta-analyses of clinical trials found no higher rates of serious adverse kidney events or bone fractures in people taking TDF compared to TAF, or TDF/FTC compared to placebo.

In a review of weight changes in clinical trials of newer antiretrovirals, also published in Clinical Infectious Diseases, a group of HIV clinicians concludes that weight tends to increase towards the societal norm in people with HIV after starting antiretroviral treatment. Any difference between regimens is explained by the weight-suppressive effects of TDF or efavirenz rather than weight-additive effects of newer drugs.

They say that anyone considering a switch from TAF to TDF should be aware that the adverse effects of TDF on kidney function on bone mineral density occur more frequently when TDF is used alongside a boosting agent (ritonavir or cobicistat), as these raise tenofovir levels. However, the use of boosted drugs is declining – the most commonly used antiretroviral that requires boosting is darunavir.

In the light of the higher risk of cardiovascular disease in people with HIV and the societal health challenge of obesity, Dr Andrew Hill asks whether the weight-suppressive and lipid-lowering effects of TDF should be considered as an unanticipated benefit of the drug. With this in mind, “clinicians need to decide whether to use TDF, which has the unexpected benefit of causing reductions in weight and lipids, or using TAF, which has lesser effects on markers of bone and renal function.”

“Once generic TDF/3TC/DTG becomes available in high-income countries for low prices, it will become increasingly difficult to justify the use of branded TAF-based treatments costing up to 1000 times more than generic TDF/FTC/DTG.”