One in five women had developed metabolic syndrome and just under half developed clinical obesity after almost four years of treatment with a combination of dolutegravir, tenofovir alafenamide and emtricitabine, final 192-week results of the ADVANCE study show.
In comparison, 12% of women taking dolutegravir/tenofovir disoproxil fumarate/emtricitabine in the study developed metabolic syndrome and 27% developed clinical obesity. Men developed metabolic syndrome and clinical obesity at lower rates on both regimens. The study investigators have previously estimated that the higher incidence of metabolic syndrome in people taking the tenofovir alafenamide-containing regimen would translate into four additional cases of diabetes per thousand people treated.
The findings, presented as a late-breaker poster at the 24th International AIDS Conference (AIDS 2022) in Montreal, underline the extent to which regimens taken by millions of people in both higher-income and lower-income countries could lead to metabolic disorders and complications including type 2 diabetes without regular monitoring of weight and metabolism.
The findings also highlight the substantial difference in the risk of weight gain between new and old formulations of tenofovir.
The ADVANCE study was a large, randomised comparison of:
- dolutegravir/tenofovir disoproxil fumarate/emtricitabine (DTG/TDF/FTC)
- dolutegravir/tenofovir alafenamide/emtricitabine (DTG/TAF/FTC)
- efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC).
The study was designed to evaluate the efficacy and safety of dolutegravir in a South African population as the country prepared to introduce the drug, and to evaluate whether a nucleoside backbone containing the newer formulation of tenofovir (TAF) reduced the risk of kidney and bone toxicities in that setting.
Forty-eight week efficacy results showed that both dolutegravir-based regimens were non-inferior to the efavirenz-based regimen. However, the study also found a higher incidence of weight gain – as measured by changes in body mass index (BMI), absolute weight and emergence of obesity – in people who received dolutegravir, especially in those randomised to receive DTG/TAF/FTC.
Subsequent 96-week follow-up confirmed the association between the TAF-containing regimen and greater weight gain. Other studies have also identified a relationship between TAF and greater weight gain, notably an international cohort study of more than 14,000 people and a large US study of people who switched from TDF to TAF. That study found no significant difference in weight gain according to the third agent used – people taking an integrase inhibitor gained only slightly more weight than people taking a non-nucleoside reverse transcriptase inhibitor.
Professor Francois Venter and colleagues presented final 192-week results of the ADVANCE, showing that approximately four years after randomisation, people taking the TAF-containing regimen had gained just under 9kg, compared with 5.8kg for people taking DTG/TDF/FTC and 3.3kg for people taking EFV/TDF/FTC.
People taking the TAF-containing regimen were significantly more likely to develop clinical obesity by week 192 (defined as a BMI of 30 or higher). Twenty-nine per cent of those taking the TAF-containing regimen had developed clinical obesity by the end of the study compared to 21% taking DTG/TDF/FTC and 15% taking EFV/TDF/FTC (p<0.001). Women developed clinical obesity on all regimens more frequently than men and this difference was especially pronounced in women taking the TAF-containing regimen. Forty-three per cent of women taking the TAF-containing regimen developed clinical obesity compared to 27% taking DTG/TDF/FTC and 20% taking EFV/TDF/FTC (p<0.001).
People taking the TAF-containing regimen were at least three times more likely to become clinically obese by the end of the study compared to people taking the efavirenz-containing regimen (hazard ratio 3.28), whereas those taking DTG/TDF/FTC did not have an elevated risk of obesity compared to people taking the efavirenz-containing regimen (HR 1.48, 95% CI 0.91-2.41, p=0.112).
Weight gain was greatest during the first 48 weeks of treatment.
The development of clinical obesity was also predicted by higher BMI at study entry (HR 1.82), higher baseline viral load (HR 1.97 per log10 higher) and being female (HR 2.14).
Clinical obesity is associated with a higher risk of developing metabolic syndrome, which in turn increases the risk of type 2 diabetes and cardiovascular disease. Metabolic syndrome is defined as central obesity plus at least two of the following factors: elevated triglycerides or medication to treat; reduced HDL cholesterol or treatment for this lipid abnormality; raised blood pressure or treatment for it or raised plasma glucose or treatment for it.
In the ADVANCE study, women and people taking the TAF-containing regimen were significantly more likely to have developed metabolic syndrome by the study’s end than others. Twenty per cent of women taking the TAF-containing regimen developed metabolic syndrome during the study compared to 7% of men, while 12% of women and 6% of men taking DTG/TDF/FTC developed metabolic syndrome.
The study findings suggest that the combination of dolutegravir and TAF is more likely to lead to substantial weight gain than combinations containing TDF. Whether TAF promotes weight gain or just removes any pharmacological barriers to weight gain is unclear. Several studies have suggested that efavirenz and TDF each suppress weight gain after starting treatment; for example, studies in pregnant women showed that women with the highest blood levels of efavirenz gained less weight after starting treatment during pregnancy, and that weight gain observed after starting integrase inhibitor treatment reflects the natural rate of increase.
Several other studies conducted in Africa and presented at AIDS 2022 showed that dolutegravir-based treatment is associated with greater weight gain. NAMSAL, conducted in Cameroon, was a randomised comparison of dolutegravir/TDF/lamivudine or lower-dose efavirenz (400mg) plus TDF/lamivudine. Previously reported 48-week results of NAMSAL showed that combining either drug with tenofovir and lamivudine resulted in similar rates of viral suppression. Four-year follow-up presented at AIDS 2022 showed that women taking dolutegravir gained a median of 8kg, compared to a weight gain of 5kg in women taking efavirenz 400mg.
In Zimbabwe, researchers looked at weight trends in 7047 adults who started or switched treatment between 2008 and 2021, comparing outcomes in people taking dolutegravir, efavirenz or atazanavir/ritonavir. The study found that people taking dolutegravir gained two to four times more weight than people taking efavirenz or atazanavir/ritonavir. Women had gained a median of 4.63 kg two years after starting or switching to dolutegravir, compared to 1.21kg for women taking efavirenz and 1.61kg for women taking atazanavir/ritonavir. Weight gain on dolutegravir was faster in the first year but continued in the second year, whereas for other regimens weight gain plateaued after the first year.
Dr Tinei Shamu of Newlands Clinic, Harare, presenting these findings, pointed out that the potential impact of weight gain is not confined to cardiovascular risk. Although some people may welcome weight gain as a sign of improved health, weight gain can also affect self-image, adherence and attitudes towards living with HIV and long-term medication.
Venter WF et al. Final week 192 results from the ADVANCE trial: first-line TAF/FTC/DTG, TDF/FTC/DTG vs TDF/FTC/EFV. 24th International AIDS Conference, Montreal, abstract PELBB01, 2022.
Shamu T et al. DTG associated weight gain: real or perceived? Real world experiences from Zimbabwe. 24thInternational AIDS Conference, Montreal, abstract PESUB17, 2022.
Mpoudi-Etame M et al. Dolutegravir versus efavirenz-400 as first-line ART in Cameroon: week 192 data of NAMSAL trial. 24thInternational AIDS Conference, Montreal, abstract 8111, 2022.