Switching from tenofovir alafenamide (TAF) to the older version of tenofovir (tenofovir disoproxil fumarate, TDF) when taking dolutegravir or other antiretrovirals is associated with weight loss or weight stabilisation and reductions in lipid levels, studies carried out in South Africa and Finland have reported.
Several studies have shown that the combination of TAF, emtricitabine and dolutegravir is associated with greater weight gain after starting HIV treatment than other combinations. Weight gain has also been seen when dolutegravir is combined with other antiretrovirals, but the weight gain is less substantial.
TAF has been widely adopted as a component of first-line treatment because of a perception that it is less likely to cause bone loss or kidney damage than the older form of tenofovir. But a meta-analysis of 14,894 participants in 14 randomised trials found no difference in safety between old and new formulations of tenofovir – although trial participants were relatively young and had normal kidney function.
Balancing the potential benefits of TAF against the long-term harms caused by weight gain when TAF is combined with dolutegravir poses a challenge. If weight gain is difficult to reverse and leads to an increased risk of cardiovascular disease and diabetes, is this a more serious long-term risk than bone loss or kidney damage?
Alternatively, is it possible that a change in treatment from TAF could reverse weight gain that occurs when taking it?
Two studies, carried out in South Africa and Finland, have recently reported on the impact of switching from TAF to TDF.
The ADVANCE study was a large, randomised trial that compared three first-line regimens in South Africa. The trial compared dolutegravir to efavirenz, and also compared dolutegravir in combination with two backbones, tenofovir alafenamide (TAF) and emtricitabine, or tenofovir disoproxil fumarate (TDF) and emtricitabine.
As well as showing that dolutegravir/based treatment was just as effective as efavirenz-based treatment in the South African setting, the ADVANCE study also demonstrated that the combination of dolutegravir and TAF was associated with greater weight gain than the other combinations studied in the trial, especially in women.
After the final 192-week study follow-up was completed, participants at Johannesburg study sites were switched to TDF/lamivudine/dolutegravir, in accordance with South African national guidelines, and followed in the CHARACTERISE sub-study for at least 52 weeks.
The study followed 70 out of 351 participants originally assigned to the TAF/emtricitabine/dolutegravir arm, 70 out of 351 participants originally assigned to the TDF/emtricitabine/dolutegravir arm and 31 out of 351 originally assigned to the TDF/emtricitabine/efavirenz arm. The lower recruitment from the efavirenz arm was due to local decisions by nurses, who did not transition patients to dolutegravir owing to large residual stocks of efavirenz.
Participants in CHARACTERISE were similar with regards to sex, baseline viral load and CD4 count but had higher body weight (mean 79kg) than participants not recruited to CHARACTERISE (74kg). Sixty-two percent of participants were women.
During the follow-up period, women who switched from TAF/emtricitabine/dolutegravir to TDF/lamivudine/dolutegravir experienced significant reductions in weight (median -1.6kg) and body mass index (median 0.57 kg/m2). No significant changes were observed in men who switched from TAF/emtricitabine/dolutegravir to TDF/lamivudine/dolutegravir.
The switch was associated with significant reductions in total cholesterol, LDL cholesterol, triglycerides, glucose and HbA1C.
In contrast, participants who switched from TDF/emtricitabine/efavirenz to TDF/3TC/dolutegravir gained weight (median +2.9kg) and had increased body mass (median +1.01 kg/m2). These increases were statistically significant in men but not in women. The switch was also associated with significant reductions in total cholesterol, HDL cholesterol and HbA1C.
Weight did not change significantly in participants who switched from TDF/emtricitabine/dolutegravir to TDF/3TC/dolutegravir, but the switch was associated with significant increases in total cholesterol, HDL cholesterol and systolic blood pressure.
Why the combination of dolutegravir and TAF should cause greater weight gain than the other combinations used in the ADVANCE trial is unclear. There is some evidence that efavirenz and TDF each have a suppressive effect on weight gain and that what has been observed in the TAF-containing arm is the weight gain that occurs after starting dolutegravir-based treatment, unconstrained by any weight-suppressive effect of TDF.
The study investigators warn that the combination of TAF and dolutegravir may not be suitable for everyone living with HIV.
“Countries such as Botswana that are moving away from TDF/3TC/DTG in favour of TAF/FTC + DTG, may want to consider preservation of TDF-containing regimens as an option for patients with ongoing, significant weight gain and metabolic disease, sadly a significant proportion of this population,” they conclude.
Finnish doctors have also reported on the impact of a switch from TAF to TDF in 146 people with HIV, matched by age, sex and antiretroviral class with 146 people who continued taking TAF. Study participants had been taking TAF for a median of 76 weeks in the switch group and 33 weeks in the control group. The study excluded people who changed any other element of their antiretroviral treatment or changed lipid-lowering medication during follow-up, to eliminate potential bias.
"TAF appears to be ‘metabolic neutral’ while TDF may display some ‘metabolic benefit’."
The study population was predominantly male (79%), White (90%), had a mean body weight of 82kg and approximately 20% in each arm were taking lipid-lowering medication. Seventy-one percent were taking an integrase inhibitor, 21% a non-nucleoside reverse transcriptase inhibitor and 8% a protease inhibitor. Baseline lipid levels were significantly higher in the switch group than the control group, although the total cholesterol: HDL cholesterol ratio was 3.8 for both groups (in the healthy range).
The study found that body weight remained stable after two years in people who switched from TAF to TDF but increased significantly in people who remained on TAF (mean +1.5kg). Total cholesterol, LDL and HDL cholesterol and triglyceride levels all fell significantly after a median follow-up of 46 weeks in the switch group but remained stable in those who continued on TAF.
After two years, triglyceride and HDL cholesterol levels remained significantly lower in the switch group, whereas LDL cholesterol levels increased significantly between year 1 and year 2 follow-up visits. Cardiovascular risk scores declined slightly in the switch group (-0.3%) and rose slightly in the control group after two years of follow-up.
The study investigators say that the decrease in LDL cholesterol (the form of fat considered the main driver of cardiovascular disease) after switching away from TAF was comparable to the increase in LDL cholesterol in studies evaluating a switch from TDF to TAF.
“The key message of this study is that TAF appears to be ‘metabolic neutral’ while TDF may display some ‘metabolic benefit’”, three HIV physicians write in an accompanying editorial comment. They suggest that treatment needs to be tailored to the individual’s overall metabolic health.
Bosch B et al. Weight and metabolic changes after switching from tenofovir alafenamide (TAF)/emtricitabine (FTC) + dolutegravir, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz to TDF/lamivudine (3TC)/DTG. Clinical Infectious Diseases, published online 15 December 2022.
Kauppinen KJ et al. Switching from tenofovir alafenamide to tenofovir disoproxil fumarate improves lipid profile and protects from weight gain. AIDS, 36: 1337-44, 2022.
Stapleton J et al. Switch back from TAF to TDF or rather switch forward from metabolic toxicities of drugs to metabolic health of people living with HIV. AIDS, 36: 1457-59, 2022.