Weight gain and metabolic syndrome with dolutegravir and TAF: results from the ADVANCE trial

15 November 2019. Related: Conference reports, Side effects, Lipodystrophy and metabolic complications, EACS 17 Basel 2019.

Polly Clayden, HIV i-Base

Dolutegravir (DTG) in combination with tenofovir alafenamide (TAF) is linked to increases in weight and clinical obesity – according to data from the ADVANCE trial presented at EACS 2019. [1]

The ADVANCE trial, conducted in South Africa, randomised 1053 treatment-naive participants to three first-line regimens: TAF/emtricitabine (FTC)/DTG vs tenofovir disoproxil fumarate (TDF)/FTC/DTG vs TDF/FTC/efavirenz (EFV).

Week 48 results, showing DTG-based regimens to be non-inferior to EFV-based ones but associated with substantial weight gain, were presented at IAS 2019 and published in the NEJM in July. [2, 3, 4]

The investigators also presented a pooled analysis with data from the NAMSAL trial comparing changes in body weight across the regimens at IAS 2019. [5]

The presentation at EACS provided additional detail on weight gain in ADVANCE.

Body weight, body mass index (BMI), lipids, fat mass, and lean mass were measured and differences between treatment arms were tested. DEXAs were performed at 48 and 96 weeks.  At the time of analysis, 531 participants had reached week 96. The evaluation will be updated when everyone reaches this time point – around April/May 2020.

At baseline, participants were about 33 years old, 99.5% were black, CD4 was approximately 330 cells/mm³, about 20% had viral load between 100,000 and 500,000 copies/mL and only about 3% had viral load above 500,000 copies/mL. About 60% were women, with baseline BMI of 26 kg/m2; for men baseline BMI was 22 kg/m2. Approximately 25% of participants were overweight and 12% obese before starting ART.

In men, the mean change in weight at 96 weeks was: 5.9 kg, 3.5 kg and 1.2 kg in the TAF/FTC/DTG, TDF/FTC/DTG TDF/FTC/EFV arms respectively.

Body composition, measured by DEXA, was 59% fat (distributed fairly evenly across trunk and limb) and the remainder lean mass in the TAF/FTC/DTG arm. Participants in the TDF/FTC/DTG arm experienced weight gain with 74% fat. And for those in the TDF/FTC/EFV arm weight gain was 100% fat.

In women, the mean change in weight at 96 weeks was: 8.3 kg, 5.3 kg and 3.4 kg in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively.

In the TAF/FTC/DTG and TDF/FTC/DTG arms weight gain was 74% fat with most of the lean mass gained in the limbs. For women in the TDF/FTC/EFV arm, weight gain was 91% fat.

The investigators adjusted competing risk regression models for: socio-demographics; baseline weight or BMI, treatment arm, CD4 count or viral load; disease history and adverse events; and concomitant medications.

After multivariate analysis, associated factors for treatment-emergent obesity were: TAF/FTC/DTG, baseline CD4, baseline viral load and baseline BMI.

Excluding baseline BMI, other associated factors were female sex, South African nationality and employment.

Factors associated with 10% or more increase in body weight were: TAF/FTC/DTG, baseline CD4, baseline viral load, female sex, age, and baseline weight.

As it has been suggested that better tolerability of newer antiretrovirals might contribute to greater weight gain the investigators performed an analysis excluding participants with GI adverse events. But the differences remained similar with mean weight change from baseline of 7.8 kg, 4.3 kg and 2.7 kg for the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV respectively.

At week 96, 27% 17% and 11% of women in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively developed treatment-emergent obesity. For men the respective proportions were: 7%, 3% and 2%.

And 51%, 32% and 23% of women in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively experienced a 10% or more increase in body weight, compared to 42%, 27% and 18% of men.

When the investigators looked at treatment-emergent metabolic syndrome (using the International Diabetes Federation definition), at week 96 they found 9%, 5% and 3% of participants in the in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV (difference TAF/FTC/DTG vs TDF/FTC/EFV, p=0.025).

When questioned whether there was a threshold for switching people with large weight gain (as some of the participants have gained 30 or 40 kg with one as much as 50 kg), presenting author Michelle Moorhouse from Ezintsha, Wits RHI explained that although they have raised this, “…most point blank refused to switch from DTG and are not happy about EFV”.

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Sixty per cent of the study participants have data available at week 96 in this new analysis, so the findings here are more robust than those presented at IAS 2019. 

There is significantly more treatment-emergent metabolic syndrome in the TAF/FTC/DTG arm (9%), compared with the TDF/FTC/EFV arm (3%).  Metabolic syndrome is a predictor of diabetes and atherosclerosis.

The sensitivity analysis, removing anyone with GI adverse events, is important as it has been claimed that weight rises faster on TAF because it is so well tolerated, so people feel better.  But this did not change the results.  The investigators do not yet have a good explanation for the greater rises in body weight on TAF. 

Twenty seven per cent of women in ADVANCE developed clinical obesity by week 96 and there is no sign of a plateau in weight gain.  The investigators are now calculating the potential effects of this weight gain on increased risks of NCDs.  These results will be submitted to CROI. 

In the QDIABETES algorithm, if weight rises by 10 kg, the risk of diabetes rises by 3 cases per 1000 people treated.  Although this does not sound much, in countries like South Africa where millions of people need ART, the absolute numbers could be substantial and create a huge extra burden on health services. 

One of the ADVANCE investigators, Andrew Hill, gave an excellent overview of weight gain and clinical obesity with new treatments looking at these issues in more detail. [6] This is a recommended webcast (and will be summarised in the next issue of HTB).

The study team are actively seeking resources to continue follow up for another two years after week 96 to properly evaluate consequences of weight gain/clinical obesity. 

Polly Clayden is on the scientific committee of ADVANCE and co-author of the NEJM paper.

References

1. 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 (EACS). Basel, Switzerland. 6–9 November, 2019. Oral abstract PS3/3.
   http://resourcelibrary.eacs.cyim.com/mediatheque/media.aspx?mediaId=78033&channel=28172 (webcast)
2. Venter WDF et al. The ADVANCE trial: Phase 3, randomised comparison of TAF/FTC/DTG, TDF/FTC/DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection.10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract WEAB0405LB.
   http://programme.ias2019.org/Abstract/Abstract/4770
3. Venter WDF et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. New England Journal of Medicine. Online ahead of print. 24 July 2019.
   https://www.nejm.org/doi/pdf/10.1056/NEJMoa1902824
4. Clayden P. Dolutegravir-based first-line non-inferior to efavirenz-based ART but associated with substantial weight gain: results from the ADVANCE study. HTB. 23 August 2019.
   https://i-base.info/htb/36581
5. Hill A et al. Progressive rises in weight and clinical obesity for TAF/FTC/DTG and TDF/FTC/DTG versus TDF/FTC/EFV: ADVANCE and NAMSAL trials. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAX0102LB.
   http://programme.ias2019.org/Abstract/Abstract/4772
6. Hill A. Are new antiretroviral treatments increasing the risks of clinical obesity? 17th European AIDS Conferenc (EACS). Basel, Switzerland. 6–9 November, 2019. Oral presentation ML1. http://resourcelibrary.eacs.cyim.com/mediatheque/media.aspx?mediaId=78021&playlistId=78022&channel=28172 (webcast)