Are Integrase Inhibitors Linked to Weight Gain? An Evidence Review
HIV treatment with integrase inhibitors appears to lead to greater increases in body weight than with other antiretrovirals. The effect seems to be more pronounced for women and black people. There also might be an additional effect with NRTIs. But it is unclear yet whether these changes are clinically significant.
Andrew Hill from University of Liverpool, Laura Waters from Mortimer Market Centre, London and Anton Pozniak from Chelsea and Westminster Hospital, London, reviewed the evidence to date for integrase inhibitor-associated weight gain. This review was published in January 2019 in the Journal of Virus Eradication. 
The authors reported that in 2017–2018, results from four observational cohort studies -- conducted in France, Brazil and the US -- suggested that integrase inhibitors were associated with greater increases in body weight, particularly among women.
The observational studies were not randomised so differences between antiretrovirals in weight gain might be explained by other factors. Hill et al noted that analysing weight change in randomised trials might be more informative.
Results from five randomised studies support the association between integrase inhibitors and weight gain. Two studies have looked at raltegravir (RAL) and three dolutegravir (DTG). One study also included bictegravir (BIC).
In the ACTG 5257 trial, including 1809 participants, those randomised to first-line RAL-based ART were significantly more likely to become either overweight or obese compared to people receiving either atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r) -- both in regimens with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Black participants were 55% more likely to become either overweight or obese than white participants.
These weight changes appeared to be associated with abdominal fat, as there was a greater increase in waist circumference among participants treated with RAL.
Results from the NEAT 001 study show greater increases in visceral fat for people treated first-line with RAL plus DRV/r, compared with DRV/r plus TDF/FTC.
SPRING-1 -- the original dose-ranging trial of DTG, including 120 participants -- reported greater increases in body weight for first-line ART in people randomised to the DTG arm compared with those receiving efavirenz (EFV) -- both with two NRTIs.
In the NEAT-022 trial, 415 participants, stable on a two NRTI plus PI-based ART, were randomised to continue the PI or to switch to DTG. There were statistically significant increases in weight for people who switched to DTG, but the difference between the arms was only 1 kg.
The Gilead 1490 trial randomised 631 participants to first-line ART with two different integrase inhibitors. This study was typical of registrational trials and conducted in a mainly white, male, asymptomatic population with high baseline CD4 cell counts.
Mean increase in body weight to week 96 was similar in the two arms: 3.5 kg weight gain with bictegravir (BIC) compared with 3.9 kg with DTG -- both combined with tenofovir alafenamide (TAF)/FTC. Hill et al suggested that, if there is an effect of dolutegravir on weight gain, this is likely to be similar with BIC.
Three other studies suggest that there may be an additional effect of NRTIs on weight gain.
In the AMBER trial, there was a greater increase in weight for participants receiving first-line ART with TAF/FTC/DRV/c (1.8 kg) compared with TDF/FTC/DRV/c (0.8 kg).
Results from a German cohort study found mean increase in body weight of 2.3 kg after switching from TDF to TAF.
The STEAL study, which evaluated a randomised switch to either abacavir (ABC) or TDF, found increases in body weight were 1 kg greater in the ABC arm at week 96.
TDF/FTC is known to reduce levels of total cholesterol, which might be associated with changes in body weight.
These three studies showed smaller increases in body weight for TDF/FTC compared to other NRTIs. Hill et al noted that at present it is not clear whether the other NRTIs are contributing to increases in body weight, or if TDF/FTC leads to decreases in body weight.
The authors explained that the observational studies and randomised trials in this review have been analysed using a range of methods and propose using categorised measures of BMI increase (eg from normal to overweight, or from overweight to obese), assuming that body weight is measured at the start and end of treatment.
They note that the FDA consider a 5% loss in weight to be clinically significant and suggest that if a treatment increases mean weight by at least 5%, this would also be clinically significant.
From this review, Hill et al draw the conclusion that it is currently unclear whether integrase inhibitors cause clinically significant changes in body weight (at least 5%), or whether these changes are statistically significant but small (less than 5%).
They stress that the effects of integrase inhibitors on body weight need to be analysed for women, by ethnicity, and the potential additional effects of NRTIs must also be evaluated. The endpoint used in these analyses should follow FDA guidelines where feasible and analyses should also include a range of laboratory markers of cardiovascular risk.
It is important to note that when the authors of this review searched for articles on body weight with integrase inhibitors they found no published data from the original phase 3 trials of dolutegravir: SINGLE, ARIA, FLAMINGO, SPRING-2 or GEMINI.
It seems that body weight was not measured prospectively in these studies so they were unable to evaluate the risk of clinical obesity. The publications from the main phase 3 clinical trials of elvitegravir, RAL and BIC do not include any information on body weight either.
And, as usual, the majority of people in phase 3 randomised trials of integrase inhibitors are white and male and results to date suggest that integrase inhibitor-associated weight gain might be greater in women and black people.
Ongoing African studies -- including ADVANCE, NAMSAL and DolPHIN 1 and 2 -- comparing DTG to EFV, with predominately black and female populations, have started reporting results or will do so this year.  These studies will provide more information on whether or not this potential effect differs by sex and ethnicity.
Clearly this phenomenon needs to be carefully monitored given the widespread introduction of DTG globally.
Changes in body weight (and shape) are difficult for patients to report because many doctors see this as being driven to lifestyle factors (diet, exercise etc).
These studies suggest a sufficient signal for significant weight gain to be reported to drug safety and surveillance databases, including the UK Yellow Card Scheme. 
- Hill A et al. Are new antiretroviral treatments increasing the risks of clinical obesity? Journal of Virus Eradication 2019;5: e45–e47.
- HIV i-Base. Adult and paediatric optimised ART trial tracker.
- UK Yellow Card Scheme
Links to other websites are current at date of posting but not maintained.
[Note from TheBodyPro: This article was originally published by HIV i-Base on Jan. 21, 2019. We have cross-posted it with their permission.]