Weight gain with integrase inhibitors and TAF: three reports from AIDS 2020
Polly Clayden, HIV i-Base
More presentations at AIDS 2020 showed weight gain among people with HIV treated with integrase strand inhibitors (INSTI) and tenofovir alafenamide (TAF).
We previously reported data showing weight increase from several African studies also presented at the conference. [1, 2, 3, 4]
First-line studies ADVANCE and NAMSAL showed persistent weight gain at week 96 – and that this was worse among women and participants also taking TAF. Second-line study VISEND showed greater weight gain with DTG and TAF compared to other ART regimens at 36 weeks. And the AFRICOS observational study reported weight gain among people receiving DTG-based ART.
As well as these, three other reports of weight gain with newer antiretrovirals at the conference were notable.
- An analysis of the US OPERA cohort showed switching to TAF from tenofovir disoproxil fumarate (TDF) to be associated with pronounced weight gain soon after switch, regardless of concurrent INSTI. 
- Centers for AIDS Research Network of Integrated Clinical Systems, another US cohort, showed short-term weight gain among people receiving first-line ART. People in this group receiving DTG or bictegravir (BIC) and TAF-based regimens six months after starting ART initiation gained more weight than those receiving other INSTI-based regimens. 
- And DTG was associated with an increase in the odds of becoming either overweight or obese in virally suppressed adolescents with HIV in Eswatini switching from an NNRTI. 
In the OPERA TDF to TAF switch evaluation, ART-experienced, virologically-suppressed (<200 copies/mL) participants in this large US cohort were included if they maintained all other antiretrovirals or switched to an INSTI.
Of 6919 included, 80% were men, approximately 40% were black and 25% Hispanic. They were approximately 45 years old and BMI was about 27 kg/m2.
The TAF switches were grouped by regimen characteristics: maintained NNRTI (n=1454), maintained boosted (n=747), maintained INSTI (n=3288) and switched to INSTI (n=1430).
The groups were similar except those that stayed on a boosted PI and switched to an INSTI were closer to 50 years old.
Using data documented from up to 48 months before switch and up to 36 months after, the investigators modelled weight change before and after switching, adjusting for age, sex, race, (including age-sex, race-sex interactions), BMI, CD4 count, endocrine disorders and concurrent medications that can affect weight.
The referent for the model was a 45 year old non-black man with baseline BMI 27 kg/m2, baseline CD4 count 700 cells/mm3 without endocrine disorders or concurrent medications.
Adjusted models revealed modest weight gain over time with TDF before switch: 0.42 kg/year (95% CI 0.26 to 0.59). But there was a steep increase in weight in the 9 months from TAF switch, followed by more modest gains or plateau after 9 months: 2.64 kg (95% CI: 2.26 to 3.01) and then 0.29 kg/year (95% CI: 0.08 to 0.51).
The effect with TAF switch was seen both among participants who maintained other antiretrovirals and those switching to an INSTI. The investigators reported no difference between INSTIs but noted that there was insufficient data for BIC after 9 months.
Seventy-eight per cent of participants who switched to an INSTI received elvitegravir (EVG); 12% switched to DTG and 9% to BIC.
The investigators concluded: “That this effect was observed across regimens suggests an independent effect of TAF on weight”.
In the second US study, investigators evaluated ART-naive participants starting INSTI-based ART between 2012– 2019 across eight Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites. 
Regimens included raltegravir (RAL), EVG, DTG, and BIC-based regimens with TDF, TAF or abacavir (ABC) and emtricitabine (FTC) or lamivudine (3TC).
The study compared weight gain with BIC vs other INSTI-based regimens within six months after starting ART using models adjusted for age, sex, race, hepatitis B and/or C virus coinfection, nadir CD4, smoking, diabetes, site, anti-psychotic medication use and regimen (including interaction between time and regimen).
There were 2080 participants included in the analyses. They were 84% male, 48% black, 34% white and 11% Hispanic. Age at baseline was 37 years and weight was 79 kg.
Those who began a DTG/TAF- or BIC/TAF-based regimen gained the most weight in the first six months after starting ART: 5.1 kg (95% CI: 3.0 to 7.2) and 4.6 kg (95% CI: 3.2 to 6.0), respectively.
Weight increase with DTG/TDF-based ART was 3.3 kg (95% CI: 2.3 to 4.3) and with other regimes 2.5 to 3 kg.
Although the p-values were not presented, the investigators noted that participants receiving DTG/TAF- or BIC/TAF-based ART gained significantly more weight than those on EVG/TDF- and EVG/TAF-based regimens. But this difference was not significant compared to participants receiving RAL/TDF-, DTG/TDF-, and DTG/ABC-based ART.
Dolutegravir in adolescents
The adolescent study looked at BMI measurements in a retrospective observational cohort of 605 virally suppressed (< 200 copies/mL) adolescents receiving care at Baylor Children’s Foundation clinic in Mbabane Eswatini between one year before starting DTG and up to one year after. 
During the study period, 295 girls and 310 boys had an average of 6.4 visits; 30% were 10–12, 46% 12–16 and 24% 17–19 years of age. About three quarters of the group switched from efavirenz and the rest nevirapine; the majority (88%) received TDF/3TC backbone and the remainder ABC/3TC.
The investigators modelled rate of change in BMI and the odds of becoming obese or overweight, adjusting for sex, other antiretrovirals in the DTG regimen, previous ART and age at DTG switch.
Adjusted models showed adolescents receiving TDF/3TC/DTG had a BMI 0.66 kg/m2 greater than those receiving ABC/3TC/DTG, p<0.001. Girls BMI was 1.371 kg/m2 greater than boys, p<0.001.
After switching to DTG, the odds of becoming overweight or obese increased by approximately 1% every day: OR 1.010, p=0.015.
But the investigators noted that this increase was largely among adolescents who were defined as thin at baseline and experienced greater BMI increase.
Further investigation into the risks of weight gain in adolescents receiving DTG-based ART with longer duration of treatment is needed, they explained.
They are planning future work in a larger sample of this cohort to estimate a predictive tool to identify adolescents who are most likely to become overweight or obese after being receiving DTG.
There were a number of sessions, presentations and posters at the conference reporting weight gain – especially associated with DTG.
These presentations stood out as they demonstrate an independent effect of TAF and very rapid early weight gain with BIC as well as DTG (of note this second analysis was funded by ViiV, the originator manufacturer of DTG and the title suggests this was a BIC effect but the two agents seem to be very similar). Both these cohorts are at least 80% men and it is likely, from what we have seen in previous studies, that this weight increase could be worse in women, particularly black women.
The observation in adolescents is also important as weight change in children and adolescents is both harder to evaluate (as they are growing) and has been poorly documented to date. The investigators urge caution in interpreting these data and the need for further investigation both from their own cohort and other groups.
- Clayden P. ADVANCE 96-week results: dolutegravir weight gain continues, especially in women and when used with TAF – no evidence of a plateau. HTB. 22 July 2020.
- Clayden P. Dolutegravir non-inferior to efavirenz at week 96 in the NAMSAL study but associated with substantial weight gain. HTB. 20 August 2020.
- Clayden P. Switching from efavirenz- to dolutegravir-based ART second-line achieved good rates of suppression: first results from the VISEND study. HTB. 20 August 2020.
- Clayden P. Dolutegravir associated with weight gain in African ART programmes: findings from AFRICOS. HTB.
- Mallon P et al. Weight gain before and after switch from TDF to TAF. AIDS 2020 virtual. 6–10 July 2020. Oral abstract OAB0604.
- Ruderman SA et al. Early weight changes associated with bictegravir-based regimens compared to other integrase inhibitors following ART-initiation in ART-naive people living with HIV. AIDS 2020 virtual. 6–10 July 2020. Poster abstract PEC0450.
- Thivalapill N et al. Optimization to dolutegravir-based ART in a cohort of virally suppressed adolescents is associated with an increase in the rate of BMI change and odds of becoming overweight. AIDS 2020 virtual. 6–10 July 2020. Oral abstract OAB0106.
This article was originally posted on 22 August 2020.