Progressive rises in weight and clinical obesity for TAF/FTC+DTG and TDF/FTC+DTG versus TDF/FTC/EFV: ADVANCE and NAMSAL trials Andrew Hill, Francois Venter, Eric Delaporte, Simiso Sokhela, Charles Kouanfack, Michelle Moorhouse, Kaitlyn McCann, Bryony Simmons, Alexandra Calmy I would like to thank you the IAS organisers and co-chairs for the opportunity to present these important results.

Disclosures Speaker fees and honoraria from Gilead Sciences, AbbVie, Cipla, Johnson and Johnson, Sanofi, Pfizer, ViiV Healthcare, Mylan and Southern African HIV Clinicians Society Conference sponsorship from Johnson and Johnson, BD, Gilead, Merck, Cipla and Mylan Part of ART optimisation collaborations Funding from USAID, Unitaid, SA MRC and study drug donations from ViiV and Gilead

Background Dolutegravir (DTG) has been associated with rises in body weight and clinical obesity, more pronounced in black people and women Tenofovir disoproxil fumarate (TDF) is associated with lower body weight, compared to tenofovir alafenamide fumarate (TAF), abacavir or NRTI-sparing treatment In the 96-week NAMSAL trial, 613 treatment-naïve patients in Cameroon were randomised to TDF/FTC+DTG or TDF/3TC/EFV400 In the 96-week ADVANCE trial, 1053 treatment-naïve patients in South Africa were randomised to TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFV Both trials measured changes in body weight, body mass index (BMI), and trunk fat (ADVANCE only) between treatment arms Recently, several observational studies and RCTs have demonstrated weight gain associated with the use of InSTIs, which is appears to be more pronounced in black PLWH and women. Compared to those receiving TAF, ABC or NRTI-sparing ART, TDF is associated with lower body weight. NAMSAL and ADVANCE are 2 RCTs among African populations which assessed body weight and BMI at each visit; ADVANCE also performed DXA scans at 3 time points – BL, week 48 and week 96 A Hill et al. Journal of Virus Eradication 2019

Drivers of weight gain/loss on ART Treatment naïve DTG or BIC Women Black TDF PI Weight gain Weight loss Drivers of weight gain or loss on ART based on studies to date suggest that: Larger increases in body weight were seen in ARV-naïve populations than in switch situations InSTIs have been associated with weight gain, more with DTG and BIC than RAL or EVG. Data presented at CROI regarding cabotegravir showed no significant weight gain but this was among HIV-negatives in a PrEP study Weight gain has also been seen with protease inhibitors but less severe TDF is associated with weight loss in these studies compared to TAF, ABC and NRTI-sparing regimens Weight gain was higher in women and black PLWH A Hill et al. Journal of Virus Eradication 2019

Clinical implications of obesity in HIV-negative (BMI ≥ 30kg/m2) Obstetric/ Birth outcomes Alzheimer’s disease Type 2 diabetes CVS disease/ hypertension Mobility/ ability to work 4-year reduction in life expectancy Obesity, defined as a body mass index of 30 kg/m2 and above has significant clinical implications, including: Adverse obstetric / birth outcomes Gestational diabetes, pre-eclampsia, venous thromboembolism, maternal death, birth defects Alzheimer’s disease Type 2 diabetes Cardiovascular disease/hypertension Reduced mobility or ability to work 4 year reduction in life expectancy M Kivimaki et al. Lancet Public Health 2017; K Bhaskaran et al. Lancet Diabetes Endocrinol 2018

NAMSAL: Study design Phase 3, randomised, open-label trial 3 study sites in Yaoundé, Cameroon The NAMSAL study, conducted in Cameroon, randomised 613 ARV-naïve adults with VL > 1000 copies/mL to DTG versus EFV400 with TDF/FTC. FU to 96 weeks, with primary endpoint at week 48 (efficacy) – presented at the Glasgow conference in 2018 The primary endpoint was to evaluate the non inferiority of DTG versus EFV4OO at the level of 50 copies/mL at week 48 Superiority test was planned if non inferiority was demonstrated Cournil A, Kouanfack C, Eymard-Duvernay S, et al. Dolutegravir- versus an efavirenz 400 mg-based regimen for the initial treatment of HIV-infected patients in Cameroon: 48-week efficacy results of the NAMSAL ANRS 12313 trial. Program and abstracts of the 2018 International Congress on Drug Therapy in HIV Infection; October 28-31, 2018; Glasgow, United Kingdom. Abstract O342. A Cournil et al. International Congress on Drug Therapy in HIV Infection 2018. Abstract O342

NAMSAL: Baseline characteristics median (IQR) unless stated TDF/3TC+DTG (n=310) TDF/3TC+EFV400 (n=303) Age, years 38 (31-46) 36 (29-43) Female, n (%) 197 (64%) 207 (68%) Body mass index, kg/m² 23 (21-26) Baseline HIV-1 ≥ 100,000 copies/mL, n (%) 207 (67%) 200 (66%) Baseline HIV-1 ≥ 500,000 copies/mL, n (%) 93 (30%) 95 (31%) CD4+ cell count, cells/mm3 289 (157-452)  271 (147-427)  No baseline differences between the study arms. Large proportion of participants had high viral loads at BL. BL BMIs were normal

NAMSAL: Changes in body weight/BMI by arm at Week 48 TDF/3TC+DTG (n=293) TDF/3TC+EFV400 (n=278) p-value for difference Mean change from baseline: Weight (kg) +5 +3 <0.001 BMI (kg/m2) +1.7 +1.2 Treatment-emergent overweight (BMI 25 – 29.9), n (%) 16% 17% n.s. Treatment-emergent obesity (BMI ≥ 30), n (%) 12% 5% <0.01 Looking at changes in body weight and BMI by arm at week 48 in NAMSAL OW = BMI 25-29.9; obese = BMI ≥ 30 Increases in weight across both study arms, higher with DTG than EFV which was statistically significant As were changes in BMI at week 48 Treatment emergent clinical obesity was higher with DTG than with EFV Highly significant differences in weight and BMI change between arms Clinical obesity (BMI ≥ 30 kg/m2) TDF/3TC+DTG higher than TDF/3TC/EFV

NAMSAL: ≥ 10% change from baseline weight (Week 48) p<0.05 n.s. More women and men receiving DTG than EFV experienced weight gain of 10% or more; however this was only statistically significant among women

NAMSAL: Treatment-emergent obesity (Week 48) p<0.01 n.s. If we consider treatment-emergent obesity, this was higher among men and women receiving DTG compared to EFV, which was statistically significant among men

ADVANCE: Study design Inclusion criteria: treatment-naïve, HIV-1 RNA level ≥ 500 copies/mL Open-label, 96-week study in Johannesburg, South Africa Study visits at Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, and 96 48-week efficacy and safety results will presented Wednesday 24 July 2019 WEAB0405LB ADVANCE is an ongoing 96 week study being conducted in inner city Johannesburg in South Africa. ADVANCE recruited 1053 ARV-naïve PLWH from age 12 with VL > 500 copies/mL. Randomised to TAF/FTC+DTG, TDF/FTC+DTG or standard of care TDF/FTC/EFV. Primary efficacy endpoint is at week 48 and will be presented on Wednesday. Study visits occurred at weeks 0, 4, 12, 12 weekly until 96 weeks. DXA scans at weeks 0, 48 and 96

ADVANCE: Baseline characteristics (1/2) TAF/FTC+DTG (n=351) TDF/FTC+DTG TDF/FTC/EFV Age, mean (SD), years 33 ± 8 32 ± 8 32 ± 7 Female 61% 59% 57% Black 99% 100% Baseline HIV-1 100,001 – 500,000 copies/mL 19% 18% 21% Baseline HIV-1 ≥ 500,000 copies/mL 3% 2% CD4+ cell count, mean (SD), cells/mm3 349 ± 225 323 ± 234 337 ± 222 Again, baseline characteristics were balanced across the three study arms. Participants were slightly younger than NAMSAL; higher BL CD4 counts and much smaller proportion with high BL viral loads.

ADVANCE: Baseline characteristics (2/2) TAF/FTC+DTG (n=351) TDF/FTC+DTG TDF/FTC/EFV Weight, mean (kg) Male 67.9 67.1 67.3 Female 68.8 69.5 70.2 BMI, mean (kg/m2) 21.7 21.6 21.8 25.6 26.1 Categories of BMI, n (%) Underweight (< 18.5) 42 (12) 35 (10) 37 (11) Normal (18.5-25) 177 (51) 190 (54) 193 (55) Overweight (25-30) 96 (27) 78 (22) 77 (22) Obese (> 30) 48 (14) 44 (13) Overall, women weighed more and had higher BMIs at BL than men in ADVANCE. Just over half the participants had a normal BMI at BL, and approximately a quarter were overweight.

ADVANCE: Changes in body weight/BMI by arm TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV Mean change in weight (kg) Week 48 +6 kg +3 kg +1 kg Week 96 +8 kg +5 kg +2 kg Treatment-emergent overweight, n (%) 23% 14% 9% 25% 13% 11% Treatment-emergent obesity, n (%) 7% 6% 19% 8% 4% Looking at changes in body weight and BMI by arm in ADVANCE at weeks 48 and 96: OW = BMI 25-29.9; obese = BMI ≥ 30 Increases in weight across all three study arms, higher with DTG than EFV which was statistically significant As were changes in BMI Treatment emergent clinical obesity was higher with DTG than with EFV For all three parameters, the changes were greater in the TAF-containing arm compared to the TDF-containing arms Highly significant differences in weight change between arms, p<0.001 Clinical obesity (BMI ≥ 30 kg/m2). TAF/FTC+DTG higher than other 2 groups (p<0.01)

ADVANCE: Mean change in weight (kg) to Week 96: men Looking at mean weight changes over 96 weeks in men: We saw greater increases in weight in the 2 DTG arms compared to the EFV arm These were higher in the TAF arm than the TDF-containing arms Changes in weight were progressive in the DTG arms to week 48, after which the rate of increase appears to plateau At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. TAF/FTC+DTG vs. TDF/FTC+DTG: p=0.806 (not significant) TAF/FTC+DTG vs. TDF/FTC/EFV: p=0.003 (p<0.01) TDF/FTC+DTG vs. TDF/FTC/EFV: p=0.004 (p<0.01)

ADVANCE: Percentage weight change (%) to Week 96: men Percentage weight changes in men over 96 weeks mirror the mean changes in weight, with: Greater percentage weight changes in the 2 DTG arms compared to the EFV arm These were greater in the TAF arm than the TDF-containing arms Percentage weight change increases were progressive in the DTG arms to week 48, after which the rate of increase appears to plateau At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. TAF/FTC+DTG vs. TDF/FTC+DTG: p=0.866 (not significant) TAF/FTC+DTG vs. TDF/FTC/EFV: p=0.003 (p<0.01) TDF/FTC+DTG vs. TDF/FTC/EFV: p=0.004 (p<0.01)

ADVANCE: Percentage change in weight over time: men % Participants Here the percentage weight gain over time in men is presented as a heat map. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. You can see that by 96 weeks there are more men who have experienced 10-20% or 20% or more weight gain in the TAF/FTC+DTG arm compared to the other 2 study arms. By week 96, close to 30% of men in the TAF/FTC+DTG arm have experienced weight gain of 10-20% or ≥ 20%. Can also see that there are more men experiencing 10% or more weight loss in the EFV arm than the DTG-containing arms.

ADVANCE: BMI category over time: men (obese at baseline excluded) % Participants Here we show for men changes in BMI category over 96 weeks, with those who were obese at BL excluded from the analysis. More men receiving TAF/FTC+DTG became overweight or obese than the other 2 study arms. Slightly more underweight men in the 2 TDF arms. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented.

ADVANCE: Changes in body composition: men Week 48 Week 96 TAF/FTC+DTG (n=109) TDF/FTC+DTG (n=124) TDF/FTC/EFV (n=114) (n=43) (n=42) (n=40) Still focussing on male participants, we can see changes in body composition as shown by DXA scanning, which was performed in ADVANCE at BL, week 48 and week 96. Changes in trunk and limb fat were higher in the DTG arms. Can see here that most of the weight gain in these arms is fat gain, both trunk and limb. In the EFV arm, we can see different changes, in that while both limb and trunk fat increased at weeks 48 and 96, at week 96 there was a loss of lean trunk mass. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. Mean change in weight is slightly lower with DXA – all participants were weighed at every visit. While the intention was to perform DXAs on all participants, this was not always possible eg very obese participants may have been too big for the scanner to accommodate and so the DXA data might underestimate mean weight change compared to the main analysis.

ADVANCE: Mean change in weight (kg) to Week 96: women Moving on to look at women in ADVANCE. Starting with mean weight changes over the study: Greater increases in weight in the 2 DTG arms compared to the EFV arm Higher in the TAF arm than the TDF-containing arms, with mean increase of 10 kg in women on this arm (in context: half of the female participants gained over 10 kg on this arm) Changes in weight were progressive in the DTG arms and do not seem to plateau at week 96 as was seen with the men in the study At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. TAF/FTC+DTG vs. TDF/FTC+DTG: p=0.0008 (p<0.001) TAF/FTC+DTG vs. TDF/FTC/EFV: p<0.0001 (p<0.001) TDF/FTC+DTG vs. TDF/FTC/EFV: p=0.044 (p<0.05)

ADVANCE: Percentage weight change (%) to Week 96: women Percentage weight changes in women over 96 weeks mirror the mean changes in weight: Greater percentage weight changes in the 2 DTG arms compared to the EFV arm Greater in the TAF arm than the TDF-containing arms, with women on this arm experiencing on average 16% increase in weight over 96 weeks Percentage weight change increases were progressive in the DTG arms to week 96 and do not appear to be plateauing at week 96 At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. TAF/FTC+DTG vs. TDF/FTC+DTG: p=0.0006 (p<0.001) TAF/FTC+DTG vs. TDF/FTC/EFV: p<0.0001 (p<0.001) TDF/FTC+DTG vs. TDF/FTC/EFV: p=0.041 (p<0.05)

ADVANCE: Percentage change in weight over time: women % Participants Here the percentage weight gain over time in women is presented as a heat map. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented. You can see that by 96 weeks there are more women who have experienced 10-20% or 20% or more weight gain in the TAF/FTC+DTG arm compared to the other 2 study arms. By week 96, around 60% of women in the TAF/FTC+DTG arm have experienced weight gain of 10-20% or ≥ 20% (compared to about 30% of men). Almost 40% of women in this arm had experience 20% or more weight gain at 96 weeks. In the EFV arm, can see more women experiencing 10% or more weight loss compared to the other 2 study arms.

ADVANCE: BMI category over time: women (obese at baseline excluded) % Participants Here we show changes in BMI category over 96 weeks for women in ADVANCE, with those who were obese at BL excluded from the analysis. More women receiving TAF/FTC+DTG became overweight or obese than the other 2 study arms: by week 96, almost 70% of women in the TAF/FTC+DTG were overweight or obese. More than 20% of women in the TAF/FTC+DTG arm became obese by week 96, compared to less than 20% in the TDF/FTC+DTG arm and less than 10% in the EFV-containing arm. There were more underweight women in the two TDF-containing arms, and this was relatively stable across the study. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented.

ADVANCE: Changes in body composition: women Week 48 Week 96 TAF/FTC+DTG (n=158) TDF/FTC+DTG (n=156) TDF/FTC/EFV (n=137) (n=60) (n=53) (n=48) Looking at the DEXA data in women: Increases in trunk and limb fat were higher in both DTG arms and increased further from week 48 to week 96 in women. Increases in both limb and trunk fat which were considerably higher in women on the TAF/FTC+DTG arm and which continued to increase substantially from week 48 to week 96. Increases in lean mass, both limb and trunk, were also higher in the DTG arms than with EFV. In the EFV arm, we can see different changes, with smaller increases in limb and trunk fat, and minimal increase in lean mass by week 96. At the time of the analysis, not all participants had reached week 96 of the study; accordingly the number of participants at each time point is represented.

ADVANCE: Factors associated obesity and weight gain (1/2) We fitted Competing-risks regression models1 for the following outcomes: Treatment-emergent obesity ≥ 10% increase in body weight Adjusted for: Sociodemographics (age, gender, nationality, relationship status, education level, employment status) Baseline factors (weight or BMI, treatment arm, CD4+ cell count, HIV viral load) Disease history and adverse events (history of hypertension, diabetes, or dyslipidaemia) Concomitant medications (contraceptives, amlodipine, psychotropic medications and prednisone) We performed multivariate analyses to adjust for various factors, including Sociodemographic factors: age, gender, nationality, relationship status, education level, employment status BL factors: weight/BMI, treatment arm, CD4 count and VL Disease history and adverse events: history of HPT, DM or dyslipidaemia Concomitant medications: contraceptives, amlodipine, psychotropic medications and prednisone 1Competing risks were pregnancy or early d/c. Follow-up started on the date of randomisation and ended on the day of event (failure or competing), or at the day of last visit if no event was observed

ADVANCE: Factors associated obesity and weight gain (2/2) After multivariable analysis, associated factors were: Treatment-emergent obesity: TAF/FTC+DTG, baseline CD4+ count, baseline VL, and baseline BMI When baseline BMI was excluded the following predictors were also significant: female sex, South African nationality, and employment ≥ 10% increase in body weight: TAF/FTC+DTG, baseline CD4+ count, baseline VL, female sex, age, and baseline weight Factors associated with treatment-emergent obesity were TAF/FTC+DTG; BL CD4 count, VL and BMI Excluding BL obesity, female sex, South African nationality and employment status were also significant Factors associated with 10% or higher increase in body weight included TAF/FTC+DTG, BL VL, female sex, age and BL weight.

ADVANCE: Changes in lipids to Week 48 Lipid (mmol/L) TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV Total cholesterol, median +0.1 -0.1 +0.3 LDL, median 0.0 HDL, median Triglycerides, median Some statistically significant differences between arms; however, of small magnitude (not clinically significant) Total cholesterol: gr1v3 <0.001; gr2v3 <0.001; gr1v2 <0.001 LDL: gr1v3 0.28; gr2v3 <0.001; gr1v2 <0.001 HDL: gr1v3 <0.001; gr2v3 <0.001; gr1v2 0.046 Triglycerides: gr1v3 0.89; gr2v3 0.006; gr1v2 0.003 While changes in lipid parameters were SS, the magnitude of changes was very small and therefore not clinically significant. However we continue to monitor lipids, glucose and CVS risk factors in study participants.

Perceptions? Administered before weight gain information leaflet and consent 68 participants surveyed by 15 July 2019: 51 women, 17 men No discontinuations for weight gain; most participant’s estimation of their weight gain was similar to the actual weight gain, with a few wild exceptions 8 women reported unhappiness with weight gain (one actually had lost 1.3 kg); 3 had actually gained < 5%, while 4 had > 10% weight gain. 2 of those who gained > 10% of their baseline weight expressed that they were very unhappy 6 women participants reported uneven weight gain: 3 abdominal, 2 upper body, 1 hip area, and 1 lower body 2 men reported unhappiness with weight loss (verified weight loss for both) Most participants were happy with the weight gain, even though they had to get new clothes as their pre-ART clothes could not fit anymore. Some viewed the weight gain as “return to health” although they had not reported weight loss at screening. Source: Dr Simiso Sokhela

Conclusions First-line DTG is associated with rises in body weight and clinical obesity in men and women (ADVANCE and NAMSAL), and increased trunk and limb fat (ADVANCE) Rises in body weight are higher in women, and if DTG is used in combination with TAF/FTC (ADVANCE) Rises in body weight on TAF/FTC+DTG are progressive and do not plateau to 96 weeks in women (ADVANCE) Longer term follow-up and re-analysis of other studies is required to evaluate consequences of weight gain/clinical obesity ADVANCE trial is ongoing, and we will continue to monitor people in the three randomised treatment arms to see what happens in the long-term. We would like to continue follow up for at least another 2 years until week 192 – we are actively pursuing funding to be able to do so. The strength of these data is that it includes 60% women in an RCT setting, and in ADVANCE, the results are supported by DXA scans. Further analyses of the DXA data to look at subcutaneous and visceral adipose tissue are planned.

Acknowledgements Thank you to the study participants; Andy Hill and his team; the ADVANCE and NAMSAL study teams Funding for ADVANCE from USAID, Unitaid, the South African Medical Research Council (SAMRC), with drug donated by ViiV Healthcare and Gilead Sciences Funding for NAMSAL from Unitaid and ANRS