Progressive rises in weight and clinical obesity for TAFFTCDTG and TDFFTCDTG versus TDFFTCEFV ADVANCE and NAMSAL trials Andrew Hill Francois Venter Eric Delaporte Simiso Sokhela Charles ID: 771373
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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
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/EFV 400In the 96-week ADVANCE trial, 1053 treatment-naïve patients in South Africa were randomised to TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFVBoth trials measured changes in body weight, body mass index (BMI), and trunk fat (ADVANCE only) between treatment arms 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 A Hill et al . Journal of Virus Eradication 2019
Clinical implications of obesity in HIV-negative (BMI ≥ 30kg/m 2 ) 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 A Cournil et al . International Congress on Drug Therapy in HIV Infection 2018. Abstract O342
NAMSAL: Baseline characteristics Characteristic, 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) 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/mm 3 289 (157-452) 271 (147-427)
NAMSAL: Changes in body weight/BMI by arm at Week 48 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/m 2 ) +1.7 +1.2 <0.001 Treatment-emergent overweight (BMI 25 – 29.9), n (%) 16% 17% n.s . Treatment-emergent obesity (BMI ≥ 30), n (%) 12% 5% <0.01 Highly significant differences in weight and BMI change between arms Clinical obesity (BMI ≥ 30 kg/m 2 ) TDF/3TC+DTG higher than TDF/3TC/EFV
NAMSAL: ≥ 10% change from baseline weight (Week 48) p<0.05 n.s.
NAMSAL: Treatment-emergent obesity (Week 48) p<0.01 n.s.
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: Baseline characteristics (1/2) Characteristic TAF/FTC+DTG (n=351) TDF/FTC+DTG (n=351) TDF/FTC/EFV (n=351) Age, mean (SD), years 33 ± 8 32 ± 8 32 ± 7 Female 61% 59% 57% Black 99% 100% 100% Baseline HIV-1 100,001 – 500,000 copies/mL 19% 18% 21% Baseline HIV-1 ≥ 500,000 copies/mL 3% 3% 2% CD4+ cell count, mean (SD), cells/mm 3 349 ± 225 323 ± 234 337 ± 222
ADVANCE: Baseline characteristics (2/2) Characteristic TAF/FTC+DTG (n=351) TDF/FTC+DTG (n=351) TDF/FTC/EFV (n=351) Weight, mean (kg) Male 67.9 67.1 67.3 Female 68.8 69.5 70.2 BMI, mean (kg/m 2 ) Male 21.7 21.6 21.8 Female 25.6 26.1 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) 35 (10) 48 (14) 44 (13)
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 (%) Week 48 23% 14% 9% Week 96 25% 13% 11% Treatment-emergent obesity, n (%) Week 48 14% 7% 6% Week 96 19% 8% 4% Highly significant differences in weight change between arms, p<0.001 Clinical obesity (BMI ≥ 30 kg/m 2 ). TAF/FTC+DTG higher than other 2 groups (p<0.01)
ADVANCE: Mean change in weight (kg) to Week 96: men
ADVANCE: Percentage weight change (%) to Week 96: men
ADVANCE: Percentage change in weight over time: men % Participants
ADVANCE: BMI category over time: men (obese at baseline excluded) % Participants
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) TAF/FTC+DTG (n=43) TDF/FTC+DTG (n=42) TDF/FTC/EFV (n=40)
ADVANCE: Mean change in weight (kg) to Week 96: women
ADVANCE: Percentage weight change (%) to Week 96: women
ADVANCE: Percentage change in weight over time: women % Participants
ADVANCE: BMI category over time: women (obese at baseline excluded) % Participants
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) TAF/FTC+DTG (n=60) TDF/FTC+DTG (n=53) TDF/FTC/EFV (n=48)
We fitted Competing-risks regression models 1 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) 1 Competing 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 (1/2)
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 ADVANCE: Factors associated obesity and weight gain (2/2)
Lipid (mmol/L) TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV Total cholesterol, median +0.1 -0.1 +0.3 LDL, median +0.1 0.0 +0.1 HDL, median +0.1 +0.1 +0.3 Triglycerides, median 0.0 -0.1 0.0 Some statistically significant differences between arms; however, of small magnitude (not clinically significant) ADVANCE: Changes in lipids to Week 48
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 body2 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. Perceptions? Administered before weight gain information leaflet and consent Source: Dr Simiso Sokhela
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 Conclusions
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