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Rising Weight and Obesity in TAF/FTC+DTG and TDF/FTC+DTG versus TDF/FTC/EFV Trials

This study analyzes the impact of different antiretroviral therapies on weight gain and clinical obesity in HIV-positive patients. Results show a progressive increase in weight and obesity with TAF/FTC+DTG and TDF/FTC+DTG regimens compared to TDF/FTC/EFV.

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Rising Weight and Obesity in TAF/FTC+DTG and TDF/FTC+DTG versus TDF/FTC/EFV Trials

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  1. 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

  2. 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

  3. 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 A Hill et al. Journal of Virus Eradication 2019

  4. Drivers of weight gain/loss on ART DTG or BIC Treatment naïve Women Black Weight gain PI Weight loss TDF A Hill et al. Journal of Virus Eradication 2019

  5. Clinical implications of obesity in HIV-negative (BMI ≥ 30kg/m2) M Kivimakiet al. Lancet Public Health 2017; K Bhaskaran et al. Lancet Diabetes Endocrinol 2018

  6. NAMSAL: Study design • Phase 3, randomised, open-label trial • 3 study sites in Yaoundé, Cameroon A Cournilet al. International Congress on Drug Therapy in HIV Infection 2018. Abstract O342

  7. NAMSAL: Baseline characteristics

  8. NAMSAL: Changes in body weight/BMI by arm at Week 48 Highly significant differences in weight and BMI change between arms Clinical obesity (BMI ≥ 30 kg/m2) TDF/3TC+DTG higher than TDF/3TC/EFV

  9. NAMSAL: ≥ 10% change from baseline weight (Week 48) p<0.05 n.s.

  10. NAMSAL: Treatment-emergent obesity (Week 48) p<0.01 n.s.

  11. 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

  12. ADVANCE: Baseline characteristics (1/2)

  13. ADVANCE: Baseline characteristics (2/2)

  14. ADVANCE: Changes in body weight/BMI by arm 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)

  15. ADVANCE: Mean change in weight (kg) to Week 96: men

  16. ADVANCE: Percentage weight change (%) to Week 96: men

  17. ADVANCE: Percentage change in weight over time: men % Participants

  18. ADVANCE: BMI category over time: men (obese at baseline excluded) % Participants

  19. ADVANCE: Changes in body composition: men Week 48 Week 96 TAF/FTC+DTG (n=109) TAF/FTC+DTG (n=43) TDF/FTC+DTG (n=124) TDF/FTC+DTG (n=42) TDF/FTC/EFV (n=114) TDF/FTC/EFV (n=40)

  20. ADVANCE: Mean change in weight (kg) to Week 96: women

  21. ADVANCE: Percentage weight change (%) to Week 96: women

  22. ADVANCE: Percentage change in weight over time: women % Participants

  23. ADVANCE: BMI category over time: women (obese at baseline excluded) % Participants

  24. ADVANCE: Changes in body composition: women Week 48 Week 96 TAF/FTC+DTG (n=158) TAF/FTC+DTG (n=60) TDF/FTC+DTG (n=156) TDF/FTC+DTG (n=53) TDF/FTC/EFV (n=137) TDF/FTC/EFV (n=48)

  25. 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) 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

  26. 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

  27. ADVANCE: Changes in lipids to Week 48 Some statistically significant differences between arms; however, of small magnitude (not clinically significant)

  28. 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

  29. 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

  30. 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

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