CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

Conclusion: Application of MR methods demonstrated potential causal effects of 6 proteins on CVD outcomes among a global population. These proteins warrant further study as interventional targets.

Background: Two African trials reported more weight gain with dolutegravir (DTG) than efavirenz (EFV), especially in women. EFV is toxic to mitochondria and is associated with lipoatrophy. We hypothesised that CYP2B6 metaboliser genotype, which predicts EFV exposure, would determine amount of weight gained and fat distribution in patients starting EFV-based ART. Methods: Participants enrolled in the EFV/TDF/FTC arm of the ADVANCE trial who consented to genetic testing were included. CYP2B6 metaboliser genotype was classified as extensive, intermediate, and slow. Outcomes included change in weight gain and trunk and limb fat on DXA from baseline to week 48 by CYP2B6 genotype. Weight gain was compared between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm. Results: 171 participants had genetic testing done. CYP2B6 metaboliser genotypes were 51 extensive, 74 intermediate, and 46 slow; median age 32 years (IQR 28–37); 57%women; median BMI 23.7 kg/m 2 (IQR 20.2–27.5); and median CD4 count 292 cells/uL (IQR 172–406). The percentage change in weight from baseline over 48 weeks differed by CYP2B6 metaboliser genotype (p=0.004; Kruskal-Wallis), but differences were more marked in women over time (see figure). In men CYP2B6 metaboliser genotype was associated with percentage change in weight initially (week 12 p=0.007; week 24 p=0.053), but the effect attenuated over time. The percentage change in limb fat on DXA (n=148) from baseline to 48 weeks differed significantly by CYP2B6 metaboliser genotype in women (p=0.008), with highest percentage increase in extensive metabolisers, but not in men (p=0.680). Percentage change in trunk fat on DXA from baseline to 48 weeks was not significantly different by CYP2B6 metaboliser genotype in women (p=0.082) or men (p=0.732). The percentage change in weight from baseline to 48 weeks was similar between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm (p=0.939). Conclusion: In Africans starting EFV-based ART CYP2B6 metaboliser genotype was associated with weight gain and, in women, with changes in limb fat. The similar weight gain observed between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm suggests off-target effects (e.g. mitochondrial toxicity) impairing weight gain in EFV slow/intermediate metabolisers could explain the greater weight gain observed with DTG in African trials.

81 RISKS OF METABOLIC SYNDROME, DIABETES, AND CARDIOVASCULAR DISEASE IN ADVANCE TRIAL Andrew Hill 1 , Kaitlyn M. McCann 2 , Victoria Pilkington 2 , Michelle A. Moorhouse 3 , Simiso Sokhela 4 , Celicia M. Serenata 4 , Alinda Vos 5 , Willem D. Venter 3 1 University of Liverpool, Liverpool, UK, 2 Imperial College London, London, UK, 3 University of the Witwatersrand, Johannesburg, South Africa, 4 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa, 5 University Medical Center Utrecht, Utrecht, Netherlands Background: In the ADVANCE trial, more patients taking first-line TAF/ FTC+DTG developed clinical obesity compared to TDF/FTC+DTG and TDF/FTC/ EFV. Common associations with obesity include type 2 diabetes, cardiovascular disease (CVD), and metabolic syndrome. This analysis aimed to quantify these risks using standard risk algorithms. Methods: In ADVANCE, 1,053 treatment-naïve patients in South Africa (99% black, 59% female) were randomized to 96 weeks of TAF/FTC+DTG, TDF/ FTC+DTG, or TDF/FTC/EFV. Weight, lipids, fasting glucose, and blood pressure (BP) were measured at baseline and week 48, and used to calculate 10-year risks of CVD and type 2 diabetes using the Framingham, QRISK, and QDIABETES equations. Participants were included in the analysis if they were between the age of 25-84 years and had complete laboratory data for all parameters in risk equations. Treatment emergent metabolic syndrome was calculated at week 48 using the International Diabetes Federation definition and differences between groups were tested using a two-sample test of proportions. Results: 296 (TAF/FTC+DTG), 286 (TDF/FTC+DTG), and 306 (TDF/FTC/ EFV) participants were included in this analysis at baseline. Vital signs and laboratory parameters were similar at baseline across all treatment arms, 82(9%) participants were being treated for hypertension, 12(1%) had diabetes, and 45(5%) had metabolic syndrome. Changes from baseline to week 48 are displayed in Table 1. The risk of developing diabetes was higher in TAF/FTC+DTG compared to TDF/FTC+DTG (p=0.0051). Statistically significant differences were shown in the risk of CVD (Framingham and QRISK) between TAF/FTC+DTG and TDF/FTC/EFV. Treatment-emergent metabolic syndrome was 8%(TDF/FTC+DTG), 6%(TDF/FTC+DTG) and 3%(TDF/FTC/EFV), with statistically significant differences between TAF/FTC+DTG and TDF/FTC/EFV (p=0.021). Conclusion: Treatment with TAF/FTC+DTG led to greater rises in weight, lipids and glucose than TDF/FTC+DTG, with small predicted 10-year risks of CVD and diabetes. There are concerns that these tools may either over- or underestimate risks in HIV and African populations. Longer term studies, with clinical or reliable surrogate endpoints in local HIV-positive populations are needed to validate these risk assessment tools.

Oral Abstracts

83

CHANGES IN BODY MASS INDEX AND THE RISK OF CARDIOVASCULAR DISEASE: THE D:A:D STUDY Kathy Petoumenos 1 , Locadiah Kuwanda 1 , Lene Ryom 2 , Amanda Mocroft 3 , Peter Reiss 4 , Stephane De Wit 5 , Christian Pradier 6 , Andrew N. Phillips 3 , Camilla Ingrid Hatleberg 2 , Antonella D'Arminio Monforte 7 , Rainer Weber 8 , Caroline Sabin 3 , Jens D. Lundgren 2 , Matthew Law 1 , for the D:A:D Study Group 1 Kirby Institute, Sydney, NSW, Australia, 2 University of Copenhagen, Copenhagen, Denmark, 3 University College London, London, UK, 4 University of Amsterdam, Amsterdam, Netherlands, 5 Vrije Universiteit Brussel, Brussels, Belgium, 6 Nice University Hospital, Nice, France, 7 Azienda Ospedaliera San Paolo, Milan, Italy, 8 University of Zurich, Zurich, Switzerland Background: Several studies have shown an increase in weight in HIV-positive people receiving some contemporary antiretrovirals (ARV). We assess the effect of changes in body mass index (BMI), from different baseline BMI levels, on the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Methods: We followed D:A:D study participants on ARV therapy from their first BMI measurement (baseline) to the first endpoint or earliest of 1/2/2016 or 6 months after last follow-up. The endpoints were CVD (composite of myocardial

82 CYP2B6 GENOTYPE AND WEIGHT-GAIN DIFFERENCES BETWEEN DOLUTEGRAVIR AND EFAVIRENZ Rulan Griesel 1 , Gary Maartens 1 , Simiso Sokhela 2 , Godspower Akpomiemie 2 , Willem D. Venter 2 , Michelle A.Moorhouse 2 , Phumla Sinxadi 1 1 University of Cape Town, Cape Town, South Africa, 2 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa

28

CROI 2020