Cardiometabolic Outcomes, Mechanisms and approach to prevention of Dolutegravir Associated Weight Gain In South Africa

南非的心脏代谢结果、机制和预防多替拉韦相关体重增加的方法

• 批准号: 10256033
• 负责人: Andre Pascal Kengne
• 金额: $ 16.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256033
• 关键词: Address; Adult; Affect; Africa; African; Age; Anthropometry; Appetite Stimulants; Attitude; Bayesian Analysis; Biological; Blood; Blood Pressure; Body Composition; Body Weight; Body Weight Changes; Body fat; Body mass index; C-Peptide; CD4 Lymphocyte Count; Cardiovascular system; Control Groups; Data; Deposition; Development; Diabetes prevention; Diet; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Energy Intake; Fatty acid glycerol esters; Female; Fibrinogen; Fibrosis; Focus Groups; General Population; Glucose; Glycosylated hemoglobin A; HIV; Health; Hepatic; Hormones; Hyperinsulinism; Hypertension; Inflammation; Insulin; Integrase Inhibitors; Interleukin-6; Intervention; Interview; Knowledge; Leptin; Life Style Modification; Limb structure; Lipids; Liver; Measures; Metabolic; Metabolic Diseases; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Participant; Perception; Play; Population; Preparation; Prevention approach; Prevention strategy; Prospective cohort study; Regimen; Resistance; Role; Serum; South Africa; South African; Vertebral column; Viral Load result; Visceral fat; Weight; Weight Gain; Woman; acceptability and feasibility; age effect; antiretroviral therapy; base; blood glucose regulation; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; clinical practice; clinically significant; cost; efavirenz; exercise intervention; ghrelin; global health; glucagon-like peptide 1; glucose tolerance; indexing; insight; insulin sensitivity; low and middle-income countries; men; mortality; muscle form; next generation; novel; pill; prevent; primary outcome; response; scale up; screening; secondary outcome; sex; tool; waist circumference; weight gain prevention

SUMMARY About 30% of people living with HIV (PLWH) in low- and middle- income countries are overweight/obese, which contributes to substantial morbidity and mortality. Alarmingly, the ADVANCE Trial data in South Africa has shown that in PLWH, initiating a dolutegravir (DTG)- vs. an efavirenz-containing ART regimen is associated with excessive (≥10%) weight gain. While this weight gain may reflect a positive return-to-health effect, it may also increase the risk of cardiometabolic complications. Due to its high potency, low resistance, single daily pill coformulation, and relatively low cost, DTG is expected to play a major role in HIV treatment in Africa. Little is known about the magnitude, clinical significance, and biologic mechanisms of DTG-related weight gain, which disproportionally affects Africans and in particular, African women. Studies investigating weight gain associated with switching from an efavirenz- to a DTG-containing ART regimen are lacking and thus critically needed to provide important and novel insights. We propose, therefore, a 12-month prospective cohort study of African men and women: PLWH who switch to DTG-based ART (N=70) (Group A), PLWH remaining on non-DTG-based ART (N=70) (Group B), and an HIV-uninfected control group (N=70) (Group C, to account for aging effect on weight gain) in Cape Town, South Africa. The specific aims are: 1) To assess the effects of switching to a DTG-based ART regimen on body composition, ectopic fat deposition, and cardiometabolic profile for PLWH; 2) To explore potential mechanisms of DTG-associated weight gain by measuring changes in orexigenic and anorexigenic hormone levels in response to glucose among PLWH who switch to a DTG-based ART regimen; 3) To adapt the South African Diabetes Prevention Package (SA-DPP) for PLWH and assess its acceptability and feasibility. Aim 1 and/or 2: Primary outcome will be absolute weight change (kg) at 12 months from baseline. Secondary outcomes will be measured at baseline, and 6- and 12-months post switch and will include: anthropometry (body mass index [BMI] and waist circumference), total and regional (trunk, limb, and visceral) fat mass and muscle mass (dual energy x-ray absorptiometry [DXA]), and hepatic fat/fibrosis as measured noninvasively by FibroScan®; glucose homeostasis including glucose tolerance, HbA1c, measures of insulin sensitivity (HOMA-IR, Matsuda index), secretion (insulinogenic index), and clearance (C-peptide/insulin molar ratio); subclinical inflammation, blood pressure, and serum lipids; orexigenic and anorexigenic hormone levels. Aim 3: Focus group discussions and in-depth interviews will be conducted to explore the knowledge, barriers, and facilitators to lifestyle modification and weight gain among PLWH as well as mitigating strategies. The overall impact of this study will be to inform appropriate weight gain prevention strategies in preparation for DTG scale-up as the backbone for the next generation of ART in Africa.

概括 在低收入和中等收入国家，约 30% 的艾滋病毒感染者 (PLWH) 超重/肥胖，这 令人担忧的是，南非的 ADVANCE 试验数据显示， 研究表明，在 PLWH 中，启动多替拉韦 (DTG) 与含依非韦伦的 ART 方案相关 体重增加过多（≥10%） 虽然这种体重增加可能反映了恢复健康的积极效果，但也可能会出现这种情况。 由于其效力高、阻力低，每天服用一次，也会增加心脏代谢并发症的风险。 药丸复合制剂和相对较低的成本，DTG 预计将在非洲的艾滋病毒治疗中发挥重要作用。 关于 DTG 相关的严重程度、临床意义和生物学机制知之甚少 体重增加，这对非洲人，尤其是非洲妇女的影响尤为严重。 缺乏与从依非韦伦 ART 方案转为含 DTG 的 ART 方案相关的体重增加 因此，我们迫切需要提供重要且新颖的见解，因此，我们建议为期 12 个月的时间。 非洲男性和女性的前瞻性队列研究：改用基于 DTG 的 ART 的 PLWH（N=70）（组 A)、仍在接受非 DTG ART 治疗的感染者 (N=70)（B 组）和未感染 HIV 的对照组 (N=70) （C 组，考虑衰老对体重增加的影响）在南非开普敦 具体目标是： 1) 评估转用基于 DTG 的 ART 方案对身体成分、异位脂肪的影响 2）探索DTG相关的潜在机制 通过测量食欲和厌食激素水平对葡萄糖的反应来增加体重 改用基于 DTG 的 ART 方案的 PLWH 3) 适应南非糖尿病预防； 针对 PLWH 的一揽子方案 (SA-DPP) 并评估其可接受性和可行性 目标 1 和/或 2：主要结果。 是 12 个月时相对于基线的绝对体重变化（kg）。次要结果将在 12 个月时测量。 基线以及转换后 6 个月和 12 个月，将包括：人体测量（体重指数 [BMI] 和腰围 周长）、总脂肪量和局部（躯干、四肢和内脏）脂肪量和肌肉量（双能 X 射线 吸收测定法 [DXA]），以及通过 FibroScan® 无创测量的肝脂肪/纤维化； 包括葡萄糖耐量、HbA1c、胰岛素敏感性测量（HOMA-IR、松田指数）、分泌 （胰岛素生成指数）和清除率（C 肽/胰岛素摩尔比）； 目标 3：焦点小组讨论和深入。 将进行访谈，探讨生活方式改变和生活方式改变的知识、障碍和促进因素。 PLWH 的体重增加以及缓解策略 这项研究的总体影响将是提供信息。 适当的体重增加预防策略，为 DTG 扩大规模做准备，作为 非洲的下一代艺术。