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

总结 在低收入和中等收入国家，大约30%的艾滋病毒感染者超重/肥胖， 导致大量的发病率和死亡率。令人担忧的是，南非的ADVANCE试验数据显示， 显示在PLWH中，启动度鲁特韦（DTG）与含依法韦仑的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积极的恢复健康的效果， 也会增加心脏代谢并发症的风险。由于其高效力，低阻力，每日单次 由于DTG是一种药丸共制剂，而且成本相对较低，预计DTG将在非洲的艾滋病毒治疗中发挥重要作用。 目前对DTG相关性的程度、临床意义和生物学机制知之甚少。 体重增加，这对非洲人，特别是非洲妇女产生了不良影响。研究调查 缺乏与从依法韦仑转换为含DTG的ART方案相关的体重增加 因此迫切需要提供重要和新颖的见解。因此，我们建议， 非洲男性和女性的前瞻性队列研究：转为基于DTG的ART的PLWH（N=70）（组 A）、仍在接受非DTG为基础的ART的PLWH（N=70）（组B）和未感染HIV的对照组（N=70） （C组，考虑年龄对体重增加的影响），南非开普敦。具体目标是：（1） 评估转换为基于DTG的ART方案对身体成分、异位脂肪 PLWH的沉积和心脏代谢特征; 2）探索DTG相关的潜在机制 体重增加，通过测量食欲和食欲激素水平的变化， PLWH转换为基于DTG的ART方案; 3）调整南非糖尿病预防 PLWH的包装（SA-DPP），并评估其可接受性和可行性。目标1和/或2：主要结局 是12个月时相对于基线的绝对体重变化（kg）。次要结局将在 基线、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、肢体和内脏）脂肪量和肌肉量（双能X射线 吸收测定法[DXA]）和FibroScan®非侵入性测量的肝脂肪/纤维化;葡萄糖稳态 包括葡萄糖耐量、HbA 1c、胰岛素敏感性指标（HOMA-IR、Matsuda指数）、分泌 （胰岛素生成指数）和清除率（C-肽/胰岛素摩尔比）;亚临床炎症，血压， 和血脂;食欲和食欲激素水平。目标3：重点小组讨论和深入 将进行访谈，以探讨改变生活方式的知识、障碍和促进因素， PLWH中的体重增加以及缓解策略。这项研究的总体影响将是告知 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。

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.