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

摘要 在中低收入国家，大约30%的艾滋病毒携带者(PLWH)超重/肥胖，这 导致相当大的发病率和死亡率。令人震惊的是，南非的先期试验数据 研究表明，在PLWH中，启动多洛替格韦(DTG)与含法那韦伦的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一种积极的健康回归效应，但它可能 也会增加心脏代谢并发症的风险。由于它的高效力，低阻力，每天一次 药丸联合制剂，以及相对较低的成本，DTG有望在非洲的艾滋病毒治疗中发挥主要作用。 与DTG相关的DTG的大小、临床意义和生物学机制知之甚少 体重增加，这不成比例地影响非洲人，特别是非洲妇女。调查研究 从efavirenz转换为含有DTG的ART方案导致的体重增加是缺乏的 因此，迫切需要提供重要和新颖的见解。因此，我们提议为期12个月。 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)，PLWH仍在接受非DTG抗逆转录病毒治疗(N=70)(B组)，以及HIV未感染对照组(N=70) (C组，考虑年龄对体重增加的影响)。具体目标是：1) 评估改用基于DTG的ART方案对身体成分、异位脂肪的影响 PLWH的沉积和心脏代谢特征；2)探讨DTG相关的潜在机制 通过测量食欲不振和厌食症激素水平的变化来增加体重 PLWH改用基于DTG的ART方案；3)适应南非糖尿病预防 (SA-DPP)，并评估其可接受性和可行性。目标1和/或目标2：主要成果 将是从基线开始12个月的绝对体重变化(公斤)。次要结果的衡量标准为 基线，转换后6个月和12个月，将包括：人体测量(身体质量指数[BMI]和腰围 周长)、总和局部(躯干、四肢和内脏)脂肪质量和肌肉质量(双能x射线 吸光度[DXA])和FibroScan®非侵入性测量的肝脏脂肪/纤维化；葡萄糖稳态 包括糖耐量、糖化血红蛋白、胰岛素敏感性(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)；亚临床炎症、血压、 和血脂；食欲和厌食激素水平。目标3：重点小组讨论和深入讨论 将进行访谈，以探索改变生活方式的知识、障碍和促进者 PLWH的体重增加以及缓解策略。这项研究的总体影响将是 适当的体重增加预防策略，为DTG的扩大做准备，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.