International Center for Excellence in Research (ICER) in Uganda: Impact of ARVs

乌干达国际卓越研究中心 (ICER)：抗逆转录病毒药物的影响

• 批准号: 10689600
• 负责人: Thomas Quinn
• 金额: $ 117.37万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689600
• 关键词: AIDS prevention; Address; Adherence; Adult; Africa; Africa South of the Sahara; Age; Anti-Retroviral Agents; Area; Burkitt Lymphoma; CD4 Lymphocyte Count; COVID-19; COVID-19 pandemic; Car Phone; Caring; Cells; Client; Clinic; Clinical; Clinical Trials; Cluster randomized trial; Cohort Analysis; Cohort Studies; Communities; Community Health Aides; Counseling; Couples; Currently Married; Data; Destinations; Disease; Effectiveness; Eligibility Determination; Enrollment; Epidemic; Female; Female Adolescents; Fishes; General Population; Geography; Goals; HIV; HIV Infections; HIV antiretroviral; Health Benefit; Herpesviridae; High Prevalence; Hospitals; Human immunodeficiency virus test; Immunologics; Incidence; Individual; Intervention; Location; Low Prevalence; Malaria; Male Circumcision; Migrant; Minority; Modeling; Monitor; Morbidity - disease rate; Mortality Decline; Operative Surgical Procedures; Participant; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Phylogenetic Analysis; Population; Population trends; Prevalence; Prevention; Prevention program; Prevention strategy; Prostitution; Public Health; Quality of Care; Research; Resources; Retrospective cohort; Risk; Rural Community; Services; Source; Testing; Time; Uganda; Viral; Viral Load result; Viremia; Woman; age group; aged; antiretroviral therapy; base; care delivery; coronavirus disease; effectiveness evaluation; first-in-human; flexibility; follow-up; genetic risk factor; high risk; immune activation; implementation barriers; implementation strategy; improved; international center; latent HIV reservoir; male; men; migration; mortality; novel; outreach; pre-exposure prophylaxis; prevention service; programs; residence; scale up; service delivery; service uptake; sex; social stigma; success; tool; transmission process; treatment as prevention; treatment guidelines; treatment services; treatment strategy; trend; uptake; viral rebound

The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study (RCCS) in Uganda and using phylogenetics to identify hotspots of HIV transmission and areas where HIV prevention efforts need to be intensified. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment as prevention. Our combination prevention study has proven the impact of effectively implemented programs on HIV incidence in the general Rakai population. Our study was the first to provide evidence of the beneficial impact of combination prevention on rural communities in sub-Saharan Africa. Despite this success, challenges remain at achieving epidemic control and we continue to describe important implementation challenges as we scale up combination prevention. We assessed the effectiveness of our VMMC program outside of the clinical trial setting and showed that effectiveness was sustained with increasing time from surgery and was similar across age groups. We assessed migration patterns using data collected between August 2011 and January 2015 from the RCCS. 29% (n=6718) of participants who migrated over 2 years were significantly more likely to be young and female. Compared to long-term residents, risk of HIV-infection was significantly elevated in women and men in the first two years following migration (women: adjIRR=1.92, 95%CI: 1.52-2.43; men: adjIRR=1.75, 95%CI: 1.33-2.33). While HIV incidence significantly declined among residents and non-recent in-migrants with scale-up of combination HIV prevention, it did not decline among recent in-migrants. HIV-infected migrants, largely women, are less likely to use ART and differentially move into hotspot fishing communities. We find that migrants moving into hotspots (prevalence 40%) had significantly higher HIV prevalence than migrants moving elsewhere, but that out-migrants from hotspots dispersed broadly, contributing minimally to HIV burden in individual destination locations. The COVID-19 pandemic presented a challenge to continuity of HIV prevention and treatment services with a risk of halting the gains made in reducing HIV incidence. We examined population trends in HIV service delivery, viral suppression and incidence before and during the COVID-19 era in Rakai. We found a slight decrease in HIV testing during the COVID-19 era but ART use and male circumcision rates increased while viral load suppression remained high above 90%. HIV incidence continued to decline from 0.48/100 person years immediately before Covid to 0.35/100 person years during Covid. In our setting, community based outreach strategies contributed to sustained HIV service delivery and continued success in HIV prevention programs. Pre-exposure prophylaxis (PrEP) is a key component of our HIV combination prevention strategy among high-risk HIV uninfected clients. During the early phase of our PrEP rollout among key populations (fisher folk, commercial sex workers, adolescent girls and truck drivers) we observed high uptake of PrEP services with 92.2% of eligible clients enrolled and started on PrEP. Despite this uptake, retention was poor with a medium retention of 45.4 days overall with male clients being at higher risk of discontinuation of PrEP In a follow-up qualitative study among PrEP users, we found that PrEP stigma and unexpected migration issues among clients were major barriers to continuation with PrEP Flexible community led delivery models may improve PrEP retention among these highly mobile clients. PrEP programs have focused on key populations at highest risk of HIV for maximum impact, however, we assessed PrEP eligibility among our general population in Rakai and found a high rate (29%) of eligibility which was also associated with an elevated HIV incidence in our general population. Wider access to PrEP in our setting will be key to achieving HIV epidemic control. Hotspots of HIV transmission have been thought to be a source of ongoing spread of HIV and potentially an important target for HIV prevention efforts. Using phylogenetic analysis, we were able to infer partial HIV transmission networks including the directionality of transmission. Using RCCS residence and migration data, HIV transmission flows were quantified between high and low prevalence areas. Most transmissions (89.2%) occurred within inland low prevalence settings while a minority (5.7%) occurred within high prevalence fishing communities. Contrary to what was hypothesized, more transmissions were documented going from low prevalence inland areas to high prevalence fishing communities (3.7%) while only 1.3% of transmissions were observed going from high prevalence fishing communities to low prevalence inland areas. Our findings suggest that geographic focus on HIV hotspots may not achieve epidemic control and wider prevention efforts are needed. Viral load monitoring (VLM) is currently being scaled up in Uganda after a decade of relying on immunologic and clinical monitoring. This provides a unique tool to investigate adherence challenges and also improve on the quality of care delivery by focusing resources on those most in need. Examining the prevalence and predictors of persistent HIV viremia and viral rebound during the current test and treat era, we found that persistent viremia declined from 20.7 to 13.3%. Younger age (15-29 vs. 40-49 years, adjRR=1.80 (95%CI=1.19-2.71), male sex (adjRR=2.09 (95%CI=1.47-2.95), never being married (vs. currently married; adjRR=1.88 (95%CI=1.34-2.62), and recent migration to the community (vs. long-term resident; adjRR=1.91 (95%CI=1.34-2.73) were factors associated with persistent viremia. Despite increases in durable VL suppression during roll-out of test and treat in hyperendemic communities, a substantial fraction of the population, whose risk profile tended to be younger, male, and mobile, remained persistently viremic. Effective implementation strategies are needed to increase engagement in HIV services to achieve maximum HIV epidemic control. We conducted a cluster randomized trial to assess the impact of community health workers equipped with a novel mobile phone-based counseling strategy to improve uptake of HIV treatment and prevention services. Despite improvements in HIV care and ART service uptake, the intervention did not clearly improve male circumcision coverage or HIV suppression. Early mortality in the first year of ART therapy continues to challenge the health benefits of treatment particularly among patients presenting with late change disease. We hypothesized that as treatment guidelines changed in Uganda to earlier initiation, significant mortality declines would occur. We conducted a retrospective cohort analysis on 6800 HIV-infected adults aged 18+ years who started ART between 2005 and 2016 at the urban-based Mengo Hospital HIV clinic to examine trends in mortality over time. The proportion of patients initiating ART with CD4 count 100 cells/ul decreased from 46% to 27% (p <0.001) and those initiating with WHO stage III or IV disease significantly decreased from 50% to 22% (p<0.001) over this time. Mortality in the first year of ART decreased by 70% over this corresponding time period, from 8.7/100 person-years to 2.5/100 person-years (p<0.001). Changing treatment guidelines and strategies to implement earlier initiation of ART have had a dramatic impact on early mortality in our setting.

在非洲引入艾滋病毒抗逆转录病毒药物（ARV）已导致发病率和死亡率大幅下降。该项目正在乌干达的拉凯社区队列研究 (RCCS) 中研究抗逆转录病毒药物对社区一级发病率的影响，并利用系统发育学来确定艾滋病毒传播的热点和需要加强艾滋病毒预防工作的地区。我们已经证明完全消除了抗逆转录病毒药物不和谐夫妇之间的传播，并继续扩大治疗作为预防。我们的联合预防研究证明了有效实施的计划对拉凯普通人群中艾滋病毒发病率的影响。我们的研究首次提供了联合预防对撒哈拉以南非洲农村社区有益影响的证据。尽管取得了这一成功，但在实现流行病控制方面仍然存在挑战，我们将继续描述在扩大联合预防方面的重要实施挑战。我们在临床试验环境之外评估了 VMMC 计划的有效性，结果表明，随着手术时间的增加，有效性持续存在，并且在不同年龄组中效果相似。 我们使用 RCCS 2011 年 8 月至 2015 年 1 月期间收集的数据评估了迁移模式。 29% (n=6718) 迁移超过 2 年的参与者明显更可能是年轻人和女性。与长期居民相比，女性和男性在移居后的头两年感染艾滋病毒的风险显着升高（女性：adjIRR=1.92，95%CI：1.52-2.43；男性：adjIRR=1.75，95%CI ：1.33-2.33）。虽然随着艾滋病毒综合预防的扩大，居民和非新移民的艾滋病毒发病率显着下降，但新移民的艾滋病毒发病率并未下降。感染艾滋病毒的移民（主要是女性）不太可能使用抗逆转录病毒疗法，并且有差异地进入热点捕鱼社区。我们发现，迁入热点地区的移民（患病率 40%）的艾滋病毒感染率明显高于迁往其他地方的移民，但从热点地区迁出的移民分布广泛，对个别目的地地点的艾滋病毒负担影响极小。 COVID-19 大流行对艾滋病毒预防和治疗服务的连续性提出了挑战，并有可能阻止在降低艾滋病毒发病率方面取得的成果。 我们研究了拉凯在 COVID-19 时代之前和期间的艾滋病毒服务提供、病毒抑制和发病率方面的人口趋势。 我们发现，在 COVID-19 时代，HIV 检测略有下降，但 ART 的使用和男性包皮环切率有所增加，而病毒载量抑制率仍高达 90% 以上。 HIV 发病率持续下降，从新冠疫情前的 0.48/100 人年下降到新冠疫情期间的 0.35/100 人年。 在我们的环境中，基于社区的外展策略有助于持续提供艾滋病毒服务并确保艾滋病毒预防计划持续取得成功。 暴露前预防 (PrEP) 是我们针对高危 HIV 未感染者的 HIV 联合预防策略的关键组成部分。 在我们在关键人群（渔民、商业性工作者、少女和卡车司机）中开展 PrEP 的早期阶段，我们观察到 PrEP 服务的使用率很高，92.2% 的合格客户注册并开始使用 PrEP。 尽管采用率如此高，但保留率很差，总体中等保留期为 45.4 天，其中男性客户停止 PrEP 的风险较高。在一项针对 PrEP 用户的后续定性研究中，我们发现客户对 PrEP 的耻辱和意外迁移问题是主要问题继续使用 PrEP 的障碍 灵活的社区主导的交付模式可能会提高这些高度流动性客户的 PrEP 保留率。 PrEP 计划侧重于艾滋病毒风险最高的关键人群，以期产生最大的影响，但是，我们评估了拉凯一般人群的 PrEP 资格，发现合格率很高 (29%)，这也与我们地区艾滋病毒发病率升高有关。一般人群。 在我们的环境中更广泛地获得 PrEP 将是实现艾滋病毒流行控制的关键。 HIV 传播热点被认为是 HIV 持续传播的来源，并且可能是 HIV 预防工作的重要目标。通过系统发育分析，我们能够推断出部分艾滋病毒传播网络，包括传播的方向性。利用 RCCS 居住和迁移数据，对高流行地区和低流行地区之间的艾滋病毒传播流量进行了量化。大多数传播（89.2%）发生在内陆低流行地区，而少数（5.7%）发生在高流行渔业社区。与假设相反，从低流行率内陆地区到高流行率捕鱼社区的传播记录较多（3.7%），而仅观察到 1.3% 的传播从高流行率捕鱼社区到低流行率内陆地区。我们的研究结果表明，对艾滋病毒热点地区的地理关注可能无法实现流行病控制，需要更广泛的预防工作。 经过十年的免疫学和临床监测之后，乌干达目前正在扩大病毒载量监测（VLM）的规模。这提供了一个独特的工具来调查依从性挑战，并通过将资源集中在最需要的人身上来提高护理服务的质量。检查当前检测和治疗时代持续性 HIV 病毒血症和病毒反弹的患病率和预测因素，我们发现持续性病毒血症从 20.7% 下降至 13.3%。 年龄较小（15-29 岁与 40-49 岁，adjRR=1.80 (95%CI=1.19-2.71)，男性（adjRR=2.09 (95%CI=1.47-2.95)），从未结婚（与目前已婚） ; adjRR=1.88 (95%CI=1.34-2.62)，最近迁移到社区（与长期居民；adjRR=1.91 (95%CI=1.34-2.73) 是与持续性病毒血症相关的因素，尽管在高流行社区开展检测和治疗期间，持久的 VL 抑制有所增加，但仍有相当一部分人患有病毒血症。风险特征往往是年轻、男性和流动性，需要有效的实施策略来增加艾滋病毒服务的参与，以实现最大限度的艾滋病毒流行控制。卫生工作者配备了一种新颖的基于手机的咨询策略，以提高艾滋病毒治疗和预防服务的采用率 尽管艾滋病毒护理和抗逆转录病毒治疗服务的采用率有所改善，但该干预措施并未明显改善男性包皮环切术的覆盖率或艾滋病毒抑制。 ART 治疗第一年的早期死亡率继续挑战治疗的健康益处，特别是对于患有晚期疾病的患者。我们假设，随着乌干达的治疗指南改为更早开始，死亡率将会显着下降。我们对 2005 年至 2016 年间在城市 Mengo 医院 HIV 诊所开始接受 ART 的 6800 名 18 岁以上 HIV 感染成年人进行了回顾性队列分析，以研究死亡率随时间变化的趋势。在此期间，CD4 计数为 100 个细胞/ul 开始 ART 的患者比例从 46% 下降至 27% (p <0.001)，而开始患有 WHO III 期或 IV 期疾病的患者比例从 50% 显着下降至 22% (p<0.001)。时间。 ART 第一年的死亡率在此期间下降了 70%，从 8.7/100 人年降至 2.5/100 人年 (p<0.001)。改变治疗指南和策略以实施早期抗逆转录病毒治疗，对我们环境中的早期死亡率产生了巨大影响。