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: 9339915
• 负责人: Thomas Quinn
• 金额: $ 134.28万
• 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/9339915
• 关键词: AIDS prevention; Abate; Accounting; Acquired Immunodeficiency Syndrome; Acyclovir; Address; Adherence; Adult; Africa; Africa South of the Sahara; Antibodies; Antiretroviral drug resistance; Antiretroviral resistance; C-reactive protein; CD14 gene; Caring; Cessation of life; Clinical; Cohort Studies; Communities; Cotrimoxazole; Couples; Cytomegalovirus; Data; Disease Progression; Epidemic; Failure; Female; Fishes; Gender; Generations; HIV; HIV Infections; HIV Seropositivity; HIV antiretroviral; HIV-1; Heterogeneity; Human Herpesvirus 2; Immune response; Immunoglobulin G; Immunologic Monitoring; Incidence; Individual; Intervention; Life; Location; Male Circumcision; Measures; Modeling; Monitor; Morbidity - disease rate; Nomads; Participant; Patient Self-Report; Patients; Pattern; Persons; Pharmaceutical Preparations; Placebos; Population; Prevalence; Prevention; Public Health; Randomized; Randomized Controlled Trials; Regimen; Reporting; Research; Resistance; Resources; Risk Behaviors; Risk Factors; Role; Services; Source; Testing; Time; Uganda; Vagina; Variant; Viral Load result; Visit; Water; Woman; antiretroviral therapy; cohort; design; experience; falls; follow-up; hazard; high risk; immune activation; improved; international center; intervention effect; meetings; men; migration; mortality; peer support; primary outcome; programs; response; scale up; seroconversion; standard of care; time interval; transmission process; uptake; viral resistance

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, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring, and potential delays in detecting virologic failure on transmitted and acquired genotypic ARV resistance. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have continued to monitor the impact of combination prevention among high risk fishing communities bordering Lake Victoria. Average ART coverage among HIV-positive persons increased from 18.6% in 2011 to 67.3% by 2015, while MMC coverage among non-Muslim men increased from 24.3% to 49.2% over the same time period. HIV incidence was 4.0 (95%CI: 2.6-5.7) between 2011 and 2012, falling to 3.3 (95%CI: 2.4-4.5) between 2012 and 2014, and to 2.9 (95%CI: 2.2-3.8) between 2014 and 2015. The aIRR comparing the period 2011-2012 to 2014-2015 was 0.75 (95%CI: 0.47-1.20); the aIRR for men was 0.75 (95%CI: 0.39-1.43) and 0.77 for women (95%CI: 0.38-1.56). Rapid scale-up of combination HIV prevention in high-risk fishing communities on Lake Victoria is feasible, and there is preliminary empirical evidence of the effects of these interventions in decreasing HIV incidence. We also 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. HIV prevalence among in-migrants was significantly higher than long-term residents in women (adjPRR=1.45; 95%CI: 1.31-1.60) but not men (adjPRR=1.03; 95%CI: 0.89-1.19), and ART use was lower among in-migrants of both genders (women: adjPRR=0.67, 95%CI: 0.57-0.78; men: adjPRR=0.73, 95%CI: 0.57-0.78). HIV prevalence among in-migrants to fishing communities, particularly in women, was higher than to other communities regardless of source location, and was positively correlated with HIV prevalence in the long-term resident population (p=0.002). HIV-infected migrants, largely women, are less likely to use ART and differentially move into hotspot fishing communities. However, migrants from these hotspots do not account for a substantial proportion of migrant-associated HIV infection elsewhere suggesting that test and treat targeted to hotspots may not abate the generalized epidemic. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We measured the levels of transmitted antiretroviral drug resistance among 75 recently infected RCCS seroconverters with documented seroconversion between 2012 and 2013. We found low rates of transmitted antiretroviral drug resistance with only 3 individuals (4%) having resistance, 2 to NNRTIs, one had PI resistance and no resistance found to NRTIs. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only.. We observed late switching to second line therapy to be a problem among 3,287 HIV-infected persons who initiated ART between 2004 and 2011, of whom 173 met the criteria for virologic failure 6 or more months after ART initiation. 121 (70%) switched to second line ART. The median timing of switching to second line ART was 7.8 months after virologic failure (IQR=3.3-15.2). Cumulative incidences of switching at 6, 12 and 24 months after virologic failure were 33.2% (95% CI=26.2 41.0), 49.8% (95% CI=42.3 57.9) and 71.9% (95% CI=64.2 79.2) respectively. Adjusted mortality was significantly higher in patients not switched to second line ART at 11.1% compared to those switched at 1.6% (p-value==0.005). Among those switched, the longer the time interval between virologic failure and regimen switch, the more patients experienced CD4 decrease and/or further increase in VL during that interval. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. Our study of Acyclovir suppressive therapy among HIV-1/HSV-2 co-infected patients showed an overall reduction in HIV-1 disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. We found a similar increase among these same women when we measured vaginal CMV shedding. We assessed the humoral immune response to CMV among women in this trial to investigate any association with disease progression and immune activation. We found that the highest CMV IgG tertile at baseline was independently associated with the primary outcome (ART initiation or death) compared to the lowest CMV IgG tertile (adjusted Hazard Ratio=1.59 95%CI=1.05-2.39; P=0.027). Among pre-ART visits, log10 CMV IgG antibody levels were positively associated with soluble CD14 and log10 C-reactive protein levels (P<0.01). The humoral immune response to CMV was associated with HIV disease progression and immune activation. Optimizing the HIV care cascade is a critical component to achieving an AIDS free generation globally. To evaluate strategies to improve engagement in HIV case and prevention, 442 ART-nave, HIV-infected adult participants were randomized to peer support or standard of care.. After a median follow-up of 363 days, intervention participants were more likely to report being in care (92% vs. 84%; p=0.018), on cotrimoxazole (89% vs. 81%; p=0.022), and adherent to safe water vessel use (23% vs. 14%; p=0.022). The intervention effect was observed primarily among participants "not in care" at baseline (n=139) with 83% vs. 53% (p=0.003) of these intervention participants in care at follow-up compared to controls, 78% vs. 58% on cotrimoxazole (p=0.02), and 20% vs. 4% adherent to safe water vessel use (p=0.017). We also evaluated the impact of patient-selected care buddies on HIV adherence to care, disease progression and conduct of daily life among pre-antiretroviral HIV-infected patients in a randomized controlled trial in Rakai. This study found that in pre-ART HIV-infected persons, having care buddies improved the conduct of daily life, but had limited effect on HIV disease progression and CD4 monitoring adherence. Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is critical for an effective and targeted HIV response. To determine variability in HIV rates we measured HIV prevalence among 17,119 individuals (54% female) from the Rakai cohort. There was large variation in HIV prevalence, ranging from 9% to 43% across communities. Fishing communities had a higher median HIV prevalence (41%, range: 37-43%) compared to trading (17%, range: 11-22%) and agrarian communities (14%, range: 9-26%); ART and male circumcision coverage were significantly lower in fishing communities. Self-reported risk behaviors were significantly higher in men compared to women and in fishing communities compared to other community types. There is substantial heterogeneity in HIV prevalence, risk factors, and service uptake across communities. These findings underscore the need for local surveillance and have important implications for the design of targeted HIV responses.

非洲引入HIV抗逆转录病毒药物（ARV）导致发病率和死亡率大大降低。该项目正在研究乌干达的Rakai社区队列研究（RCCS）对ARV对社区级别发病率的影响，ARV对HIV不一致的夫妻中HIV传播的影响，免疫学监测的影响以及检测病毒学失败对传播和获得的GEACERIED GEATIRED GENOTYPIC ARV抵抗的潜在延迟。我们已经显示出ARV上不和谐的夫妻之间完全消除了传播，并继续扩大治疗。 我们继续监测与维多利亚湖接壤的高风险捕鱼社区中预防联合组合的影响。 HIV阳性人士的平均艺术覆盖范围从2011年的18.6％增加到到2015年的67.3％，而非穆斯林男性的MMC覆盖率从同一时期从24.3％增加到49.2％。在2011年至2012年期间，HIV发病率为4.0（95％CI：2.6-5.7），2012年至2014年间降至3.3（95％CI：2.4-4.5），在2014年至2015年之间的2.9（95％CI：2.2-3.8）之间。男性的AIRR为0.75（95％CI：0.39-1.43），女性为0.77（95％CI：0.38-1.56）。 可行的维多利亚湖高危捕捞群落中艾滋病毒联合预防的联合艾滋病毒预防是可行的，并且有初步的经验证据表明，这些干预措施对降低艾滋病毒的发病率的影响。我们还使用2011年8月至2015年1月从RCCS收集的数据评估了迁移模式。 29％（n = 6718）在2年中迁移的参与者更有可能年轻和女性。 HIV prevalence among in-migrants was significantly higher than long-term residents in women (adjPRR=1.45; 95%CI: 1.31-1.60) but not men (adjPRR=1.03; 95%CI: 0.89-1.19), and ART use was lower among in-migrants of both genders (women: adjPRR=0.67, 95%CI: 0.57-0.78; men: AdjPRR = 0.73，95％CI：0.57-0.78）。不论原始位置如何，在捕鱼社区，特别是在妇女中的艾滋病毒患病率都比其他社区高，并且与长期居民人口中的艾滋病毒患病率呈正相关（p = 0.002）。感染了艾滋病毒的移民，主要是妇女，不太可能使用艺术，而差异化进入热点捕鱼社区。但是，来自这些热点的移民并不能说明其他地方与移民相关的HIV感染的很大比例，这表明针对热点的测试和治疗可能不会减轻普遍的流行病。 在撒哈拉以南非洲使用ARV的使用的一个问题是，随着非果皮B HIV-1感染的个体，病毒抗性随着时间的流逝而发展的程度。我们测量了75名最近感染的RCCS血清传播抗逆转录病毒耐药性的水平。2012年至2013年之间具有记录的血清转化。我们发现，只有3个具有抵抗力的人（4％），2至NNRTIS的传播抗逆转录病毒耐药性较低，一个人（4％）具有PI抗性和无抵抗力和无抵抗力。在资源有限的设置中，识别失败的ART的病毒负载监测（VLM）并未广泛使用；大多数计划仅使用临床或免疫监测（IM）。我们观察到迟到的第二线治疗是在2004年至2011年之间发起ART的3,287名HIV感染者中的一个问题，其中173人符合ART启动后6或更长时间的病毒性衰竭标准。 121（70％）改用第二行艺术。切换到第二行ART的中位时间是病毒衰竭后7.8个月（IQR = 3.3-15.2）。病毒衰竭后6、12和24个月开关的累积发生率分别为33.2％（95％CI = 26.2 41.0），49.8％（95％CI = 42.3 57.9）和71.9％（95％CI = 64.2 79.2）。 与切换为1.6％的患者相比，未切换为11.1％的患者的调整死亡率明显更高（p值== 0.005）。 在切换的人中，病毒学衰竭和方案开关之间的时间间隔越长，在此间隔内，CD4的患者越减少和/或进一步增加。 单纯疱疹病毒2型（HSV-2）已显示在细胞水平上上调HIV-1复制。我们在HIV-1/HSV-2共感染患者中对Acyclovir抑制疗法的研究表明，与安慰剂相比，HIV-1疾病进展的总体降低了25％（P = 0.04）。在通过基线VL分层的亚分析中，与安慰剂相比，用Acyclovir处理的基线HIV VL> 50 000拷贝/ml疾病进展率降低了38％（p = 0.03）。在次要分析中，我们发现在ARV启动后的头三个月，GUD和HSV-2脱落的速率翻了一番，返回基线，返回基线6个月，这表明可能有虹膜效应。当我们测量阴道CMV脱落时，我们发现这些同一妇女的增长类似。 在这项试验中，我们评估了女性对CMV的体液免疫反应，以研究与疾病进展和免疫激活相关的任何关联。 我们发现，基线时最高的CMV IgG三分线与最低的CMV IgG tertile（调整后危险比= 1.59 95％CI = 1.05-2.39; P = 0.027）相比，与主要结果（ART启动或死亡）独立相关。 在前访问中，Log10 CMV IgG抗体水平与可溶性CD14和Log10 c反应蛋白水平呈正相关（P <0.01）。 对CMV的体液免疫反应与HIV疾病进展和免疫激活有关。 优化艾滋病毒护理级联是在全球范围内实现自由艾滋病的关键组成部分。 To evaluate strategies to improve engagement in HIV case and prevention, 442 ART-nave, HIV-infected adult participants were randomized to peer support or standard of care.. After a median follow-up of 363 days, intervention participants were more likely to report being in care (92% vs. 84%; p=0.018), on cotrimoxazole (89% vs. 81%; p=0.022), and adherent to safe water使用船只（23％vs. 14％； P = 0.022）。与对照组相比，在基线（n = 139）的参与者中，主要观察到干预效果，其中83％（n = 139），其中这些干预参与者在随访时进行了护理，共瑞唑唑的58％vs.58％（p = 0.02）（p = 0.02），以及20％vs. 4％vs. 4％vos to Safe Waterel inserel witherel witherel witherel witherel anderel anderel anderel anderel anderel anderel anderelsel posseleel andersel posselel andsel possel possel possel possel（p = = 0.017）p = 0.017）（p = = 0.017）。我们还评估了在Rakai的一项随机对照试验中，我们评估了患者选择的护理伙伴对艾滋病毒依从性，疾病进展和日常生活中日常生活的影响。 这项研究发现，在预先感染的HIV的人中，有照顾好友改善了日常生活的行为，但对HIV疾病进展和CD4监测依从性的影响有限。 了解艾滋病毒负担在各个社区和局部差异的驱动因素的程度对于有效且有针对性的艾滋病毒反应至关重要。为了确定艾滋病毒率的变异性，我们测量了Rakai队列中17,119名（54％女性）的HIV患病率。艾滋病毒患病率差异很大，整个社区的范围从9％到43％。与交易（17％，范围：11-22％）和农业社区（14％，范围：9-26％）相比，捕鱼社区的艾滋病毒中位患病率（41％，范围：37-43％）更高（41％，范围：37-43％）；在捕鱼社区中，艺术和男性包皮环切术的覆盖范围明显降低。与其他社区类型相比，与女性和捕鱼社区相比，男性和捕鱼社区的自我报告的风险行为明显更高。 艾滋病毒患病率，危险因素和服务吸收范围的非均质性存在很大的异质性。这些发现强调了对局部监测的需求，并对有针对性的艾滋病毒反应的设计具有重要意义。