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: 8336260
• 负责人: Thomas Quinn
• 金额: $ 88.8万
• 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/8336260
• 关键词: Acyclovir; Address; Adult; Africa; Africa South of the Sahara; Aftercare; Age; Alcohol consumption; Anti-Retroviral Agents; Antiretroviral resistance; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Caring; Cell Count; Child; Chronic Hepatitis B; Client; Clinical; Clinical Trials; Cohort Studies; Communities; Couples; Critical Illness; Cross-Sectional Studies; Data; Diagnosis; Disease; Disease Progression; Enrollment; Etiology; Europe; Exposure to; Failure; Fibrosis; Fishes; Frequencies; Gender; Genotype; HIV; HIV Infections; HIV-1; Hepatitis B Prevalence; Herbal Medicine; Highly Active Antiretroviral Therapy; Hospital Mortality; Hospitals; Human Herpesvirus 2; Hyperglycemia; Hypoglycemia; Immunologic Monitoring; Immunologics; Incidence; Individual; Interruption; Intervention; L Cells; Laboratories; Lamivudine; Liver Fibrosis; Liver diseases; Monitor; Morbidity - disease rate; Mothers; Multivariate Analysis; Mutation; Nevirapine; North America; Nucleosides; Occupational; Outcome; Participant; Patient Monitoring; Patients; Pattern; Persons; Pharmaceutical Preparations; Placebos; Plasma; Population; Population Study; Predisposition; Prevalence; Prevention; Protease Inhibitor; Public Health; Publishing; RNA-Directed DNA Polymerase; Randomized Clinical Trials; Randomized Controlled Trials; Recruitment Activity; Regimen; Research; Resistance; Resources; Risk; Role; Rural; Sepsis; Site; Staging; Test Result; Thymidine; Time; Treatment Protocols; Uganda; Viral Load result; analog; antiretroviral therapy; arm; base; cohort; efavirenz; follow-up; glucose monitor; improved; indexing; international center; male; meetings; mortality; non-nucleoside reverse transcriptase inhibitors; open label; point of care; primary outcome; programs; prospective; resistance mutation; response; scale up; septic; transmission process; treatment effect; viral resistance

The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. However, ARV programs have encountered many challenges, some of which are similar to those observed in North America and some of which differ, including the availability of ARV regimens, widespread use of nevirapine for prevention of mother-to-child HIV transmission, and the presence of non-B HIV subtypes. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study 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 genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression. We are currently evaluating the impact of ARVs on HIV incidence among HIV discordant couples. 250 HIV-1 discordant couples were followed between 2004-2009. During this period 32 HIV-1-positive partners were initiated on ARVs since they met immunologic criteria for initiation of therapy. 42 HIV-1 transmissions occurred prior to ARV initiation with an incidence of 9.2/100 pyo. In the 32 couples in which HIV-1 index partners started ARVs, no HIV-1 transmissions occurred while on ARVs. Data from this study as well as others demonstrate that antiretroviral therapy reduces the risk of HIV transmission among HIV-1 discordant couples. 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 genotyped 16 HIV-1-infected individuals with virologic failure, who were enrolled in an open-label, randomized clinical trial of short-cycle treatment interruption. All patients receiving efavirenz-containing HAART had > 1 efavirenz resistance mutation develop during follow-up. The majority (86%) developed lamivudine resistance during follow-up but no thymidine analog mutations (TAMs) developed during the median duration of virologic failure of one year. In summary, genotype resistance to both efavirenz and lamivudine developed early during the course of treatment after virologic failure. TAMs did not emerge early despite moderate exposure to thymidine analogs thereby preserving the use of these alternative anti-retroviral drugs. We also analyzed antiretroviral drug susceptibility in HIV from participants failing first and second line antiretroviral treatment (ART) regimens in Rakai, Uganda. At baseline, seven of 31 participants had mutations associated with resistance to either nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs or NNRTIs). Most participants failing first-line ART had mutations to NNRTIs (86%) and lamivudine (78%), but only 22% had other NRTI mutations. None of the six participants failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. 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 compared the genotypic resistance patterns between patients with VLM to those with IM in Kampala, Uganda. Between 2004-2008, 559 antiretroviral nave clients were enrolled in a prospective cohort, initiated ART, and monitored with viral load and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months and immunologically monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Virologic failure rates at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and 10% in the IM group at 36-40 months. 60% patients in the VLM group compared to 93% in the IM group, (P<0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. 48% of VLM patients had an M184V mutation compared to 87% in the IM group (P<0.0001). Only 8% of VLM patients developed thymidine analogue mutations (TAMS) whereas 51% of IM patients developed TAMS (P<0.0001) with 17% developing 3 or more TAMS. Routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. We have continued to examine the etiology of severe sepsis in Ugandan hospitals and evaluate interventions to improve mortality outcomes. Dysglycemia during sepsis is associated with poor outcomes in resource rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without benefit of laboratory support. We studied the utility of point-of-care (POC) glucose monitoring to predict mortality in 418 severely septic patients three hospitals in Uganda. Euglycemia occurred in 33.5% of patients, 16.3% of patients were hypoglycemic and 50.2% were hyperglycemic. In multivariate analyses hypoglycemia remained significantly associated with in-hospital mortality. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We have previously published data that individuals who are HSV-2 seropositive at the time of HIV-1 seroconversion had higher HIV viral loads at 5 and 15 months post-seroconversion. Daily suppression of HSV-2 reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. We enrolled 440 HIV-1, HSV-2 dually infected adults with CD4+ T-cell counts 300-400 cells/L and not on antiretroviral therapy in a randomized controlled trial with each arm receiving either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (p=0.029). In a sub-analysis stratified by baseline VL quintile, the two highest VL quintiles showed the strongest treatment effect (p=0.03) while the lowest two lowest VL quintiles showed no efficacy (p=0.688). Acyclovir reduced the rate of disease progression by 27%, with the greatest impact occurring among individuals with high baseline VL. Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on antiretroviral treatment, particularly among those with high viral loads. Liver disease is a leading cause of mortality among HIV-infected persons in the US and Europe. However, data regarding the effects of HIV and ART+ on liver disease in Africa are sparse. We conducted a study of 500 HIV-infected participants in an HIV care program in rural Rakai, Uganda who were frequency-matched by age, gender and site to 500 HIV-uninfected participants in a population cohort. The prevalence of hepatitis B coinfection in the study population was 5%. The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (P=0.008). HIV infection was associated with a 50% increase in liver fibrosis. Fibrosis was also associated with male gender, herbal medicine use, heavy alcohol consumption, occupational fishing and chronic HBV infection. Among HIV-infected participants, ART reduced fibrosis risk (P=0.030). The burden of liver fibrosis among HIV-infected rural Ugandans is high. These data suggest that liver disease may represent a significant cause of HIV-related morbidity and mortality in Africa.

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。但是，ARV计划遇到了许多挑战，其中一些类似于北美观察到的挑战，其中一些挑战不同，其中一些挑战包括ARV方案的可用性，广泛使用奈韦拉平在预防母亲到孩子的艾滋病毒传播以及非B HIV子类型的存在。 This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study 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 genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease进展。我们目前正在评估ARV对HIV不一致夫妇中HIV发病率的影响。在2004年至2009年之间，跟踪了250个HIV-1不一致的夫妇。在此期间，32 HIV-1阳性伴侣是在ARV上启动的，因为它们符合开始治疗的免疫学标准。 42 HIV-1传输发生在ARV启动之前，发病率为9.2/100 PYO。在HIV-1指数伙伴开始ARV的32对夫妇中，在ARV上没有HIV-1传输。这项研究的数据以及其他数据表明，抗逆转录病毒疗法降低了HIV-1不一致的夫妻中HIV传播的风险。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。我们基于病毒学衰竭的16个HIV-1感染的个体，他们参加了短周期治疗中断的开放标签，随机临床试验。所有接受Efavirenz Haart的患者在随访期间都会出现> 1 efavirenz耐药性突变。大多数（86％）在随访期间发展了lamivudine耐药性，但在病毒学衰竭持续时间为一年的中间持续时间中没有胸苷模拟突变（TAM）。总而言之，在病毒衰竭后治疗期间，对efavirenz和Lamivudine的基因型抗性均出现。尽管中度暴露于胸苷类似物，因此TAM并未尽早出现，从而保留了这些替代性抗报告药物的使用。我们还分析了乌干达Rakai的第一线和第二线抗逆转录病毒治疗（ART）方案的参与者的抗逆转录病毒药物易感性。在基线时，31名参与者中有7个具有与对核苷或非核苷逆转录酶抑制剂（NRTIS或NNRTIS）抗性有关的突变。大多数失败一线ART的参与者对NNRTIS（86％）和Lamivudine（78％）有突变，但只有22％具有其他NRTI突变。 六线蛋白酶抑制剂（PI）方案的六个参与者中没有一个没有PI耐药性突变。 六（16％）的参与者患有不一致的基因型和表型测试结果。 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；大多数程序仅使用临床或免疫监测（IM）。我们将VLM患者之间的基因型抗性模式与乌干达坎帕拉的IM患者进行了比较。 在2004 - 2008年之间，有559名抗逆转录病毒中殿的客户被招募到了前瞻性队列，启动ART，并每6个月接受病毒载荷和CD4+细胞计数进行监测（VLM组）。从2008年2月到2009年6月，将有36-40个月的ART客户用下了36-40个月的客户，每6个月对CD4+细胞计数进行免疫学监测，被招募到横断面研究（IM组）。 VLM组的12、24和36个月的病毒衰竭率分别为12％，6％和8％，在36-40个月的IM组中为10％。 VLM组的60％患者为IM组的93％（P <0.0001）至少有1个非核苷逆转录酶突变。 48％的VLM患者患有M184V突变，而IM组为87％（P <0.0001）。 只有8％的VLM患者出现了胸苷模拟突变（TAM），而51％的IM患者患有TAM（P <0.0001），其中17％的TAM出现了3个或更多的TAM。 在ART的头三年中，常规病毒负荷监测降低了对乌干达常用ART的累积基因型抗性速率。 我们继续研究乌干达医院中严重败血症的病因，并评估干预措施以改善死亡率。败血症期间的血糖症与资源丰富的环境中的结果不佳有关。 在资源有限的环境中，低血糖通常在临床上被诊断出而没有实验室支持。 我们研究了葡萄糖监测点（POC）葡萄糖监测的效用，以预测乌干达的418名严重化粪池患者的死亡率。 33.5％的患者发生了尤格西血症，有16.3％的患者为降血糖，高血糖患者为50.2％。 在多元分析中，低血糖与院内死亡率保持显着相关。 在资源有限的环境中，低血糖的纠正可能会改善重症患者的预后。 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。我们以前已经发布了数据，即HIV-1血清转化时HSV-2血清阳性的个体在转换后5个月和15个月时具有更高的HIV病毒载荷。 HSV-2的每日抑制降低了血浆HIV-1浓度，并已证明在一项临床试验中会适度延迟HIV-1疾病进展。 我们调查了乌干达Rakai的HIV-1疾病进展的每日抑制作用的影响。 我们在一项随机对照试验中招募了440 HIV-1，HSV-2双感染成年人，具有CD4+ T细胞计数为300-400个细胞/L，而不是抗逆转录病毒疗法，每个手臂每天接受Acyclovir 400 mg，每天两次或安慰剂。参与者进行了24个月。 主要结果是CD4 <250或WHO期IV疾病的ART启动。 总体而言，安慰剂组的110名参与者和治疗臂的95名参与者达到了主要终点（p = 0.029）。 在通过基线VL五分位数分层的亚分析中，两个最高的VL五分位数显示出最强的治疗效果（P = 0.03），而最低的两个最低VL五分位数没有疗效（P = 0.688）。 Acyclovir将疾病进展率降低了27％，在高基线VL的个体中的影响最大。 在尚未接受抗逆转录病毒治疗的HSV-2/HIV-1双感染者中，可能需要在抑制性acyclovir中进行抑制。 肝病是美国和欧洲艾滋病毒感染者死亡的主要原因。但是，有关艾滋病毒和艺术+对非洲肝病的影响的数据很少。 我们对乌干达农村农村的HIV护理计划中的500名HIV感染者进行了一项研究，这些参与者按年龄，性别和现场匹配，对人口组的500名HIV未感染的参与者进行了频率。 研究人群中丙型肝炎的患病率为5％。在HIV感染者中，明显的纤维化患病率为17％，HIV未感染的参与者为11％（P = 0.008）。 HIV感染与肝纤维化增加50％有关。纤维化也与男性性别，草药使用，大量饮酒，职业捕鱼和慢性HBV感染有关。在感染HIV的参与者中，ART降低了纤维化风险（P = 0.030）。 HIV感染的乌干达农村地区的肝纤维化负担很高。这些数据表明，肝病可能是非洲与HIV相关的发病率和死亡率的重要原因。