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.

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。然而，抗逆转录病毒项目遇到了许多挑战，其中一些挑战与北美观察到的情况相似，另一些则不同，包括抗逆转录病毒治疗方案的可用性、奈韦拉平预防艾滋病毒母婴传播的广泛使用以及存在非 B HIV 亚型。该项目正在乌干达拉凯社区队列研究中研究抗逆转录病毒药物对社区一级发病率的影响、抗逆转录病毒药物对艾滋病毒不一致夫妇中艾滋病毒传播的影响、免疫监测的影响以及检测病毒学失败对基因型抗逆转录病毒耐药性的潜在延迟，以及抑制性阿昔洛韦治疗在 HSV-2/HIV-1 共感染个体中对 HIV-1 疾病进展的作用。我们目前正在评估抗逆转录病毒药物对艾滋病毒不一致夫妇中艾滋病毒发病率的影响。 2004年至2009年间，对250对HIV-1不一致的夫妇进行了跟踪调查。在此期间，32 名 HIV-1 阳性伴侣开始接受抗逆转录病毒药物治疗，因为他们符合开始治疗的免疫学标准。 42 例 HIV-1 传播发生在抗逆转录病毒治疗之前，发病率为 9.2/100 pyo。在 HIV-1 指数伴侣开始抗逆转录病毒药物治疗的 32 对夫妇中，在服用抗逆转录病毒药物期间没有发生 HIV-1 传播。这项研究以及其他研究的数据表明，抗逆转录病毒治疗可降低 HIV-1 不一致的夫妇中 HIV 传播的风险。撒哈拉以南非洲地区增加使用抗逆转录病毒药物引起的一个担忧是，随着时间的推移，非 B 分支 HIV-1 感染者中病毒耐药性的发展程度。我们对 16 名病毒学失败的 HIV-1 感染者进行了基因分型，这些人参加了一项短周期治疗中断的开放标签、随机临床试验。所有接受含依非韦伦 HAART 的患者在随访期间均出现 > 1 依非韦伦耐药突变。大多数人（86%）在随访期间出现拉米夫定耐药，但在一年的病毒学失败中位持续时间内没有出现胸苷类似物突变（TAM）。总之，在病毒学失败后的治疗过程早期，对依非韦伦和拉米夫定产生了基因型耐药性。尽管适度接触胸苷类似物，TAM 并未早期出现，从而保留了这些替代抗逆转录病毒药物的使用。我们还分析了乌干达拉凯一线和二线抗逆转录病毒治疗 (ART) 方案失败的参与者的 HIV 抗逆转录病毒药物敏感性。在基线时，31 名参与者中有 7 名患有与核苷或非核苷逆转录酶抑制剂（NRTI 或 NNRTI）耐药相关的突变。大多数一线 ART 失败的参与者都患有 NNRTI (86%) 和拉米夫定 (78%) 突变，但只有 22% 患有其他 NRTI 突变。 未能接受二线蛋白酶抑制剂 (PI) 治疗方案的 6 名参与者均未出现 PI 耐药突变。 六名（16%）参与者的基因型和表型测试结果不一致。 用于识别未能接受 ART 的个体的病毒载量监测 (VLM) 在资源有限的环境中尚未广泛使用；大多数计划仅使用临床或免疫学监测 (IM)。我们比较了乌干达坎帕拉 VLM 患者与 IM 患者之间的基因型耐药模式。 2004 年至 2008 年间，559 名抗逆转录病毒新手患者被纳入前瞻性队列，开始 ART，并每 6 个月监测一次病毒载量和 CD4+ 细胞计数（VLM 组）。从 2008 年 2 月到 2009 年 6 月，998 名接受 ART 治疗 36-40 个月并每 6 个月用 CD4+ 细胞计数进行免疫学监测的患者被招募进入横断面研究（IM 组）。 VLM组在12、24和36个月时的病毒学失败率分别为12%、6%和8%，而IM组在36-40个月时为10%。 VLM 组中有 60% 的患者具有至少 1 个非核苷逆转录酶突变，而 IM 组中有 93% (P<0.0001)。 48% 的 VLM 患者有 M184V 突变，而 IM 组的这一比例为 87% (P<0.0001)。 只有 8% 的 VLM 患者出现胸苷类似物突变 (TAMS)，而 51% 的 IM 患者出现 TAMS (P<0.0001)，其中 17% 出现 3 个或更多 TAMS。 在乌干达，ART 的前 3 年中的常规病毒载量监测降低了对常用 ART 的累积基因型耐药率。 我们继续检查乌干达医院严重脓毒症的病因，并评估改善死亡率的干预措施。脓毒症期间的血糖异常与资源丰富地区的不良预后相关。 在资源有限的环境中，低血糖通常是在没有实验室支持的情况下进行临床诊断的。 我们研究了护理点 (POC) 血糖监测在预测乌干达三所医院 418 名严重脓毒症患者死亡率方面的效用。 33.5%的患者出现血糖正常，16.3%的患者出现低血糖，50.2%的患者出现高血糖。 在多变量分析中，低血糖仍然与院内死亡率显着相关。 纠正低血糖可以改善资源有限环境中危重患者的预后。 2 型单纯疱疹病毒 (HSV-2) 已被证明可以在细胞水平上调 HIV-1 复制。我们之前发布的数据表明，在 HIV-1 血清转化时 HSV-2 血清阳性的个体在血清转化后 5 个月和 15 个月时的 HIV 病毒载量较高。每日抑制 HSV-2 可降低血浆 HIV-1 浓度，一项临床试验已显示可适度延缓 HIV-1 疾病进展。 我们在乌干达拉凯调查了每日抑制性阿昔洛韦对 HIV-1 疾病进展的影响。 我们在一项随机对照试验中招募了 440 名 HIV-1、HSV-2 双重感染成人，其 CD4+ T 细胞计数为 300-400 个细胞/L，且未接受抗逆转录病毒治疗，每组接受每日两次口服阿昔洛韦 400 mg 或安慰剂；参与者被跟踪24个月。 主要结局是 CD4 <250 或针对 WHO IV 期疾病开始 ART。 总体而言，安慰剂组的 110 名参与者和治疗组的 95 名参与者达到了主要终点 (p=0.029)。 在按基线 VL 五分位数分层的子分析中，两个最高 VL 五分位数显示出最强的治疗效果 (p=0.03)，而最低两个最低 VL 五分位数则显示没有疗效 (p=0.688)。 阿昔洛韦将疾病进展率降低了 27%，其中对基线 VL 较高的个体影响最大。 对于尚未接受抗逆转录病毒治疗的 HSV-2/HIV-1 双重感染个体，尤其是病毒载量较高的个体，可能需要使用抑制性阿昔洛韦。 肝病是美国和欧洲艾滋病毒感染者死亡的主要原因。然而，有关艾滋病毒和 ART+ 对非洲肝病影响的数据很少。 我们对乌干达拉凯农村地区艾滋病毒护理项目中的 500 名艾滋病毒感染者进行了一项研究，这些参与者按年龄、性别和地点与人口队列中的 500 名未感染艾滋病毒的参与者进行频率匹配。 研究人群中乙型肝炎合并感染的患病率为 5%。 HIV 感染者中显着纤维化的患病率为 17%，未感染 HIV 的参与者中显着纤维化的患病率为 11%（P=0.008）。 HIV 感染与肝纤维化增加 50% 相关。纤维化还与男性、草药使用、酗酒、职业捕鱼和慢性乙型肝炎病毒感染有关。在 HIV 感染者中，ART 降低了纤维化风险（P=0.030）。 感染艾滋病毒的乌干达农村居民的肝纤维化负担很高。这些数据表明，肝病可能是非洲艾滋病毒相关发病率和死亡率的一个重要原因。