IMPACT OF INTESTINAL DYSFUNCTION ON ANTIRETROVIRAL THERAPY IN INDIA

印度肠道功能障碍对抗逆转录病毒治疗的影响

• 批准号: 7501579
• 负责人: Rita Caroline Isaac
• 金额: $ 4.94万
• 依托单位: CHRISTIAN MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501579
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Affect; Anti-Retroviral Agents; CD4 Lymphocyte Count; Cells; Cohort Studies; Country; Data; Developed Countries; Developing Countries; Development; Diagnosis; Diarrhea; Disease; Disruption; Dose; Drops; Epidemic; Excretory function; Failure; Functional disorder; Funding; Future; Goals; Government; HIV; HIV Infections; Highly Active Antiretroviral Therapy; India; Individual; Intestines; Lactulose; Lead; Life; Longitudinal Studies; Malabsorption Syndromes; Managed Care; Mannitol; Measures; Mutation; Nevirapine; Numbers; Oral Administration; Patients; Permeability; Plasma; Policies; Preparation; Prevalence; Probability; Public Health; Public Sector; Resistance; Resistance development; Resources; Rural Population; Scheme; Severities; Testing; Therapeutic; Time; Treatment Failure; Treatment Protocols; Urine; Viral; Viral Load result; Virus; Week; Xylose; absorption; antiretroviral therapy; base; care systems; cohort; cost; follow-up; improved; innovation; non-nucleoside reverse transcriptase inhibitors; programs; response; success; sugar

DESCRIPTION (provided by applicant): HIV/AIDS is fast becoming a major threat in the Indian sub-continent with a steep increase in the number of AIDS cases. South India is one of the regions hardest hit by HIV/AIDS. The increasing number of AIDS cases has a direct impact on the already overburdened public health care system and warrants optimal management of AIDS cases with a special focus on antiretroviral therapy. The recent Government of India antiretroviral therapy (ART) roll-out program under the 3 million by 5 global initiative, has made it possible for many to have access to first line NNRTI based ART. As second line therapy is not available in India due to cost, the need for the initial regimen to be durable is critical. HAART regimens may fail because of insufficient adherence, viral resistance or because intestinal dysfunction leading to poor absorption of antiretroviral agents. The central hypothesis of this proposal is that more than 50% of those who become eligible for HAART in India will have marked intestinal dysfunction in terms of absorption capacity that will potentially lead to sub-therapeutic levels of antiretrovirals in plasma, failure of therapy and emergence of viral resistance. A longitudinal cohort study to test this hypothesis is proposed which will measure adherence, intestinal function and development of resistance. Specific aim 1 will determine the prevalence of intestinal dysfunction in a cohort of HIV infected individuals in India, at the time of initiation of HAART using the tests d-xylose and mannitol:lactulose excretion in the urine following oral administration of these sugars. Specific Aim 2 will determine the association between intestinal dysfunction and response to HAART as measured by CD4 cell count and BMI at baseline, 6 and 12 months and viral load and viral resistance mutation at baseline and 12 months in a cohort of HIV seropositive individuals initiated on nevirapine based HAART. Specific Aim 3 will document change in intestinal function at 6 and 12 months in response to the initiation of nevirapine based HAART, and specific aim 4 will determine the association between intestinal dysfunction and levels of nevirapine administered in the fixed dose combination preparations provided through the Government of India roll out ART program in India. Nevirapine levels will be measured 2 weeks after the initiation of the treatment, at 2hrs after morning dose and again at 6 and 12 months. This proposed study offers an opportunity to objectively measure the magnitude of the intestinal dysfunction at the time of start of HAART in India, and its impact on failure of therapy and emergence of viral resistance mutations. The data from this proposed study will inform future directions in the management of HIV/AIDS in India. PUBLIC HEALTH RELEVANCE: About 80% of the People Living with HIV/AIDS in India can have access to antiretroviral therapy (ART) only through the public funded ART roll-out program. The current policy in India is to start NNRTI based HAART when the CD4 cell count drops to d200 cell/mm3. As second line therapy is not available in India through the public funded ART program due to cost, the need for the initial regimen to be durable is critical. This proposed longitudinal study has policy implications at the national program level, if a significant proportion of patients found to have intestinal dysfunction at a CD4 cell count of d200 cell/mm3, and it is associated with sub-therapeutic levels of nevirapine and failure to therapy.

描述（由申请人提供）：艾滋病毒/艾滋病正在迅速成为印度次大陆的主要威胁，艾滋病病例数量急剧增加。印度南部是艾滋病毒/艾滋病最严重的地区之一。艾滋病病例数量的增加对已经不堪重负的公共卫生保健系统产生了直接影响，需要对艾滋病病例进行最佳管理，特别注重抗逆转录病毒治疗。印度政府最近在 300 万乘 5 全球倡议下推出了抗逆转录病毒治疗 (ART) 计划，使许多人能够获得基于 NNRTI 的一线 ART。由于成本原因，印度无法提供二线治疗，因此初始治疗方案的持久性至关重要。 HAART 治疗方案可能因依从性不足、病毒耐药性或肠道功能障碍导致抗逆转录病毒药物吸收不良而失败。该提案的核心假设是，在印度，超过 50% 符合 HAART 资格的患者将出现明显的肠道吸收能力功能障碍，这可能会导致血浆中抗逆转录病毒药物低于治疗水平、治疗失败和出现病毒耐药性。提出了一项纵向队列研究来检验这一假设，该研究将测量依从性、肠道功能和耐药性的发展。具体目标 1 将确定印度一群 HIV 感染者在开始 HAART 时肠道功能障碍的患病率，使用测试口服这些糖后 d-木糖和甘露醇：乳果糖在尿液中的排泄情况。具体目标 2 将确定肠道功能障碍与 HAART 反应之间的关联，通过基线、6 个月和 12 个月时的 CD4 细胞计数和 BMI 以及基线和 12 个月时的病毒载量和病毒耐药突变来测量一组开始接受基于奈韦拉平的 HAART 的 HIV 血清阳性个体。具体目标 3 将记录 6 个月和 12 个月时肠道功能的变化，以响应基于奈韦拉平的 HAART 的启动，具体目标 4 将确定肠道功能障碍与印度政府在印度推出 ART 计划提供的固定剂量组合制剂中施用的奈韦拉平水平之间的关联。奈韦拉平水平将在治疗开始后 2 周、早晨给药后 2 小时以及第 6 个月和 12 个月时再次测量。这项拟议的研究提供了一个机会来客观地衡量印度HAART开始时肠道功能障碍的严重程度，及其对治疗失败和病毒耐药突变出现的影响。这项拟议研究的数据将为印度艾滋病毒/艾滋病管理的未来方向提供信息。公共卫生相关性：印度约 80% 的艾滋病毒/艾滋病感染者只能通过公共资助的 ART 推广计划获得抗逆转录病毒治疗 (ART)。印度目前的政策是当 CD4 细胞计数降至 d200 细胞/mm3 时启动基于 NNRTI 的 HAART。由于成本原因，印度无法通过公共资助的 ART 计划提供二线治疗，因此初始治疗方案的持久性至关重要。如果在 CD4 细胞计数为 d200 个细胞/mm3 时发现很大比例的患者存在肠道功能障碍，并且与奈韦拉平的亚治疗水平和治疗失败相关，则这项拟议的纵向研究对国家计划层面具有政策意义。