IMPACT OF INTESTINAL DYSFUNCTION ON ANTIRETROVIRAL THERAPY IN INDIA

描述(申请人提供)：艾滋病毒/艾滋病正迅速成为印度次大陆的一个主要威胁，艾滋病病例数量急剧增加。南印度是受艾滋病影响最严重的地区之一。艾滋病病例的增加对本已不堪重负的公共保健系统产生了直接影响，因此有必要对艾滋病病例进行最佳管理，特别注重抗逆转录病毒疗法。最近，印度政府在300万/5全球倡议下推出了抗逆转录病毒疗法(ART)计划，使许多人能够获得基于NNRTI的一线抗逆转录病毒疗法。由于二线治疗在印度由于成本的原因而不可用，最初的治疗方案需要持久，这一点至关重要。HAART方案可能会因为粘附性不足、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。这项建议的中心假设是，在印度有资格接受HAART的患者中，超过50%的人将在吸收能力方面出现明显的肠道功能障碍，这可能会导致血浆中抗逆转录病毒药物的亚治疗水平、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，该研究将测量粘附性、肠道功能和耐药性的发展。具体目标1将在启动HAART时，使用D-木糖和甘露醇测试：口服这些糖后尿液中的乳果糖排泄，确定印度一组艾滋病毒感染者的肠道功能障碍的患病率。具体目标2将确定肠功能障碍与HAART反应之间的关系，通过基线、6个月和12个月的CD4细胞计数和BMI来衡量，以及在基线和12个月开始使用奈韦拉平的HAART的HIV血清阳性个体队列中的病毒载量和病毒耐药性突变之间的关系。特定目标3将记录6个月和12个月时因奈韦拉平为基础的HAART的启动而发生的肠道功能变化，特定目标4将确定肠道功能障碍与通过印度政府推出的ART计划提供的固定剂量组合制剂中给予的奈韦拉平水平之间的联系。奈韦拉平的水平将在治疗开始后2周、早晨服药后2小时以及6个月和12个月时再次测定。这项拟议的研究提供了一个机会，客观地衡量在印度开始HAART时肠道功能障碍的程度，以及它对治疗失败和出现病毒耐药性突变的影响。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/艾滋病患者只能通过公共资助的抗逆转录病毒疗法(ART)推广计划获得抗逆转录病毒疗法(ART)。印度目前的政策是，当CD4细胞计数降至d200cell/mm3时，开始基于NNRTI的HAART。由于成本原因，二线疗法在印度无法通过公共资助的ART计划获得，因此最初的治疗方案需要持久，这一点至关重要。这项拟议的纵向研究具有国家计划层面的政策含义，如果发现有相当大比例的患者在CD4细胞计数为d200 cell/mm3时有肠道功能障碍，并且这与奈韦拉平的亚治疗水平和治疗失败有关。

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.