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: 8277041
• 负责人: Rita Caroline Isaac
• 金额: $ 5万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277041
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Affect; Anti-Retroviral Agents; CD4 Lymphocyte Count; Cells; Cohort Studies; Country; Data; Developing Countries; Development; Diagnosis; Diarrhea; Disease; Dose; Drops; Epidemic; Excretory function; Failure; Functional disorder; Funding; Future; Goals; Government; HIV; HIV Infections; Health; Healthcare Systems; Highly Active Antiretroviral Therapy; India; Individual; Intestines; Lactulose; Lead; Life; Longitudinal Studies; Malabsorption Syndromes; Managed Care; Mannitol; Measures; Nevirapine; Oral Administration; Patients; Permeability; Plasma; Policies; Preparation; Prevalence; Probability; Public Health; Public Sector; Regimen; Resistance; Resistance development; Resources; Rural Population; Scheme; Severities; Testing; Therapeutic; Time; Treatment Failure; Urine; Viral Load result; Virus; Xylose; absorption; antiretroviral therapy; base; cohort; cost; follow-up; improved; innovation; non-nucleoside reverse transcriptase inhibitors; policy implication; programs; resistance mutation; response; success; sugar; viral resistance

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。印度南部是受艾滋病毒/艾滋病影响最严重的地区之一。艾滋病病例不断增加，对已经负担过重的公共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疗法。印度政府最近在300万人/5人全球倡议下推出的抗逆转录病毒疗法（ART）推广计划，使许多人能够获得基于NNRTI的一线ART。由于成本原因，印度无法获得二线疗法，因此，对初始方案的持久性的需求至关重要。HAART方案可能会因为依从性不足、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。该提案的中心假设是，在印度，超过50%的有资格接受HAART的患者在吸收能力方面将有明显的肠道功能障碍，这可能导致血浆中抗逆转录病毒药物的亚治疗水平，治疗失败和病毒耐药性的出现。提出了一项纵向队列研究来验证这一假设，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HIV感染者队列中肠道功能障碍的患病率，在开始HAART时，使用口服这些糖后尿液中的d-木糖和甘露醇：乳果糖排泄试验。具体目标2将确定肠道功能障碍与HAART应答之间的相关性，通过基线、6个月和12个月时的CD 4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，该队列中的HIV血清阳性个体开始接受基于奈韦拉平的HAART治疗。具体目标3将记录开始基于奈韦拉平的HAART治疗后6个月和12个月时肠功能的变化，具体目标4将确定肠功能障碍与通过印度政府在印度推出ART计划提供的固定剂量复方制剂中奈韦拉平给药水平之间的相关性。将在治疗开始后2周、早晨给药后2小时以及第6个月和第12个月再次测量奈韦拉平水平。这项拟议的研究提供了一个机会，可以客观地测量印度HAART开始时肠道功能障碍的程度，以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：印度大约80%的艾滋病毒/艾滋病感染者只能通过公共资助的抗逆转录病毒疗法推广方案获得抗逆转录病毒疗法。印度目前的政策是当CD 4细胞计数降至d200 cell/mm 3时开始基于NNRTI的HAART。由于成本问题，印度无法通过公共资助的ART项目获得二线治疗，因此，最初的治疗方案必须具有持久性。如果在CD 4细胞计数d200 cell/mm 3时发现有相当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，则拟定的纵向研究在国家项目水平上具有政策意义。