Chemoprophylaxis and HIV Host Interactions

化学预防和 HIV 宿主相互作用

• 批准号: 6841471
• 负责人: Robert M. Grant
• 金额: $ 45.12万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841471
• 关键词: AIDS education /prevention; HIV infections; T lymphocyte; antiAIDS agent; attenuated microorganism; chemoprevention; clinical research; cost effectiveness; cryopreservation; drug resistance; drug screening /evaluation; histocompatibility typing; host organism interaction; human immunodeficiency virus 1; human subject; immune response; microorganism immunology; patient oriented research; polymerase chain reaction; serology /serodiagnosis; virus genetics; virus infection mechanism; virus load; virus replication

DESCRIPTION (provided by applicant): UNAIDS estimates that 14,000 new HIV-1 infections occur every day despite widespread knowledge of the protective effects of abstinence and condom use. There are no vaccine candidates or topical microbicides that are known to protect humans from HIV-1 infection. Hence, novel approaches to HIV prevention warrant urgent evaluation. Recognizing this situation, the National Institutes of Health and the Bill and Melinda Gates Foundation are sponsoring a randomized clinical trial of the safety and effectiveness of daily oral tenofovir versus placebo in Cambodia. Tenofovir is a potent inhibitor of HIV-1 replication that is licensed for treatment of AIDS and has prophylactic effects in animal models. The clinical trial in progress will evaluate whether chemoprophylaxis with tenofovir reduces that rate of seroconversion during the period of treatment. The same group of investigators now proposes to extend this work to test the hypothesis that daily oral tenofovir may have durable benefits (or risks), compared with placebo, that extend beyond the period of chemoprophylactic treatment, including attenuation of the course of infection among those who become infected despite chemoprophylaxis (aim 1) due to preservation of immune responses (aim 2a) from prolonged viral antigen exposure (aim 3a). The durability of these benefits will be assessed during longitudinal follow-up. Those who remain seronegative despite viral exposure during chemoprophylaxis may develop HIV-specific immune responses (aim 2b) due to viral exposure that is contained by the antiviral drug (aim 3b). Seronegative individuals previously exposed to chemoprophylaxis may become partially resistant to HIV-1 infection due to the measured immune responses, or other factors, that will decrease seroincidence or attenuate the course of infection if seroconversion occurs (aim 4). We will also determine whether drug resistant infections occur more commonly during and after chemoprophylaxis exposure, and whether the drug resistant viruses remain predominate over time even after chemoprophylaxis is stopped, which has implications for secondary transmission. The proposed prospective cohort of seroconverting and seronegative women who have completed the randomized trial of tenofovir versus placebo are uniquely valuable. The evaluation of post-chemoprophylactic benefits and risks bears directly on the utility of this novel approach to HIV-1 prevention. Even if tenofovir chemoprophylaxis is found to be ineffective in preventing seroconversion, the proposed cohort will provide uniquely valuable insights into how extremely early suppression of viral replication with antiviral agents may influence viral-host interactions that govern HIV-1 disease progression.

描述（由申请人提供）：联合国艾滋病规划署估计，尽管禁欲和使用避孕套的保护作用得到广泛了解，但每天仍有14，000例新的HIV-1感染病例发生。没有已知的候选疫苗或局部杀微生物剂可以保护人类免受HIV-1感染。因此，迫切需要对预防艾滋病毒的新办法进行评价。认识到这种情况，美国国立卫生研究院和比尔和梅林达盖茨基金会正在赞助一项随机临床试验，在柬埔寨进行每日口服替诺福韦与安慰剂的安全性和有效性比较。替诺福韦是一种有效的HIV-1复制抑制剂，被批准用于治疗艾滋病，并在动物模型中具有预防作用。正在进行的临床试验将评估用替诺福韦进行化学预防是否会降低治疗期间的血清转化率。同一组研究人员现在提议将这项工作扩展到检验每日口服替诺福韦可能具有持久益处的假设（或风险），与安慰剂相比，超过化学预防治疗期，包括在那些尽管进行了化学预防（AIM 1）但仍被感染的人中，由于免疫应答（AIM 2A）的保存而免于长期的病毒抗原暴露（目标3a）。将在纵向随访期间评估这些受益的持久性。那些在药物预防期间尽管病毒暴露但仍保持血清阴性的患者可能会由于抗病毒药物所包含的病毒暴露（目的3b）而产生HIV特异性免疫应答（目的2b）。由于测定的免疫应答或其他因素，先前暴露于化学预防的血清阴性个体可能对HIV-1感染产生部分抗性，如果发生血清转换，则会降低血清发生率或减弱感染过程（目的4）。我们还将确定耐药感染是否在化学预防暴露期间和之后更常见，以及即使在化学预防停止后，耐药病毒是否仍随着时间的推移而占主导地位，这对继发性传播有影响。已完成替诺福韦与安慰剂随机试验的血清转化和血清阴性妇女的前瞻性队列研究具有独特的价值。后化疗预防的好处和风险的评价直接承担的效用，这种新的方法来预防HIV-1。即使发现替诺福韦药物预防在预防血清转换方面无效，拟议的队列也将提供独特的有价值的见解，了解使用抗病毒药极早期抑制病毒复制可能如何影响控制HIV-1疾病进展的病毒-宿主相互作用。