Acyclovir to Prevent HIV Acquisition in HSV-2+ Persons

描述(由申请人提供)：单纯疱疹病毒2型(HSV-2)感染一直被确认为艾滋病毒感染的风险因素，HSV-2血清阳性者感染艾滋病毒的风险增加2-5倍。一项概念验证、随机、双盲、安慰剂对照试验于2001年在赞比亚、津巴布韦和南非的异性恋妇女以及美国和秘鲁的男男性行为者(MSM)中启动，以评估在HSV-2+高危人群中抑制HSV-2的有效性。在RO1和HPTN的资助下，该试验已招募了1430人。由于延迟以及新的操作和监管要求，本申请申请资金以完成试验。假设是，每天标准剂量的阿昔洛韦400毫克，每天2次，将通过降低临床和亚临床HSV-2重新激活的比率，将异性恋妇女和男男性接触者中的艾滋病毒发病率降低50%。具体目标是：1)衡量每天服用400毫克阿昔洛韦预防HSV-2血清阳性、艾滋病毒阴性的异性恋妇女和感染艾滋病毒高风险的男男性接触者感染艾滋病毒的有效性；2)确定每天两次的阿昔洛韦抑制疗法在减少HSV-2血清阳性、HIV阴性的HSV-2患者生殖器溃疡和亚临床HSV-2重新激活方面的效果；以及3)评估HSV-2血清阳性、艾滋病毒阴性的人每天两次接受阿昔洛韦抑制疗法的依从性。随着最近的数据加强了HSV-2重新激活、更高的血浆HIV RNA水平和更快的HIV疾病进展之间的联系，增加了第四个目标：4)衡量每天两次的阿昔洛韦抑制疗法在HIV感染后前6个月对HIV血浆病毒RNA水平的疗效。假设：阿昔洛韦400 mg/次将在设定的时间点降低HIV RNA，潜在地导致疾病进展缓慢，并降低对伴侣的传染性。这项试验将招募2820名(1410名/ARM)非洲妇女和男男性接触者，并对艾滋病毒感染进行18个月的随访。实施情况良好(6个月内随访92%)，对研究药物的依从性高(93.4%的来访者报告服用了75%的研究药物)，没有与研究药物有关的严重不良事件。总体艾滋病毒获得率为2.5%(95%CI 0.9至4.1)，这表明高危人群已登记在册，试验将回答研究问题。鉴于全球艾滋病毒高危人群中的HSV-2感染率很高，这种方法可以通过提供一种安全、可接受和成本效益高的方法来降低艾滋病毒的易感性，从而对公共卫生产生重大影响。

DESCRIPTION (provided by applicant): Herpes simplex type-2 (HSV-2) infection has been consistently identified as a risk factor for HIV acquisition, with 2-5-fold increased risk of HIV acquisition in HSV-2 seropositive persons. A proofof- concept, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of HSV-2 suppression among HSV-2+ persons at high risk of HIV was initiated in 2001 among heterosexual women in Zambia, Zimbabwe, and South Africa and men who have sex with men (MSM) in the U.S. and Peru. With RO1 and HPTN funding, the trial has enrolled 1430 persons. This application requests funds to complete the trial due to delays and new operational and regulatory requirements. The hypothesis is that standard doses of daily acyclovir 400 mg bid will reduce HIV incidence by 50% in heterosexual women and MSM by decreasing rates of clinical and subclinical HSV-2 reactivation. Specific aims are: 1) To measure the efficacy of daily generic acyclovir 400 mg bid in preventing HIV acquisition among HSV-2 seropositive, HIV-negative heterosexual women and MSM at high risk of HIV infection; 2) To determine the effect of twice daily acyclovir suppressive therapy on reducing the frequency of genital ulcers and subclinical HSV-2 reactivation among HSV-2 seropositive, HIV-negative persons; and 3) To assess adherence with twice daily acyclovir suppressive therapy among HSV-2 seropositive, HIVnegative persons. With recent data strengthening the association between HSV-2 reactivation, higher plasma HIV RNA levels, and faster HIV disease progression, a fourth aim has been added: 4) To measure the efficacy of twice daily acyclovir suppressive therapy on HIV plasma viral RNA levels during the first 6 months after HIV infection. Hypothesis: Acyclovir 400 mgbid will lower HIV RNA at setpoint, potentially resulting in slower disease progression and lower infectivity to partners. The trial will enroll 2820 (1410/arm) African women and MSM with 18 months follow-up for HIV acquisition. Implementation has been excellent (92% follow-up at 6 months), high' adherence to study drug (93.4% of visits reported 75% of study drug taken); and no serious adverse events related to study drug. Overall HIV acquisition rate has been 2.5% (95% Cl 0.9 to 4.1), indicating enrollment of high risk persons and that the trial will answer the study question. Given high HSV-2 infection rates globally in persons at risk for HIV, this approach could have great public health impact by providing a safe, acceptable and cost-effective method to reduce HIV susceptibility.