Acyclovir to Prevent HIV Acquisition in HSV-2+ Persons

描述（由申请人提供）：2型单纯疱疹（HSV-2）感染一直被认为是HIV感染的一个危险因素，在HSV-2血清阳性的人群中，HIV感染的风险增加了2-5倍。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）中开展了一项概念验证、随机、双盲、安慰剂对照试验，以评估在艾滋病毒高危人群中抑制HSV-2的疗效。在RO1和HPTN的资助下，该试验已招募了1430人。由于延迟和新的操作和监管要求，本申请需要资金来完成试验。假设每日标准剂量的阿昔洛韦400mg / bid将通过降低临床和亚临床HSV-2再激活率，使异性恋妇女和男男性行为者的艾滋病毒发病率降低50%。具体目的是：1)测定每日通用阿昔洛韦400mg bid在HSV-2血清阳性、HIV阴性的异性恋女性和HIV感染高危人群中预防HIV感染的效果；2)确定每日2次阿昔洛韦抑制治疗对降低HSV-2血清阳性、hiv阴性人群生殖器溃疡发生频率和亚临床HSV-2再激活的效果；3)评估HSV-2血清阳性、hiv阴性患者每日2次阿昔洛韦抑制治疗的依从性。最近的数据加强了HSV-2再激活、较高的血浆HIV RNA水平和更快的HIV疾病进展之间的关联，因此增加了第四个目标：4)在HIV感染后的前6个月内，测量每天两次的阿昔洛韦抑制治疗对HIV血浆病毒RNA水平的影响。假设：400mgbid的阿昔洛韦将降低设定点的HIV RNA，可能导致疾病进展缓慢和对伴侣的传染性降低。该试验将招募2820名（1410名/支）非洲妇女和男男性行为者，随访18个月，以了解HIV感染情况。实施情况非常好（92%的随访6个月），对研究药物的依从性很高（93.4%的随访报告75%的研究药物服用）；没有与研究药物相关的严重不良事件。总体艾滋病毒感染率为2.5% (95% Cl 0.9至4.1)，表明纳入了高风险人群，该试验将回答研究问题。鉴于全球面临艾滋病毒感染风险的人群中2型单纯疱疹病毒的感染率很高，这种方法可以提供一种安全、可接受和具有成本效益的方法来降低艾滋病毒易感性，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.