Novel Therapies For Herpes Simplex Virus Infections

我们已经完成了一项随机、多中心、双盲、安慰剂对照的第三阶段研究，以评估万乃洛韦在防止异性伴侣传播HSV方面的效果。血清阳性的来源伴侣随机接受万乃洛韦500 mg每日一次或安慰剂治疗8个月，对血清阴性的敏感伴侣每月监测临床和亚临床(血清学)HSV感染情况。如果在任何时候，感染源或易感性伴出现与生殖器疱疹相适应的临床症状，则对他们进行评估并使用开放标签万乃洛韦进行治疗。这项研究的主要终点是有临床证据的夫妇在易感伴侣中首次出现生殖器HSV-2感染的比例。每个终点都由外部终点委员会确认，并通过血清学、聚合酶链式反应或培养确认所需的临床体征/症状以及实验室确认的HSV-2感染。次要终点包括易感性伴出现生殖器疱疹临床症状的时间、易感性伴血清转换的时间和源伴首次HSV复发的时间。在随机阶段之后，来源合作伙伴有资格获得12个月的开放标签万乃洛韦。每3个月跟踪一次登记在这一开放标签阶段的患者的不良事件。2001年6月30日登记截止，共有3996对夫妇被筛选，1498对夫妇被随机纳入研究。在NIH，我们总共筛选了76对夫妇，其中38对符合随机分组的条件。 这项研究的分析表明，与安慰剂相比，每日一次的万乃洛韦500毫克抑制疗法将症状性生殖器疱疹的传播减少了75%(0.5%对2.2%)。此外，与安慰剂相比，万乃洛韦抑制疗法将病毒的总体获得率降低了48%(1.9%对3.6%)。两组患者的不良事件发生率没有差异。2003年5月14日，美国食品和药物管理局咨询委员会一致建议批准使用万乃洛韦每日一次的抑制疗法，以减少其他健康的、异性恋、一夫一妻制夫妇的生殖器疱疹传播。

We have completed our participation in a randomized, multicenter, double blind, placebo-controlled phase III study to evaluate the effect of valaciclovir in preventing the transmission of HSV in heterosexual couples. The seropositive source partner was randomized to receive valaciclovir 500 mg once daily or placebo for 8 months, and the susceptible seronegative partner was monitored monthly for clinical and subclinical (serological) acquisition of HSV. If, at any point, either the source or the susceptible partner presented with clinical symptoms compatible with genital herpes, they were evaluated and treated wit open label valaciclovir. The primary endpoint of the study was the proportion of couples with clinical evidence of a first-episode of genital HSV-2 infection in the susceptible partner. Each endpoint was confirmed by an external Endpoint Committee and required clinical signs/symptoms as well as laboratory confirmation of HSV-2 infection by serology, PCR or culture. Secondary endpoints included the time to clinical symptoms of genital herpes in the susceptible partner, the time to seroconversion in the susceptible partner and the time to first recurrence of HSV in the source partner. After the randomization phase, source partners were eligible to receive 12 months of open label valaciclovir. Patients enrolled in this open-label phase were followed every 3 months for adverse events. The enrollment period was closed on June 30, 2001, with 3996 couples screened, and 1498 couples being randomized in the study. At NIH, we screened a total of 76 couples, with 38 couples being eligible for randomization. Analysis of the study showed that once-daily suppressive therapy with valaciclovir 500 mg reduced transmission of symptomatic genital herpes by 75% versus placebo (0.5 percent vs 2.2 percent). In addition, suppressive therapy with valaciclovir reduced the overall acquisition of the virus by 48% versus placebo (1.9 percent vs. 3.6 percent). There were no differences in the adverse events profile between the two groups. In May 14 2003, the U.S. Food and Drug Administration Advisory Committee unanimously recommended the approval of once-daily suppressive therapy with valaciclovir for the reduction of transmission of genital herpes in otherwise healthy, heterosexual, monogamous couples.