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III期研究，以评估伐昔洛韦预防异性恋夫妇传播HSV的效果。血清阳性的源伴侣随机接受伐昔洛韦500 mg每日一次或安慰剂治疗8个月，敏感的血清阴性伴侣每月监测一次HSV的临床和亚临床（血清学）获得。如果，在任何时候，无论是源或易感的合作伙伴与生殖器疱疹的临床症状兼容，他们进行了评估和治疗开放标签伐昔洛韦。该研究的主要终点是有临床证据表明易感伴侣首次发生生殖器HSV-2感染的夫妇比例。每个终点均由外部终点委员会确认，并需要临床体征/症状以及通过血清学、PCR或培养确认HSV-2感染。次要终点包括易感性伴侣出现生殖器疱疹临床症状的时间、易感性伴侣出现血清转换的时间和源性伴侣出现HSV首次复发的时间。在随机化阶段后，源合作伙伴有资格接受12个月的开放标签伐昔洛韦。入组该开放标签阶段的患者每3个月接受一次不良事件随访。入组期于2001年6月30日结束，筛选了3996对夫妇，并在研究中随机分配了1498对夫妇。在NIH，我们共筛选了76对夫妇，其中38对夫妇符合随机分组的条件。 研究分析显示，与安慰剂相比，每日一次伐昔洛韦500 mg抑制治疗可使症状性生殖器疱疹的传播减少75%（0.5% vs 2.2%）。此外，与安慰剂相比，伐昔洛韦的抑制性治疗使病毒的总体获得减少了48%（1.9%对3.6%）。两组之间的不良事件特征无差异。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每日一次的伐昔洛韦抑制治疗，以减少生殖器疱疹在其他健康的异性恋一夫一妻制夫妇中的传播。

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.