Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials.
Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials.
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DOI：
10.1016/s0140-6736(11)61750-9
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发表时间：
2012-02-18
期刊：
影响因子：
168.9
通讯作者：
Wald, Anna
中科院分区：
文献类型：
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作者：
Johnston, Christine;Saracino, Misty;Kuntz, Steve;Magaret, Amalia;Selke, Stacy;Huang, Meei-Ii;Schiffer, Joshua T.;Koelle, David M.;Corey, Lawrence;Wald, Anna
最近的研究表明，单纯疱疹病毒2型（HSV-2）的短期亚临床发作是皮肤和粘膜病毒脱落的主要形式。我们评估了标准或高剂量抗病毒治疗是否降低了这种脱落的频率。为了确定标准剂量（SD）和高剂量（HD）抗病毒治疗是否抑制生殖器HSV脱落的短发作，将华盛顿州西雅图的HSV-2血清阳性、HIV血清阴性的人纳入三项独立但互补的随机、开放标签、交叉研究，比较1）无药物与阿昔洛韦400 mg每日两次（SD-ACV），2）伐昔洛韦500 mg每日一次（SD-VAL）至阿昔洛韦800 mg每日三次（TID）（HD-ACV），和3）SD-VAL至HD-VAL（1 gm TID）。研究组持续4-7周，间隔一周洗脱期。参与者每天4次获得生殖器拭子用于定量HSV DNA PCR。主要终点是每个研究组的脱落率的人内比较。在113名随机化的参与者中，90名符合主要终点分析的条件。参与者收集了23，605个拭子;其中1272个（5.4%）检测到HSV。与SD-ACV（拭子的1.2%，IRR= 0.05，95% CI= 0.03 - 0.08）相比，无药物组的HSV脱落率显著更高（拭子的18.1%）。在所有剂量下均发生突破性再活化（拭子的SD-ACV 1.2%、SD-VAL 5.2%、HD-ACV 4.2%和HD-VAL 3.3%）。与SD-VAL相比，HD-VAL的脱落较少（IRR=0·54，95% CI=0·44-0·66），可能是由于粘膜HSV清除更快（HD-VAL为4·7 log/6小时，SD-VAL为4·4 log/6小时，（p=0·02））。然而，SD-VAL（22.6）和HD-ACV（20.2，p= 0.54）以及SD-VAL（14.9）和HD-VAL（16.5，p= 0.34）的年突破性发作相似。无论剂量如何，突破性发作时间较短（中位数7-10小时），80%为亚临床发作。研究的目的不是为了在抗病毒剂量之间进行试验间比较。除HD-VAL治疗时头痛发生率增加外，所有治疗方案均耐受良好。即使在高剂量抗疱疹治疗期间，亚临床生殖器HSV再激活的短暂爆发也很常见，这可能是抑制性抗病毒治疗期间HSV-2持续传播的原因。需要更有效的抗病毒治疗来消除HSV-2传播
Recent studies indicate that short subclinical episodes of herpes simplex virus type 2 (HSV-2) are the predominant form of skin and mucosal viral shedding. We evaluated whether standard or high-dose antiviral therapy reduced the frequency of such shedding. To determine whether short episodes of genital HSV shedding are suppressed on standard dose (SD) and high-dose (HD) antiviral therapy, HSV-2 seropositive, HIV seronegative persons in Seattle, WA were enrolled into three separate but complementary randomized, open-label, cross-over studies comparing 1) no medication to aciclovir 400 mg twice daily (SD-ACV), 2) valaciclovir 500 mg daily (SD-VAL) to aciclovir 800 mg three times daily (TID) (HD-ACV), and 3) SD-VAL to HD-VAL (1 gm TID). Study arms lasted 4–7 weeks, separated by one week wash-out. Participants obtained genital swabs four times daily for quantitative HSV DNA PCR. The primary endpoint was within-person comparison of shedding rate on each study arm. Of 113 participants randomized, 90 were eligible for analysis of the primary endpoint. Participants collected 23,605 swabs; of these 1272 (5·4%) had HSV detected. HSV shedding was significantly higher during the no medication arm (18·1% of swabs) compared with SD-ACV (1.2% of swabs, IRR=0·05, 95% CI=0·03–0·08). Breakthrough reactivations occurred on all doses (SD-ACV 1·2%, SD-VAL 5·2%, HD-ACV 4·2%, and HD-VAL 3·3% of swabs). HD-VAL was associated with less shedding compared with SD-VAL (IRR=0·54, 95% CI=0·44–0·66), likely due to more rapid clearance of mucosal HSV (4·7 logs/6 hours on HD-VAL vs. 4·4 logs/6 hours on SD-VAL, (p=0·02)). However, the annualized breakthrough episodes was similar on SD-VAL (22·6) and HD-ACV (20·2, p=0·54) and SD-VAL (14.9) and HD-VAL (16·5, p=0·34). Regardless of dose, breakthrough episodes were short (median 7–10 hours) and 80% were subclinical. Studies were not designed to make inter-trial comparisons between antiviral doses. Except for increased incidence of headaches on HD-VAL, all regimens were well-tolerated. Short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and likely account for continued transmission of HSV-2 during suppressive antiviral therapy. More potent antiviral therapy is needed to abolish HSV-2 transmission