The oral bioavailability of acyclovir is poor, with only 15-30% of the oral formulations being absorbed (173). Following a 200 mg dose, a peak concentration of about 0.5 µg/ml is attained at approximately 1.5 to 2.5 hours (236). Higher doses of acyclovir result in higher serum concentrations. Food does not substantially alter extent of absorption. After intravenous doses of 2.5 to 15 mg/kg, steady state concentrations of acyclovir range from 6.7 to 20.6 µg/ml. Acyclovir is widely distributed; high concentrations are attained in kidneys, lung, liver, heart, and skin vesicles; concentrations in the CSF are about 50% of those in the plasma (236). Acyclovir crosses the placenta and accumulates in breast milk. Protein binding ranges from 9% to 33% and less than 20% of drug is metabolized to biologically inactive metabolites.

        口服 阿昔洛韦的生物利用度很差，口服后仅15－30%被吸收(173)。口服阿昔洛韦200mg后，在1.5－2.5小时达到峰值血药浓度，约0.5ug/ml(236)。药物剂量越大，血药浓度越高。食物一般不影响药物吸收。静脉注射阿昔洛韦2.5－15 mg/kg，稳态血药浓度为6.7 － 20.6 µg/ml。阿昔洛韦在体内广泛分布，在肾脏、肺脏、肝脏、心脏及皮肤水疱中的浓度较高，脑脊液中的药物浓度约为血浆浓度的50%(236)。阿昔洛韦可通过胎盘，可在乳汁中浓聚，其蛋白结合率为9%-33%，少于20%的药物在体内经代谢而失活。

               In the absence of compromised renal function, the half life of acyclovir is 2 to 3 hours in older children and adults and 2.5 to 5 hours in neonates with normal creatinine clearance. More than 60% of administered drug is excreted in the urine (236). Elimination is prolonged in patients with renal dysfunction; the half life is approximately 20 hours in persons with end stage renal disease, necessitating dose modifications for those with creatinine clearance less than 50 ml/min/1.73 m² (131). Acyclovir is effectively removed by hemodialysis but not by continuous ambulatory peritoneal dialysis (124).

        在肾功能正常的情况下，年长儿和成人的半衰期为2-3小时，在肌酐清除率正常的新生儿为2.5－5小时。超过60%的药物经肾脏排泄(236)。肾功能不全患者的药物消除延长，终末期肾衰患者的半衰期为20小时，故对于肌酐清除率小于50 ml/min/1.73 m²的患者，需要调整药物的剂量(131)。血液透析可以有效地清除阿昔洛韦，而持续性腹膜透析则不能清除(124)。

               Acyclovir is a safe drug which is generally very well tolerated. Oral acyclovir sometimes causes mild gastrointestinal upset, rash, and headache. If it extravasates, intravenous acyclovir can cause severe inflammation, phlebitis, and sometimes a vesicular eruption leading to cutaneous necrosis at the injection site. If given by rapid intravenous infusion or to poorly hydrated patients or those with pre existing renal compromise, intravenous acyclovir can cause reversible nephrotoxicity due to the formation of acyclovir crystals precipitating in renal tubules and causing an obstructive nephropathy. Administration of acyclovir by the intravenous route occasionally is associated with rash, sweating, nausea, headache, hematuria, and hypotension. High doses of intravenous acyclovir (60 mg/kg/day) in neonates and prolonged use of oral acyclovir following neonatal disease have been associated with neutropenia (108, 113).

        阿昔洛韦是安全、耐受性良好的药物。口服阿昔洛韦有时会引起轻度的胃肠道不适、皮疹及头痛等。如果静脉注射出现外渗，则会导致严重的炎症反应、静脉炎，有时甚至在注射部位出现水疱或皮肤坏死。如果静脉注射过快，或者水化不充分，或有基础性肾功能不全，药物可以在肾小管内形成结晶，导致梗阻性肾病，引起可逆性肾脏损害。静脉注射阿昔洛韦有时会引起皮疹、出汗、恶心、头痛、血尿及低血压等不良反应。新生儿若静脉注射阿昔洛韦(60 mg/kg/day)剂量过大，或口服时间过长则可能出现中性粒细胞减少(108, 113)。

               The most serious side effect of acyclovir is neurotoxicity, which usually occurs in subjects with compromised renal function who attain high serum concentrations of drug (186). Neurotoxicity is manifest as lethargy, confusion, hallucinations, tremors, myoclonus, seizures, extrapyramidal signs, and changes in state of consciousness, developing within the first few days of initiating therapy. These signs and symptoms usually resolve spontaneously within several days of discontinuing acyclovir.

        阿昔洛韦最严重的不良反应是神经毒性，通常发生在肾功能不全的患者，由于血药浓度过高所致(186)。神经毒性可表现为无力、神志混乱、幻觉、震颤、肌阵挛、癫痫、锥体外系表现以及意识障碍等，一般在治疗最初几天内发生。这些症状及体征通常在停药几天后自行消退。

               Although acyclovir is mutagenic at high concentrations in some in vitro assays, it is not teratogenic in animals. Limited human data suggest that acyclovir use in pregnant women is not associated with congenital defects or other adverse pregnancy outcomes (220).

        尽管一些体外实验观察到，高浓度阿昔洛韦有致突变作用，但动物模型并未观察到其有致畸效应。有限的人体资料显示，妊娠妇女应用阿昔洛韦并未发生胎儿的先天性缺陷或其它不良后果(220)。

               A limited number of adverse drug interactions with acyclovir have been reported. Subjects being treated with both zidovudine and acyclovir can develop severe somnolence and lethargy. The likelihood of renal toxicity is increased when acyclovir is administered with nephrotoxic drugs such as cyclosporine and amphotericin B. Concomitant administration of probenicid decreases renal clearance of acyclovir and prolongs its half life; conversely, acyclovir can decrease the clearance of drugs such as methotrexate that are eliminated by active renal secretion.

        少数文献报道阿昔洛韦的不良药物相互作用较少。同时应用齐多夫定和阿昔洛韦可能发生严重的嗜睡和无力症状。与肾毒性药物联合应用，如环孢霉素和两性霉素B，药物的肾毒性会增加。合用丙磺舒会降低阿昔洛韦的肾脏清除率，从而延长阿昔洛韦的半衰期，相反，阿昔洛韦会减缓由肾脏分泌的药物的清除，例如甲氨喋呤。

Alternative Therapy

其它药物

Valaciclovir: Valaciclovir is the L valyl ester of acyclovir that is rapidly converted to acyclovir after oral administration by first-pass metabolism in the liver (98). Licensed in 1995, it has a safety and efficacy profile similar to which of acyclovir but offers potential pharmacokinetic advantages.

伐昔洛韦：伐昔洛韦是阿昔洛韦的左旋缬氨酸酯，口服后经过肝脏的首过效应，迅速转化为阿昔洛韦(98)。该药在1995年上市，其安全性及有效性与阿昔洛韦相似，而在药代动力学方面具有优势。

               As a prodrug of acyclovir, valaciclovir has the same mechanism of action, antiviral spectrum, and resistance profiles as those of its parent drug, acyclovir. Following oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first pass intestinal and hepatic metabolism. The bioavailability of valaciclovir exceeds 50%, which is three to five times greater than that of acyclovir (207). Peak serum concentrations, attained about 1.5 hours after a dose, are proportional to the amount of drug administered; they range from 0.8 to 8.5 µg/ml for doses of 100 to 2,000 mg (245). The area under the drug concentration time curve approximates that seen after intravenous acyclovir. All other pharmacokinetic characteristics are similar to those of acyclovir (158).

        作为阿昔洛韦的前体，伐昔洛韦与阿昔洛韦具有相同的作用机制、抗病毒谱及耐药性。口服伐昔洛韦后，经肠肝首过代谢，迅速而完全地转换为阿昔洛韦。伐昔洛韦的生物利用度超过50%，比阿昔洛韦高3-5倍(207)。口服伐昔洛韦约1.5小时后血药浓度达峰值，峰值血药浓度与药物剂量呈线性关系，剂量在100-2000mg时，其血药峰值浓度为0.8－8.5ug/ml(245)。药时曲线下面积与静脉注射阿昔洛韦相似，其它的药代动力学特性与阿昔洛韦相似(158)。

               The profiles of adverse effects and potential drug interactions observed with valaciclovir therapy are the same as those observed with acyclovir treatment. Neurotoxicity has not been reported in humans to date, although it has been observed in animal models (98). Manifestations resembling thrombotic microangiopathy have been described in patients with advanced HIV disease receiving very high doses of valaciclovir (8 grams per day), but the multitude of other medications being administered to such patients makes the establishment of a causal relationship to valaciclovir difficult (19). Although causation has not been established, use of valaciclovir at such high doses should involve evaluation of potential risks and benefits.

        伐昔洛韦的药物副作用及潜在的药物相互作用与阿昔洛韦相同。尽管在动物模型上观察到了神经毒性，但目前尚无相关临床报道(98)。有报道在进展期HIV患者，应用大剂量伐昔洛韦（8g/日）后出现血栓性微血管病的临床表现，但由于这些患者可能同时存在着其它的作用机制，因此难以肯定伐昔洛韦与微血管病之间存在因果关系(19)，尽管如此，在应用大剂量的药物之前应充分评价潜在的风险与收益。

               With decreasing creatinine clearance, the dosing interval should be spread. With significant renal impairment, the dose should also be reduced in half. Acyclovir is removed during hemodialysis, and therefore an extra dose of valaciclovir should be administered following completion of hemodialysis. Supplemental doses of valaciclovir are not required following chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD).

        在肌酐清除率下降的患者，应延长用药间隔，严重肾功能受损患者，用药剂量应减半。因为伐昔洛韦可被血液透析清除，因此在血透后应补充一次伐昔洛韦剂量，而在接受持续性腹膜透析（CAPD）和持续性动静脉血滤/透析（CAVHD）的患者，治疗后却不需要追加药物剂量。

Famciclovir: Famciclovir is the inactive diacetyl ester prodrug of penciclovir, an acyclic nucleoside analogue. Following oral ingestion and systemic absorption, famciclovir is rapidly deacetylated and oxidized to form the active parent drug penciclovir.

泛昔洛韦：泛昔洛韦是无活性的喷昔洛韦双乙酰酯，是喷昔洛韦的前体药物，一种核苷类似物。口服消化及吸收后，泛昔洛韦发生快速去乙酰化和氧化作用，形成活性的喷昔洛韦。  

               In cells which are infected with HSV, the viral TK phosphorylates penciclovir to its monophosphate derivative, which in turn is converted to the active penciclovir triphosphate by cellular kinases. Penciclovir triphosphate inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate for incorporation into the growing DNA strand. While penciclovir triphosphate is neither an obligate DNA chain terminator nor an inactivator of the DNA polymerase, once incorporated penciclovir triphosphate does retard the rate of subsequent nucleotide incorporation. Penciclovir is approximately 100 fold less potent than acyclovir in inhibiting herpesvirus DNA polymerase activity. By virtue of its high intracellular concentrations and long intracellular half-life (7 to 20 hours), though, it remains an effective antiviral agent.

        在感染HSV的细胞内，病毒的TK将喷昔洛韦转化为单磷酸盐衍生物，后者进一步在细胞激酶作用下转化为有活性的三磷酸喷昔洛韦。三磷酸喷昔洛韦通过与三磷酸脱氧鸟苷竞争，掺入病毒DNA链中，从而抑制病毒DNA聚合酶。三磷酸喷昔洛韦既不是DNA链的终止子，也不是DNA聚合酶的灭活物，一旦三磷酸喷昔洛韦掺入DNA链中，会阻止后续的核苷掺入。喷昔洛韦对病毒DNA聚合酶的抑制作用比阿昔洛韦低100倍，但由于其细胞内浓度高，细胞内半衰期长（7-20小时），因此仍是一种有效的抗病毒药物。

               The bioavailability of penciclovir following oral administration of famciclovir is about 70%. Peak concentrations of drug after intravenous administration of 10 mg/kg are approximately six-fold higher than those attained after oral doses of 250 mg. Food delays absorption but does not affect the final plasma drug concentration. Following oral administration, little or no famciclovir is detected in plasma or urine. The plasma half life of penciclovir is about 2.5 hours, and almost three quarters is recovered unchanged in the urine. Measurable penciclovir concentrations are not detectable in plasma or urine following topical administration of penciclovir cream. A 12 hour dosing interval is recommended for those with creatinine clearances between 30 and 50 ml/min/1.73m², and a 24 hour interval for those with creatinine clearances less than 30 ml/min/1.73m² (25).

        口服泛昔洛韦后，喷昔洛韦的生物利用度约是70%。静脉注射10mg/kg后获得的血药峰浓度比口服250mg后获得的血药峰浓度高6倍多。食物会影响药物吸收，但不会影响最终的血药物浓度。口服给药后，血浆及尿中几乎检测不到伐昔洛韦。喷昔洛韦的血浆半衰期约为2.5小时，约3/4药物以原型经尿排出。局部应用喷昔洛韦软膏后，在血浆或尿中检测不到喷昔洛韦。肌酐清除率在30-50ml/min/1.73m2的患者，推荐用药间隔为12小时，而对肌酐清除率小于30ml/min/1.73m2的患者，用药间隔应为24小时(25)。

               Famciclovir is as well tolerated as acyclovir. Complaints of nausea, diarrhea, and headache occurred in clinical trials, but at frequencies similar to those reported by placebo recipients. No clinically significant drug interactions have been reported to date, although concentrations of famciclovir among volunteers increase by about 20% in patients receiving concomitant cimetidine or theophylline administration. Dose reduction of famciclovir is recommended for patients with compromised renal function. A 12 hour dosing interval is recommended for persons with creatinine clearances between 30 and 50 ml/min/1.73m², and a 24 hour interval for those with creatinine clearances less than 30 ml/min/1.73m² (25).

        泛昔洛韦与阿昔洛韦一样，耐受性好。临床研究报道的不良反应有恶心、腹泻及头痛，其发生率与安慰剂组相似。虽然在同时合用西米替丁或茶碱的志愿者，泛昔洛韦血药浓度升高20％，但是目前临床上还没有显著的药物相互作用的报道。肾功能不全的患者应用泛昔洛韦时建议减少剂量。当肌酐清除率在30-50 ml/min/1.73m²时,用药间隔应为12小时，肌酐清除率小于30 ml/min/1.73m²时,用药间隔应为24小时(25)。

Resistance to Antiviral Agents Used for Treatment and Prevention of HSV

防治治疗和预防HSV感染时抗病毒药物的耐药性

               Resistance of HSV to acyclovir has become an important clinical problem, especially among immunocompromised patients exposed to long-term therapy (71). Viral resistance to acyclovir usually results from mutations in the viral TK gene although mutations in the viral DNA polymerase gene also occur rarely. Although these acyclovir resistant isolates exhibit diminished virulence in animal models, among HIV infected patients they can cause severe, progressive, debilitating mucosal disease and (rarely) visceral dissemination (80). Acyclovir resistant strains of HSV also have been recovered from cancer chemotherapy patients, bone marrow and solid organ transplant recipients, children with congenital immunodeficiency syndromes, and neonates (108, 134, 164, 166, 176). Although it is uncommon, genital herpes caused by acyclovir resistant isolates has also been reported in immunocompetent hosts who usually have received chronic acyclovir therapy (122, 156).

        HSV耐阿昔洛韦是目前临床的重要问题，尤其是免疫缺陷患者长期治疗以后(71)。病毒耐阿昔洛韦通常是病毒TK基因的突变的结果，病毒的DNA聚合酶基因突变发生较低。尽管在动物模型上阿昔洛韦耐药株的毒力减弱，在HIV患者身上仍可引起严重的、进展性粘膜病变，甚至内脏弥漫性病变（罕见）(80)。在肿瘤化疗、骨髓移植、实体器官移植患者、先天性免疫缺陷患儿及新生儿身上也可以分离出耐阿昔洛韦的HSV病毒株(108, 134, 164, 166, 176)。尽管不常见，有文献报道，免疫功能正常的患者发生阿昔洛韦耐药株引起的生殖器疱疹，这些患者通常接受长期阿昔洛韦治疗(122, 156)。

               Because penciclovir, like acyclovir, must be activated by the viral encoded TK enzyme, TK deficient viral strains are resistant to both acyclovir and penciclovir. Strains of HSV whose resistance to acyclovir is conferred by alteration of the TK enzyme or by DNA polymerase mutations may remain sensitive to penciclovir (110).

        因为由于喷昔洛韦与阿昔洛韦一样，必须被病毒编码的TK激活，因此TK缺陷的病毒株对喷昔洛韦和阿昔洛韦都耐药。由于TK酶改变或DNA聚合酶突变所致的耐阿昔洛韦病毒株，可能仍然对喷昔洛韦敏感(110)。

Special/Specific Infections

特异性特殊感染

Orolabial Herpes: Treatment of primary gingivostomatitis in pediatric patients using oral acyclovir decreases time to cessation of symptoms by 30-50%, and time to lesion healing by 20-25% (6). Compared with patients receiving placebo, subjects treated with oral acyclovir at 600 mg/m²/dose administered four times per day for 10 days (Table 7) experienced cessation of drooling in 4 days (vs. 8 days in placebo recipients) and resolution of gum swelling in 5 days (vs. 7 days in placebo recipients). Intraoral lesions in acyclovir recipients healed at 6 days (vs. 8 days in placebo recipients), and extraoral lesions healed in 7 days (vs. 9 days in placebo recipients) (6).

口唇疱疹：用阿昔洛韦治疗儿童原发性龈口炎，症状消退时间大约缩短30-50%，病变愈合时间大约缩短20-25%(6)。与安慰剂相比，口服阿昔洛韦600 mg/m²/次，每日四次，共服10日(Table 7)，患儿可在4日内停止流涎（安慰剂组为8日），在5日内牙龈肿胀消退（安慰剂组为7日）。治疗组口腔内病变愈合时间为6日（安慰剂组为8日），口腔外病变愈合时间为7日（安慰剂组为9日）(6)。

               Oral acyclovir has a more modest effect in the treatment of recurrent herpes labialis (178, 179), and treatment of these patients should be individualized (Table 7) (114). In general, therapeutic benefit is enhanced if treatment is initiated as soon as possible after onset of symptoms, preferably within 24 to 48 hours of onset of the recurrence. Among patients who start treatment in the prodrome or erythema lesion stage, acyclovir therapy (400 mg five times a day for five days) reduces the duration of pain by approximately one-third, and the healing time to loss of crust by approximately one-fourth (215). Topical acyclovir cream may also modestly decrease the duration of a clinical recurrence of herpes labialis by approximately half a day (approximately four and a half days for topical acyclovir recipients, compared with approximately five days for placebo recipients) (213), although benefit of topical acyclovir is not conferred by acyclovir ointment, which has a polyethylene glycol base (201, 209).

        口服阿昔洛韦对治疗复发性口唇疱疹也有效(178, 179)，治疗应遵循个体化原则(Table 7) (114)。通常症状出现后尽早开始治疗疗效较好，最好在复发出现后24-48小时。若在出现前驱症状或仅有红斑时即给予阿昔洛韦治疗（每日5次，每次400mg，共5日），患者的疼痛持续时间会减少近1/3，病变愈合的时间亦会缩短近1/4(215)。局部涂阿昔洛韦软膏也可以缩短复发性口唇疱疹的病程约半天（局部用药患者平均病程约4天半，而安慰剂组平均为5天），局部使用阿昔洛韦的益处不能归于阿昔洛韦软膏，因为它用聚乙二醇做基质。(213)。

               Prophylactic acyclovir also has been used to prevent reactivation of herpes labialis following exposure to ultraviolet radiation, facial surgery, or exposure to sun and wind while skiing (84, 210, 211). Topical acyclovir cream also is effective in preventing recurrent herpes labialis in skiers (177) and in persons with a history of frequent recurrences of herpes labialis (82). Long-term suppressive therapy reduces the number of recurrences of oral infection in those with histories of frequent recurrences (189). In one study of 400 mg of oral acyclovir administered twice daily for four months, clinical recurrences were reduced by more than half, and culture-confirmed recurrences were reduced by more than two-thirds (189).

        预防性使用阿昔洛韦，同样可以用于预防紫外线照射、颜面部手术或滑雪运动时日晒、吹风等引起的口唇疱疹复发 (84, 210, 211)。滑雪运动员(177)和反复复发口唇疱疹者(82)局部涂阿昔洛韦软膏可以有效预防疱疹复发。长期抑制性治疗可以减少反复复发者口腔感染的复发次数(189)。有研究显示，口服阿昔洛韦 400mg，每日两次，连续服用4个月以后，其临床复发次数减少了一半多，而培养阳性的复发次数减少了2/3以上。

               Topical penciclovir (Denavir) for the treatment of recurrent herpes labialis reduces time to healing and duration of pain by about half a day (26). Topical penciclovir cream decreases the time to lesion healing by approximately one to two days when compared with placebo (26, 214), and is equally effective as topical acyclovir cream (137). Additional benefit is noted in a reduction in lesion area; faster loss of lesion-associated symptoms; and reductions in daily assessments of pain, itching, burning, and tenderness (26). Faster healing and pain resolution occurs both among patients who first apply penciclovir cream in the prodrome and erythema stages and among those who start treatment in the papule and vesicle lesion stages (214). Application of medicine should begin as early as possible, preferably during the prodromal phase, and should be continued every two hours during waking hours for four days (Table 7).

        局部用喷昔洛韦（Denavir）治疗复发性口唇疱疹可以缩短病变愈合时间和疼痛的持续时间大约半天(26)。和安慰剂相比，局部用喷昔洛韦软膏可使病变愈合时间缩短近1-2天(26, 214)，疗效与局部用阿昔洛韦软膏相同(137)。局部用喷昔洛韦还可以缩小病变范围，加速病变相关症状的消退，以及减少每日的疼痛、瘙痒、烧灼及触痛等症状(26)。无论是在前驱期或红斑期开始治疗的患者，还是已经处于丘疹、水疱阶段才开始治疗的患者，应用喷昔洛韦软膏均能起到加速病变愈合及缓解疼痛的作用(214)。药物治疗应尽早开始，尤其在前驱期，白天坚持每两小时应用一次，持续应用4日(Table 7)。

               Valaciclovir administered at high doses for short periods of time (2 grams orally twice a day for 1 day) reduces the time to lesion healing and time to cessation of pain and/or discomfort compared to placebo, with the overall duration of the episode being decreased by approximately one day (Table 7) (212). However, early valaciclovir treatment does not appear to increase the likelihood that a clinical recurrence will be aborted prior to cold sore lesion development (42, 212). Valaciclovir administered as a 500 mg dose once daily is effective in suppressing recurrences of herpes labialis, with almost two-thirds of treated patients remaining recurrence-free during four months of suppressive therapy compared with approximately one-third of placebo recipients (14, 15).

        与安慰剂相比，短期大剂量应用伐昔洛韦（每日口服两次，每次2g，仅服1日），可有效缩短病变愈合的时间以及疼痛和/或不适的消失时间，总的病程可缩短近1日(Table 7) (212)。然而，早期应用伐昔洛韦并不能阻止口唇疱疹的出现(42, 212)。伐昔洛韦500mg每日一次，可以有效地抑制口唇疱疹的复发，近2/3接受抑制治疗的患者，可在4个月内保持无复发状态，而接受安慰剂的患者只有近1/3保持无复发(14, 15)。

Genital Herpes: For the treatment of first episode genital herpes, the dose of oral acyclovir is 200 mg orally five times per day, or 400 mg orally three times per day (Table 8). Neither higher doses of oral acyclovir nor the addition of topical acyclovir provide added benefit (237). Duration of therapy in first episode disease is 7-10 days (5). Acyclovir therapy for the treatment of first episode genital herpes reduces the duration of viral shedding by about a week, time to healing of lesions by approximately four days, and time to complete resolution of signs and symptoms by approximately two days (36, 146).

生殖器疱疹：治疗生殖器疱疹首次发作时，阿昔洛韦的口服剂量是200mg 每日5次，或400mg 每日3次(Table 8)。无论增加阿昔洛韦的口服剂量或局部应用阿昔洛韦均不能增加疗效(237)。首次发作的疗程一般是7-10天(5)。阿昔洛韦治疗首次发作的生殖器疱疹，可缩短排放病毒时间近1周，病变愈合时间缩短近4日，症状体征完全消失的时间缩短近2日(36, 146)。

               For the episodic treatment of recurrent genital herpes, dosing options for acyclovir include 200 mg orally five times per day, or 800 mg orally two times per day, administered for five days (5) (Table 8). Topical acyclovir provides no clinical benefit in the episodic management of recurrences and is not recommended (50, 140). A recent study indicates that two days of oral acyclovir therapy (800 mg three times per day) is also efficacious in the episodic treatment of genital HSV recurrences (238). When started within 24 hours of the onset of a genital herpes recurrence, oral acyclovir reduces the duration of viral shedding by approximately two days, time to healing by just over a day, and time to complete resolution of signs and symptoms by approximately a day (230). Episodic treatment does not reduce the length of time to subsequent recurrence (163, 184, 193).

        治疗复发性生殖器疱疹时，阿昔洛韦的口服剂量是200mg，每日5次，或800mg，每日2次，疗程5日(5) (Table 8)。局部应用阿昔洛韦对复发性感染无治疗效果，不推荐使用(50, 140)。近期有研究报道，阿昔洛韦两日疗法（800mg，每日三次）治疗复发性生殖器HSV感染同样有效(238)。若在发病的24小时内即开始用药，口服阿昔洛韦可缩短排放病毒时间近2日，病变愈合时间缩短1日多，临床症状及体征消失的时间缩短近1日(230)。单次治疗并不会缩短以后复发的病程(163, 184, 193)。

               In addition to the treatment of an active genital herpes infection, acyclovir has been effectively used to prevent recurrences of genital herpes. The most frequent indication for suppressive acyclovir therapy is in patients with frequently recurrent genital infections, in whom chronic suppressive acyclovir therapy reduces the frequency of recurrences by approximately 75% (66, 147, 148, 151, 221). One quarter to one third of patients on suppressive therapy experience no further recurrences while taking acyclovir. Daily administration of acyclovir maintains a high degree of efficacy and little toxicity, even after more than 5 years of continuous suppressive therapy (85). Suppressive therapy reduces the frequency of asymptomatic shedding of HSV in the genital tract by more than 80% (239, 242). The acyclovir dose when used as suppressive therapy is 400 mg administered twice daily (Table 8).

        除能够治疗活动性生殖器疱疹病毒感染外，阿昔洛韦可有效预防生殖器疱疹复发。频繁复发的生殖器疱疹感染是使用阿昔洛韦抑制疗法的最佳适应症，阿昔洛韦长期抑制疗法可减少复发约75% (66, 147, 148, 151, 221)。1/4至1/3长期服用阿昔洛韦的患者没有复发。即使服药长达5年以上，每日服用阿昔洛韦仍保持高度有效性而且低毒性(85)。抑制性治疗可减少无症状性生殖器排放病毒达80%以上(239, 242)。阿昔洛韦抑制性治疗的剂量是400mg 每日两次(Table 8)。

               In the episodic treatment of genital herpes, famciclovir reduces time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts when compared with placebo (194). Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning are also reduced (194). For suppression of genital HSV recurrences, famciclovir delays the time to the first recurrence of genital herpes when compared with placebo (63, 149). For the episodic treatment of recurrent genital HSV disease, the dosage of famciclovir is 125 mg twice daily, administered for 5 days (Table 8). The recommended dose for suppression of genital HSV is 250 mg twice daily for up to one year (Table 8). Note that the lack of harmonization of treatment regimens resulted from different doses of famciclovir being studied in the clinical trials; this produced the unusual dosage recommendation of decreasing the suppression dose to treat a genital HSV recurrence. The safety and efficacy of famciclovir therapy beyond one year of treatment have not been established.

        与安慰剂相比，泛昔洛韦可以缩短生殖器疱疹的病变愈合、病毒排出及病变演变的时间，包括病变处的水肿、水疱、溃疡、破裂等(194)，也可以缩短临床症状消失的时间，减轻病变部位的触痛、疼痛和烧灼感 (194)。同安慰剂相比，伐昔洛韦抑制治疗可以推迟生殖器疱疹的首次复发(63, 149)。治疗复发性生殖器HSV感染，泛昔洛韦的剂量是125mg，每日两次，疗程5日 (Table 8)。而推荐的抑制性治疗剂量是250mg，每日两次，疗程1年以上(Table 8)。由于缺乏一致的治疗方案，造成临床研究的药物剂量不统一，从而使推荐用于治疗复发感染的剂量偏低。泛昔洛韦治疗1年以上的安全性和有效性尚不清楚。

               Valaciclovir treatment of first-episode genital HSV is as effective as acyclovir therapy, while at the same time providing a more favorable dosing schedule compared with acyclovir (74). In the treatment of recurrent genital HSV, valaciclovir decreases the duration of lesions, the duration of pain, and the duration of viral shedding when compared to placebo (216). Valaciclovir also is as effective as acyclovir for the episodic treatment of recurrent genital HSV, again providing a more favorable dosing schedule compared with acyclovir (230). It should be administered for three to five days when administered as episodic treatment (5, 133). Valaciclovir is also effective in suppressing recurrences of genital HSV when administered as once-daily suppressive therapy (185). Adult treatment doses for HSV-1 and HSV-2 infections (Table 8) are: 1) 1 gram orally twice daily for 7-10 days for first episode genital herpes; 2) 500 mg orally twice daily for 3-5 days for episodic treatment of recurrent genital HSV disease; and 3) 1 gram orally once daily for suppression of recurrent genital HSV. Suppression of recurrent oral herpes infections also has been accomplished with single daily doses of 500 mg.

        伐昔洛韦治疗生殖器HSV首次发作的疗效与阿昔洛韦相当，而服药方式更方便(74)。同安慰剂相比，伐昔洛韦治疗生殖器HSV复发可以缩短病程，减轻疼痛，缩短排放病毒时间(216)。伐昔洛韦治疗生殖器疱疹复发的疗效也与阿昔洛韦相当（230），疗程为3-5日(5, 133)。伐昔洛韦口服每日一次，抑制生殖器HSV复发同样有效(185)。HSV-1和HSV-2感染的成人治疗剂量(Table 8)分别是：1)治疗生殖器疱疹首次发作，1g口服，每日两次，疗程7-10日；2)治疗生殖器HSV复发，500mg口服，每日两次，疗程3-5日；3)抑制生殖器疱疹复发， 1g口服，每日1次。每日500mg单剂量口服也可以抑制口唇疱疹的复发。

Neonatal Herpes: For neonatal HSV disease, intravenous acyclovir at 60 mg/kg/day delivered in three divided daily doses is currently recommended (Table 7) (3, 112). The dosing interval of intravenous acyclovir may need to be increased in premature infants, based upon their creatinine clearance (70). Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease, and 14 days for patients with HSV infection limited to the SEM (3). The primary apparent toxicity associated with the use of this dose of intravenous acyclovir is neutropenia, with approximately one-fifth of patients with localized HSV disease (CNS or SEM) developing an absolute neutrophil count (ANC) of <1,000/µL (112). Although the neutropenia resolves either during continuation of intravenous acyclovir or following its cessation, it is prudent to monitor neutrophil counts at least twice weekly throughout the course of intravenous acyclovir therapy, with consideration being given to decreasing the dose of acyclovir or administering granulocyte colony stimulating factor (GCSF) if the absolute neutrophil count (ANC) remains below 500/µL for a prolonged period of time (112). All patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved (111, 113).

新生儿疱疹：治疗新生儿HSV感染，目前推荐阿昔洛韦60 mg/kg/每日，分三次静脉注射(Table 7) (3, 112)。早产儿需根据肌酐清除率延长用药间隔 (70)。弥漫型或中枢型HSV感染的新生儿的疗程为21天，而SEM型的疗程为14天(3)。该剂量阿昔洛韦静脉注射的最主要副作用是中性粒细胞减少，约1/5的局灶性感染（中枢型或SEM）患者出现中性粒细胞绝对计数（ANC）<1,000/µL (112)。虽然继续静脉用药或停药，中性粒细胞减少能够恢复，但在静脉注射阿昔洛韦时，应严密监测中性粒细胞计数，至少每周两次，如果中性粒细胞绝对计数(ANC)持续低于500/ul，应考虑减少阿昔洛韦剂量或予以粒细胞集落刺激因子（GCSF）(112)。所有中枢系统受累的HSV感染患者均应在静脉阿昔洛韦治疗接近结束时复查腰穿，证实脑脊液中的病毒PCR检测为阴性，从而结束治疗(113)。若脑脊液PCR检测仍为阳性，应继续静脉注射阿昔洛韦，直到PCR结果转阴为止(111, 113)。

Herpes Simplex Encephalitis: For herpes simplex encephalitis, intravenous acyclovir should be administered at 30 mg/kg/day for 14-21 days for the treatment of HSE (Table 7) (251). Some experts recommend higher dosages of intravenous acyclovir be considered (45 mg/kg/day), although neurotoxicity can be a limiting factor in increasing the dose in larger children and adults. A randomized, controlled trial of long-term suppressive oral valaciclovir therapy following the treatment of the acute HSE disease is currently being conducted by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group. This study will determine whether subclinical reactivation of HSV within the brain contributes to the neurologic impairment experienced by many HSE survivors. At the current time, however, no evidence exists to suggest that suppressive oral valaciclovir therapy is beneficial in preventing neurologic complications.

单纯疱疹脑炎：治疗单纯疱疹脑炎，静脉注射阿昔洛韦的剂量为30 mg/kg/日，疗程14-21天(Table 7) (251)。由于顾虑药物的神经毒性，不能增加药物的剂量，但仍有一些专家推荐年长儿和成人使用大剂量阿昔洛韦(45 mg/kg/日)静脉注射。国家变态反应和感染疾病协会(NIAID)抗病毒治疗协作组正在进行一项随机对照临床研究，HSE患者在急性期治疗后，予以长期口服伐昔洛韦抑制治疗。该研究旨在评价HSE存活者的神经系统损害，是否和脑组织中潜伏的HSV病毒的亚临床活动有关。然而，到目前为止还没有证据表明，口服伐昔洛韦抑制治疗可有效预防神经系统并发症。

HSV keratitis or keratoconjunctivitis: Topical therapy with acyclovir for HSV ocular infections is effective, but probably not superior to trifluridine (Table 7) (94). Long-term suppressive therapy reduces the number of recurrences of ocular infection in those with histories of frequent recurrences (90, 91).

HSV角膜炎及角结膜炎：局部用阿昔洛韦治疗HSV眼部感染有效，但其疗效可能并不优于曲氟尿苷 (Table 7) (94)。对有反复复发史的患者，长期抑制治疗可减少复发的次数(90, 91)。

Review Article:  Javey G, Zuravleff G.  Keratitis. 2007.

Underlying Diseases

基础疾病

HSV Disease in the Immunocompromised Host: Acyclovir also is indicated for the treatment of disseminated HSV infections in otherwise normal hosts, including pregnant women, and mucocutaneous HSV infections in immunocompromised hosts (114). Similarly, HSV infections of the lip, mouth, skin, perianal area, or genitals may be much more severe in immunocompromised patients than in normal hosts, with HSV lesions tending to be more invasive, slower to heal, and associated with prolonged viral shedding. Intravenous acyclovir therapy is very beneficial in such patients (Table 7) (235). Immunocompromised patients receiving acyclovir have a shorter duration of viral shedding and more rapid healing of lesions than patients receiving placebo (150). Oral acyclovir therapy is also very effective in immunocompromised patients (203).

免疫缺陷宿主的HSV感染：阿昔洛韦同样可用于治疗免疫功能正常的特殊人群（如妊娠妇女）的播散型HSV感染，以及免疫功能低下患者的皮肤粘膜HSV感染(114)。免疫功能低下患者的口唇、皮肤、肛周或生殖器的HSV感染可能比免疫功能正常者更严重，病毒形成的病变更具侵袭性，愈合更慢，排放病毒时间也更长。静脉注射阿昔洛韦治疗免疫功能低下患者的HSV感染非常有效(Table 7) (235)。与安慰剂相比，免疫功能低下患者静脉注射阿昔洛韦可缩短排放病毒时间及病变愈合加速(150)。同样，免疫功能低下患者口服阿昔洛韦的治疗也非常有效(203)。

               Acyclovir prophylaxis of HSV infections is of clinical value in severely immunocompromised patients, especially those undergoing induction chemotherapy or transplantation. Intravenous or oral administration of acyclovir reduces the incidence of symptomatic HSV infection from about 70% to 5-20% (195). A sequential regimen of intravenous acyclovir followed by oral acyclovir for 3 to 6 months can virtually eliminate symptomatic HSV infections in organ transplant recipients. A variety of oral dosing regimens, ranging from 200 mg 3 times daily to 800 mg twice daily, have been used successfully.

        对于免疫功能严重低下的患者，特别是进行化疗或器官移植的患者，预防性应用阿昔洛韦具有重要的临床意义。静脉或口服阿昔洛韦可使有症状的HSV感染发生率由70%降低至5-20%(195)。对器官移植的患者，在静脉注射阿昔洛韦后继续口服阿昔洛韦3-6个月，可以完全消除有症状的HSV感染发生。临床有多种口服治疗方案，200mg 每日3次，到 800mg 每日两次，不同剂量的方案均有效。

Fuchs J, et al. Clinical and Virologic Efficacy of Herpes Simplex Virus Type 2 Suppression by Acyclovir in a Multicontinent Clinical Trial. J Infect Dis 2010;201:1164-1168.

Alternative Therapy

其它治疗方法

Combinations of Antiviral Agents: Unlike antiviral management of HIV infections, combination antiviral therapy is not employed in the antiviral treatment of HSV infections. Empiric changes in classes of antiviral agents are sometimes made based upon the clinician’s judgment that a resistant virus could be present.

抗病毒药物的联合治疗：与HIV的抗病毒治疗不同，抗HSV感染不主张联合药物治疗。目前临床医师通常凭经验判断病毒出现耐药，更换其它种类的抗病毒药物治疗。

Passive Immunotherapy with Polyclonal Antibodies: As noted above, cell mediated immune responses likely play the central role in controlling recurrent HSV infections (120, 169, 170, 171, 217). While there is some degree of cross-protection conferred by pre-existing HSV-1 antibody on the acquisition of HSV-2 infection (32, 55, 67, 75, 81, 100, 145, 160, 190), the protection is incomplete. Similarly, vaccines have been developed which generate robust humoral responses yet fail to protect against HSV-2 infection (217). As such, it is difficult to envision a circumstance whereby passive antibody immunotherapy will play a role in the management of genital HSV infection and disease.

多克隆抗体的被动免疫治疗：如前文所述，细胞介导的免疫反应在控制HSV感染复发过程中发挥着关键的作用(120, 169, 170, 171, 217)。体内存在的HSV-1抗体对HSV-2感染有一定程度的交叉保护作用，但保护作用不完全(32, 55, 67, 75, 81, 100, 145, 160, 190)。同样，已研制开发了疫苗，疫苗虽可产生强的体液免疫反应，但仍不能有效防御HSV-2的感染(217)。因此，被动免疫治疗对生殖器HSV感染无效。

               In contrast to genital disease, the protection against infection and amelioration of disease severity afforded by neutralizing and ADCC antibodies in neonatal HSV may portend a future role for passive immunotherapy in conjunction with antiviral treatment. Both human and humanized antibodies directed against gB and gD have been shown to be beneficial as prophylactic and therapeutic agents in animal models of HSV infection (17, 31, 106, 127). In humans, both maternal antibody status (35, 174, 264, 265) and type of maternal infection (primary vs. recurrent) (33, 34, 35, 52, 159) influence transmission of HSV from mother to baby. Neonates with higher neutralizing antibody titers are less likely to become infected with HSV following perinatal exposure of passage through an infected birth canal (174), illustrating the protective effects of preexisting antibody in preventing neonatal HSV disease. Among HSV-infected neonates, anti-HSV neutralizing antibody titers have been shown to correlate with the extent of the disease (223), with babies with higher neutralizing antibody titers being more likely to have localized disease (and less likely to have disseminated disease) once they are infected. Similarly, high maternal or neonatal anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels are each independently associated with an absence of disseminated HSV infection (121).

        与生殖器感染相反，中和抗体及ADCC抗体可有效防止新生儿的HSV感染，改善病程，展现了被动免疫联合抗病毒治疗的前景。HSV感染的动物模型显示，人或人化的抗gB、gD抗体能有效预防和治疗HSV感染(17, 31, 106, 127)。对人类而言，母体的抗体水平(35, 174, 264, 265)及母亲的感染类型（原发或复发性）(33, 34, 35, 52, 159)均影响HSV病毒的母婴传播。具有高滴度中和抗体的新生儿，在围产期通过感染的产道时，发生HSV感染的机率减少(174)，说明已经存在的抗体对新生儿具有保护力。在HSV感染的新生儿中，其体内的抗HSV中和抗体滴度与病情有关(223)，中和抗体滴度高的患儿更易发生局灶性感染（或更不易发生播散型感染）。同样，母体或胎儿抗HSV的ADCC抗体滴度高或新生儿中和抗体水平高，是不发生播散性感染的独力相关因素(121)。

               While antibody therapy offers promise for improving neonatal HSV disease prevention and outcome, studies in humans have yet to be performed. In addition, an HSV hyperimmune globulin preparation does not exist, and the amount of anti-HSV antibodies present in conventional intravenous gammaglobulin (IVIG) preparations is low and variable, such that unacceptable large volumes would need to be injected to potentially confer protective immunity. For these reasons, use of IVIG in the management of neonates with HSV disease cannot be recommended at this time. Any development of a monoclonal antibody against HSV would of course require extensive testing in humans before therapeutic recommendations could be made.

        抗体治疗能预防新生儿HSV感染和改善预后，但人体研究还未进行。另外，目前还没有抗HSV的高效价免疫球蛋白，常规用静脉丙种球蛋白（IVIG）中的抗HSV抗体含量很低且不稳定，因此要想获得针对HSV的保护作用，就需要相当大剂量的IVIG，而这一点在目前难以实现。因此目前HSV感染的新生儿不推荐使用IVIG。任何一种单克隆HSV抗体都必须通过广泛的临床验证后，才能被推荐用于临床治疗。

ADJUNCTIVE THERAPY AND OTHER ISSUES Guided Medline Search

辅助治疗及其它

               Despite the advances in our understanding of genital herpes, considerable shame, embarrassment, and stigma remain among infected persons (2). For many patients, the psychological impact is far more severe than the physical consequences of the disease (39). Shock, anger, guilt, low self-esteem, fear of transmission of the infection to others, and impaired sexual function are common and can interfere substantially with relationships (2). Anecdotal experience suggests that the diagnosis of neonatal herpes has a similar negative impact on the parents' relationship, with guilt and anger over the baby's illness and its association with genital herpes often leading to separation and divorce. A listing of helpful resources which provide reliable herpes information can be found in Table 9.

        尽管目前人们对于生殖器疱疹的认识已明显提高，但感染者还是存在着很多诸如羞愧、窘迫及耻辱等情绪(2)。对于很多患者而言，心理上的影响比躯体的病变要严重得多(39)。患者常常表现出震惊、愤怒、内疚、低自尊，担心把疾病传给他人及性功能障碍等，进而影响到夫妻关系(2)。有趣的是，新生儿疱疹感染的诊断同样会对夫妻关系产生消极的影响，内疚和愤怒情绪超过了孩子的疾病，孩子患病与母亲生殖器疱疹的关系，常导致分居和离婚。表格9中列出了一系列有帮助的资源，能提供可靠的关于生殖器疱疹的信息。

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

治疗终点

HSE: Persistence of viral DNA in the CSF as detected by PCR occurs in virtually all cases of HSE through the first week following initiation of antiviral therapy (128, 175, 187). During the second week of therapy, HSV DNA is detected in the CSF of approximately half of the patients, and 20% or fewer of patients have a positive PCR result beyond day 15 of antiviral therapy (128, 187). An end-of-therapy lumbar puncture should be performed to document that the CSF has become PCR-negative prior to stopping parenteral antiviral therapy. PCR analysis of sequential CSF specimens will also improve monitoring of viral reactivation during relapses following completion of antiviral therapy (59, 77, 87, 97, 108, 142).

HSE：在开始抗病毒治疗的第一周内，用PCR方法可检测，所有HSE患者脑脊液中持续存在HSV DNA(128, 175, 187)。在治疗的第二周，只有近一半患者的脑脊液HSV DNA阳性，而在治疗15天以上，脑脊液HSV DNA阳性率降至20%以下(128, 187)。在治疗接近尾声时，只有当复查腰穿证实脑脊液HSV DNA已转阴时，才能停止抗病毒治疗。在结束抗病毒治疗后，连续监测脑脊液的PCR，有利于监测病毒感染的复发(59, 77, 87, 97, 108, 142)。

               Quantitative PCR may also have a role in monitoring response to therapy (261), although evaluation for this purpose has been limited to date (57). While at least one investigation failed to correlate amount of virus present with severity of outcome (187), other studies have found a relation between HSV viral load in the CSF and likelihood of future neurologic impairment (64). Specifically, HSV DNA concentrations of greater than 100 copies/µL CSF correlate both with reduced level of consciousness at presentation and with likelihood of future neurologic impairment (64).

        定量PCR有助于监测治疗效果(261)，虽然目前研究很少(57)。至少一项研究发现病毒载量和预后无关 (187)，而其它研究发现，脑脊液中的HSV病毒载量与神经系统损伤关(64)。脑脊液中HSV DNA超过100拷贝/ul与患者就诊时的意识障碍程度和神经系统后遗症相关(64)。

Neonatal HSV: The available data for neonatal HSV suggest that having HSV DNA detected in CSF at or after completion of intravenous therapy is associated with poor outcomes (111, 141). As such, all patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved.

新生儿HSV：新生儿HSV感染的研究显示，在静脉治疗结束时或之后，若脑脊液中仍能检测出HSV DNA，则提示患儿预后不良(111, 141)。因此，所有中枢受累的HSV感染者，在静脉注射阿昔洛韦治疗结束时均应复查腰穿，在确定PCR检测为阴性后，才可停止治疗(113)。脑脊液PCR检测持续阳性的患者应继续静脉抗病毒治疗，直至PCR结果转阴。

VACCINES Guided Medline Search

疫苗

               Numerous attempts to develop a vaccine to prevent HSV disease or infection have failed over the past several decades. However, a candidate HSV-2 glycoprotein D subunit vaccine adjuvanted with alum combined with 3-deacylated monophosphoryl lipid A (MPL) has recently demonstrated promising results. In two large Phase III studies, the vaccine has been demonstrated to be safe and, in a subset of volunteers, effective in preventing HSV-1 or -2 genital herpes disease (vaccine efficacy ~ 75%) and HSV-2 infection (vaccine efficacy ~ 40%) (218). In both studies, efficacy was limited to women who were HSV-1 and -2 seronegative prior to vaccination, with no evidence of vaccine efficacy in men or in women who were HSV 1+/2- prior to vaccination. Because these earlier trials were neither designed nor powered to assess efficacy in HSV 1-/2- women, another Phase III trial by GlaxoSmithKline (GSK) and NIAID is currently enrolling subjects.

        在过去的几十年间，进行了大量的工作，研制用于预防HSV感染的疫苗，但都失败了。HSV-2糖蛋白D亚基疫苗，以硫酸铝钾和3-脱酰单磷脂酰脂质A（MPL）为载体，显示出一定的应用前景。两项大型III期临床研究显示，该疫苗安全，在志愿者亚组，该疫苗可以有效预防HSV-1或HSV-2生殖器疱疹（疫苗效能75%）和HSV－2感染（疫苗效能40％）(218)。在这两项研究中，只有接种前HSV-1和HSV-2血清阴性的女性有效，而对男性和接种前HSV 1+/HSV 2-的女性无效。因为早期的临床研究并未将HSV 1-/HSV 2-的女性患者纳入，因此近期由葛兰素史克 (GSK) 和 NIAID进行的另一项III期临床研究将会补充这一缺陷。

PREVENTION Guided Medline Search

预防

Cesarean Delivery: Cesarean delivery in a woman with active genital lesions can reduce the infant's risk of acquiring HSV (35, 159). To prevent neonatal HSV disease, cesarean section should be performed if genital HSV lesions or prodromal symptoms are present at the time of delivery. As a method to reduce the incidence of neonatal HSV disease, however, cesarean delivery has a number of drawbacks, including the fact that 60-80% of babies who develop neonatal HSV disease are born to women without a history of genital herpes (253, 258, 264), and thus will not be prevented with this approach. Furthermore, neonatal infections have occurred in spite of cesarean delivery performed prior to the rupture of membranes (168, 253).

剖腹产：有活动性生殖器病变的产妇采用剖腹产，可以减少新生儿感染HSV的机率(35, 159)。为预防新生儿HSV感染，若临产时存在生殖器疱疹或已出现前驱期临床症状，应采取剖腹产。剖腹产虽然可以减少新生儿HSV感染的机率，但也有很多缺陷，比如60-80%感染HSV的新生儿的母亲并没有生殖器疱疹的病史(253, 258, 264)，因此剖腹产就不能预防这些感染的发生。此外，如果新生儿在胎膜破裂之前已发生HSV感染，剖腹产也不能预防感染的发生 (168, 253)。

Antiviral Suppression of Seropositive Partner in Discordant Relationship: In a recent report, suppressive therapy with valaciclovir 500 mg once daily for 8 months decreased the rate of symptomatic HSV infection in the seronegative partner by 75 percent, and reduced the likelihood of acquisition of genital HSV-2 infection (symptomatic or asymptomatic) by 48 percent (53). However, risk of transmission was not completely eliminated.

血清阳性配偶的抗病毒抑制治疗

        近期一项研究报道，使用伐昔洛韦500mg 每天一次，连续用药8个月，抑制病毒治疗，使血清阴性的配偶出现症状性HSV感染的发生率下降75%，生殖器HSV-2感染（有症状或无症状）的发生率下降48%。但并不能完全阻断病毒的传播。

Condoms: A recent study of 528 monogamous couples discordant for HSV-2 infection found that when condoms were used during more than 70 percent of sexual encounters between an HSV-2-positive man and an HSV-2-negative woman, transmission was reduced by more than 60 percent (241). The means by which to achieve more consistent condom use by discordant couples, however, remains to be determined.

避孕套：最近一项包括528对单一性伴侣的单方HSV-2感染的研究发现，当HSV-2阳性的男性与HSV-2阴性的女性在性生活时，避孕套使用率在70%以上，病毒传播的机率下降60%以上(241)。然而如何在单方患病的配偶中推广长期使用避孕套仍有待解决。

Antiviral Prophylaxis During Pregnancy: Because of acyclovir’s safety record in pregnancy (220), along with a desire to decrease neonatal HSV disease and reduce cesarean deliveries performed for the indication of herpes, utilization of oral acyclovir near the end of pregnancy to suppress genital HSV recurrences has become increasingly common in clinical practice. Several small studies suggest that suppressive acyclovir therapy during the last weeks of pregnancy decreases the occurrence of clinically apparent genital HSV disease at the time of delivery (29, 199, 200), with an associated decrease in cesarean section rates for the indication of genital HSV (29, 200). However, because viral shedding still occurs (albeit with reduced frequency) (199, 244), the potential for neonatal infection likely is not completely avoided. Additional studies are needed to more definitively establish the safety and effectiveness of late pregnancy maternal HSV suppressive therapy, including the potential for neutropenia in neonates born to women receiving antiviral suppressive therapy (108, 109, 202). Data currently do not support the routine utilization of suppressive oral acyclovir or valaciclovir in gravid women with a history of recurrent genital herpes (115).

妊娠期的预防性抗病毒治疗：由于孕妇使用阿昔洛韦是安全的，(220)，为降低新生儿HSV感染和减少剖腹产，目前临床上越来越多地在妊娠末期口服阿昔洛韦，以抑制生殖器疱疹复发。一些小规模的临床研究发现，在妊娠的最后几周应用阿昔洛韦抗病毒治疗，可降低分娩时显性生殖器疱疹感染 (29, 199, 200)，也能降低因生殖器疱疹而行剖腹产的机率(29, 200)。但是由于仍有病毒排放（虽然概率降低）(199, 244)，因此新生儿感染的可能性仍不能完全避免。关于妊娠晚期HSV感染母亲的抑制治疗的安全性及有效性，还需要更深入细致的研究，包括新生儿粒细胞减少症发生的潜在危险性 (108, 109, 202)。近期的研究并不支持，对有复发性生殖器疱疹病史的妊娠妇女，常规应用口服阿昔洛韦或伐昔洛韦做抑制性的抗病毒治疗(115)。

INFECTION CONTROL

感染控制

               Persons with active mucocutaneous herpetic lesions should be managed with contact precautions. If lesions are localized to one area, standard precautions may suffice. Persons with HSV infection of the central nervous system who do not have lesions should be managed with standard precautions.

        发生有活动性粘膜、皮肤疱疹感染的患者，应防止接触性传染。如病变局限在一个区域，标准防护措施即可防止病毒传染。如果患者仅有中枢神经系统感染而没有皮肤、粘膜损害，应予以标准的防护措施。

COMMENTS AND CAVEATS

注意事项和警告

               Perhaps the most prominent challenge impacting clinical benefit of acyclovir therapy relates to the timing of drug initiation following onset of disease symptoms. In the case of life-threatening HSV disease such as HSE or neonatal HSV, consideration of HSV as a possible cause of the illness is needed in order to then initiate acyclovir therapy. In the case of less severe but still consequential infections, such as primary genital herpes, the patient must present to medical attention, be correctly diagnosed, and then started on antiviral therapy as quickly as possible to achieve maximal benefit. Despite the tremendous advances in diagnostics and therapeutics employed in the management of HSV disease, nothing as yet usurps the judgment of the clinician as he or she cares for their patient. For example, false negative (and false positive) CSF PCR results are well documented in the literature. If the physician’s clinical suspicion is that HSV disease of the CNS is likely, the management course should not be diverted solely upon the basis of one negative HSV CSF PCR result. While the technologic achievement represented by PCR is phenomenal, the art of medicine must always prevail over simply the science of medicine.

        影响阿昔洛韦疗效的最主要的因素可能是出现临床症状后的用药时间。对于危及生命的HSV感染，如HSE或新生儿HSV感染，只要考虑到HSV感染的可能性，就应立即开始治疗。而对于危险性较小的HSV感染，如原发性生殖器疱疹，患者应在明确诊断后尽快开始抗病毒治疗，以期获得最大治疗效果。尽管目前在HSV感染的诊断及治疗方面有很多新进展，但是临床医师的综合判断还是最重要的。例如，在文献中就有脑脊液PCR检测假阴性（或假阳性）的报道。如果临床医师怀疑中枢神经系统HSV感染，那么不能单凭一次阴性的脑脊液PCR检测结果就随意更改治疗方案。尽管PCR检测技术已经获得了长足的进步，但医疗的综合判断艺术永远高于单纯的实验室技术。

               Over the next decade, continued advances in the development of molecular techniques for the detection of HSV DNA in CSF and perhaps the genital tract will occur. The predominant areas where advances will occur are in decreasing the time required to run the test, increasing the numbers of viruses detected in a single test, developing and applying quantitative assays to detect viral load, and standardizing systems to ensure their reproducibility from clinical laboratory to clinical laboratory. Examples of multiple viruses detected in a single test include herpesvirus consensus PCR (28, 152) and multiplex nested-PCR (79). Quantitative PCR from CSF (1) will allow for monitoring of the therapeutic response to antiviral treatment as experience with interpreting test results increases. Real-time PCR provides advantages of speed and quantitativeness compared with conventional PCR (104), while at the same time reducing the likelihood of contamination because no post-amplification analysis using amplified products is required (104). Examples of new systems capable of yielding reproducible results from lab to lab include LightCycler, with real-time detection of PCR products by fluorescence resonance energy transfer assay (72) and the capability of simultaneous detection and typing of HSV (38), as well as time-resolved fluorometry (95).

        未来十年，分子生物学技术的发展将使脑脊液的HSV DNA检测更加完善，或许能检测生殖道的HSV DNA。最主要的进步可能是缩短检测时间，增加单一试剂盒检测的病毒种类，研发定量检测技术，测定病毒载量，以及建立标准化检测系统，从而确保不同实验室之间检测结果的一致性。例如单一试剂盒检测多种病毒的技术包括多种疱疹病毒检测PCR (28, 152)和多元嵌套性PCR(79)。脑脊液定量PCR (1)将能监测抗病毒治疗的疗效。和普通PCR技术相比，实时定量PCR检测在检测速度及定量方面更具优势(104)，同时因不需要应用扩增产物进行分析，大大减少了标本污染机会(104)。新的检测系统能实现实验室间检测结果的可重复性，例如LightCycler系统，应用荧光光谱能量转换方法，进行实时定量的PCR检测(72)，可同时检测HSV病毒和分型(38)，也可进行定时的荧光检测(95)。

               An area in which development of new technology could significantly impact neonatal HSV is that of identifying mothers at the time of delivery who are actively shedding HSV from the genital tract. Development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery, as has been explored for the detection of group B Streptococcus colonization (23), could lead to management algorithms designed to minimize neonatal exposure to the virus, thereby preventing neonatal infection in the first place. Such technological advances should be encouraged.

        能鉴别分娩时母体的生殖道活动性病毒排放的技术，将大大改变新生儿HSV感染。研发床旁快速核酸检测试剂盒，在分娩时实时测定母体生殖道中的HSV DNA，就像检测B组链球菌定植一样(23)，将有效地减少新生儿的病毒暴露，从而在第一线预防新生儿感染。应大力开发这样的先进技术。

TABLES AND FIGURES

Table 1. Clinical Manifestations and Type of Infection

Table 2. Clinical Manifestations of Primary HSV-2 Genital Herpes

Table 3.  Clinical Manifestations of Recurrent Genital Herpes

Table 4.  Diagnostic Tests for HSV Infection and Disease [Download PDF]

Table 5. Herpes Blood Tests Quick Reference Guide (from http://www.ashastd.org/pdfs/blood_test.pdf, accessed February 3, 2005) [Download PDF]

Table 6. Recommended uses of HSV type-specific serologic testing

Table 7. Therapeutic management of nongenital HSV infections [Download PDF]

Table 8. Therapeutic management of genital HSV infections (HSV-2 or HSV-1) [Download PDF]

Table 9. Telephone and Online Resources for Herpes Information

Figure 1. Herpes simplex gingivostomatitis [From Reference (250)]

图1：HSV牙龈口腔炎 [参考文献250]

Figure 2. Recurrent herpes simplex labialis [From Reference (250)]

图2： HSV口唇感染 [参考文献250]

Figure 3. Primary genital HSV lesions [From Reference (115)]

图3：女性外生殖器HSV感染 [参考文献115]

Figure 4. Illustration of viral latency and reactivation [From Reference (30)]

图4：病毒的潜伏和激活 [参考文献30]

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