An international, randomized, double-blind, placebo-controlled, study of valacyclovir for the suppression of herpes simplex virus type 2 genital herpes in newly diagnosed patients.

BACKGROUND: Antiviral suppressive therapy of genital herpes is often initiated based on the established pattern of recurrences in an individual. Because most persons with first episode herpes simplex virus type 2 (HSV-2) infection experience recurrences and because viral shedding occurs frequently in the first year after infection, we examined the strategy of initiating suppressive therapy shortly after diagnosis of genital HSV-2 infection. SUBJECTS AND METHODS: From June 16, 2004 to July 26, 2006, 384 subjects from 74 sites in the United States, Canada, Argentina, Brazil, and Chile who were newly diagnosed with a first recognized episode of genital herpes at the time of the screening visit or within 3 months before the screening visit were randomized (2:1) to receive valacyclovir 1 g once daily or placebo for 24 weeks. Subjects were instructed to return to clinic during suspected genital herpes outbreaks for clinician confirmation of recurrences. RESULTS: Valacyclovir significantly prolonged the time to first recurrence of HSV-2 genital herpes in newly diagnosed subjects compared with placebo, with approximately 43% of subjects on placebo and 71% of subjects on valacyclovir recurrence-free at 24 weeks (P <0.001). Valacyclovir significantly reduced the mean number of genital HSV-2 recurrences per month occurring during the 24-week study period (0.11 for valacyclovir, 0.48 for placebo, P <0.001). Adverse events were comparable in the valacyclovir and placebo arms. CONCLUSION: Valacyclovir 1 g once daily administered for 24 weeks was well-tolerated and effective in suppressing genital herpes recurrences in immunocompetent newly diagnosed persons without an established recurrence pattern.     

Famciclovir reduces viral mucosal shedding in HSV-seropositive persons

OBJECTIVE: Many cases of herpes simplex virus (HSV) infection occur through asymptomatic shedding from persons without evidence of clinical disease. This study explores whether famciclovir reduces HSV shedding in HSV-2 seropositive persons with or without a history of symptomatic genital herpes. STUDY DESIGN: One hundred twenty-seven HSV-2 seropositive participants were randomly assigned to 42 days of famciclovir, followed by 14 days of washout and 42 days of placebo, or vice versa. All subjects swabbed the genital/perianal area; those with HSV-1 infection also swabbed the oral area daily for HSV DNA PCR. RESULTS: Famciclovir reduced genital and oral HSV shedding from 11.4% of days during the placebo period to 4.7% of days during famciclovir therapy. The reduction was greater in participants with a history of genital herpes (74%) than in those without such a history (30%). In multivariate analyses, famciclovir protected against total (clinical and subclinical) genital shedding among persons with a clinical history of genital herpes (RR, 0.23; 95% CI, 0.15-0.35; P < 0.001). Among HSV-2 seropositive participants without a history of genital herpes, 60% had HSV detected in the genital area at least once during the study. Famciclovir therapy did not result in a statistically significant reduction in total HSV shedding in participants without a history of genital herpes. CONCLUSION: Famciclovir therapy decreases genital HSV shedding in HSV-seropositive persons, especially those with a history of genital herpes. Overall, antiviral drugs may have varying effects on symptomatic and asymptomatic viral shedding, depending on the clinical history of the disease.     

The effect of daily valacyclovir suppression on herpes simplex virus type 2 viral shedding in HSV-2 seropositive subjects without a history of genital herpes

BACKGROUND: A substantial number of HSV-2 seropositive individuals lack a history of clinically recognized genital herpes. These individuals can transmit disease during periods of asymptomatic viral shedding. The frequency of asymptomatic shedding and the efficacy of antiviral therapy in reducing shedding has not been assessed in this population. OBJECTIVE: To compare the effect of valacyclovir 1 g once daily for 60 days versus placebo on asymptomatic viral shedding in immunocompetent, HSV-2 seropositive subjects without a history of symptomatic genital herpes infection. STUDY DESIGN: Seventy-three subjects were randomized to receive valacyclovir 1 g daily or placebo for 60 days each in a 2-way crossover design. A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction. RESULTS: Fifty-six subjects with at least 1 polymerase chain reaction measurement in both treatment periods comprised the primary efficacy population. Valacyclovir significantly reduced shedding during subclinical days compared to placebo [mean, 1.5% vs. 5.1% of subclinical days (P <0.001), a 71% reduction]. Eighty-four percent of subjects had no shedding while receiving valacyclovir versus 54% of subjects on placebo (P <0.001). Eighty-eight percent of patients receiving valacyclovir had no recognized signs or symptoms versus 77% for placebo (P = 0.033). Valacyclovir was not associated with any safety risk compared with placebo. CONCLUSIONS: In this study, asymptomatic viral shedding occurred in a substantial number of HSV-2 seropositive subjects without a history of genital herpes. Valacyclovir 1 g daily significantly reduced asymptomatic shedding compared with placebo in this population.     

Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding

BACKGROUND: Daily antiviral therapy with famciclovir and valacyclovir has been shown to be effective in reducing both symptomatic and asymptomatic reactivation of herpes simplex virus type 2 (HSV-2) when compared to placebo. However, few comparative studies between the 2 antivirals have been performed. OBJECTIVES: To compare the clinical and virologic effects of famciclovir and valacyclovir administered as daily suppressive therapy for persons with genital herpes. STUDY DESIGN: Two randomized, double-blind, placebo-controlled studies comparing daily famciclovir 250 mg bid with valacyclovir 500 mg qd were performed. Study 1 randomized 320 participants and compared the clinical effect of the drugs given for 16 weeks, and study 2 enrolled 70 HSV-2 seropositive subjects and compared the virologic effect of the drugs given for 10 weeks. RESULTS: In study 1, the time to first recurrence was similar in famciclovir and valacyclovir recipients, hazard ratio (HR) 1.17 (95% CI, 0.78-1.76), but time to first virologically confirmed recurrence was shorter among famciclovir recipients, HR = 2.15 (95% CI, 1.00-4.60). In study 2, HSV was detected on 3.2% of days among famciclovir recipients and 1.3% of days among valacyclovir recipients, relative risk 2.33 (95% CI, 1.18-4.89). CONCLUSION: Valacyclovir appear to be somewhat better than famciclovir for suppression of genital herpes and associated shedding. Further comparative trials of antiviral drugs for various indications should be performed as acyclovir and penciclovir appear to have different ability to abrogate HSV reactivation.     

Recurrent genital herpes among women: symptomatic v. asymptomatic viral shedding.

To investigate whether asymptomatic shedding of herpes simplex virus occurs in women with recurrent genital herpes, six women with documented disease were followed up twice weekly with viral cultures and pelvic examination. During the study period of 1330 patient days and 452 patient visits, 26 episodes of genital herpesvirus infection were recorded. Twenty-three (88%) episodes were accompanied by signs and symptoms. Three (14%) of the culture-positive recurrences were asymptomatic. In one episode an asymptomatic lesion was noted, and in two instances viral shedding from the vulva or cervix occurred in the absence of visible herpetic lesions. Three of the six women had evidence of recurrent cervical herpesvirus infection. No relationships between menstrual cycle and sexual activity and the onset of recurrence were noted.     

Recurrent genital herpes among women: symptomatic v. asymptomatic viral shedding.

To investigate whether asymptomatic shedding of herpes simplex virus occurs in women with recurrent genital herpes, six women with documented disease were followed up twice weekly with viral cultures and pelvic examination. During the study period of 1330 patient days and 452 patient visits, 26 episodes of genital herpesvirus infection were recorded. Twenty-three (88%) episodes were accompanied by signs and symptoms. Three (14%) of the culture-positive recurrences were asymptomatic. In one episode an asymptomatic lesion was noted, and in two instances viral shedding from the vulva or cervix occurred in the absence of visible herpetic lesions. Three of the six women had evidence of recurrent cervical herpesvirus infection. No relationships between menstrual cycle and sexual activity and the onset of recurrence were noted.     

伐昔洛韦与阿昔洛韦治疗初发生殖器疱疹的对比研究

目的 评价伐昔治疗初发生殖器疱疹的疗效和安全性。方法 将２８例初发生殖器疱疹患者随机分为伐昔洛韦治疗组和阿昔洛韦对照组。治疗后第１、２、３、５、７、２０天分别作临床观察,对部分病例作治疗后病毒培养。结果 治疗组和对照组的症状消失时间、皮损愈合时间、治疗后病毒和时间差异均无显著性意义（Ｐ〉０．０５）。两组病例不良反应相似且轻微。结论 伐昔洛韦 是治疗初发生残器疱疹的安全有效药物。     

Does frequency of genital herpes recurrences predict risk of transmission? Further analysis of the valacyclovir transmission study

BACKGROUND: The benefit of suppressive antiviral therapy for reducing the risk of herpes simplex virus (HSV)-2 transmission to sex partners may be enhanced if persons at high risk for transmission can be identified. OBJECTIVE: To determine whether frequency of genital herpes recurrences is associated with increased risk of HSV-2 transmission. METHODS: Analysis of recurrence frequency and shedding frequency (subset) among participants in a randomized controlled trial of valacyclovir 500 mg qd versus placebo for reducing the risk of HSV-2 transmission. RESULTS: Overall, 1484 monogamous HSV-2-serodiscordant couples participated and 41 HSV-2 transmissions occurred during the 8-month trial; 40 were able to provide a history of recurrence frequency. The rate of recurrences per year before study entry did not differ between source partners who transmitted and those who did not, 4.8 versus 5.1, respectively. Similarly, the mean frequency of recurrences observed during the study also did not differ among those who transmitted versus those who did not for placebo recipients (4.4 vs. 4.8) or valacyclovir recipients (1.4 vs. 1.3). Among the 40 source partners who transmitted HSV-2, 8 of 27 placebo recipients and 7 of 13 valacyclovir recipients had no recurrences during the study. CONCLUSION: Clinical assessment of HSV-2 disease severity as defined by the frequency of genital herpes recurrences does not predict the risk of transmission to sexual partners. Though patients with frequent recurrences are most likely to benefit clinically from suppressive therapy, frequency of recurrences is not helpful in identifying persons who are most likely to transmit HSV-2.     

Valacyclovir in the Treatment of Herpes Simplex,Herpes Zoster,and Other Viral Infections

BACKGROUND: Genital herpes and herpes labialis are prevalent, physically and psychologically painful, and often disabling. Herpes zoster is often very painful and may result in months or years of postherpetic neuralgia (PHN). Over the past two decades, the treatment of these conditions has been transformed by guanosine nucleoside antivirals such as valacyclovir (Valtrex, a highly bioavailable prodrug of acyclovir (Zovirax, and famciclovir (Famvir), a highly bioavailable prodrug of penciclovir (Denavir). OBJECTIVE: We describe the pharmacology, pharmacokinetics, and clinical efficacy of valacyclovir for the treatment of herpes simplex, herpes zoster, and other viral infections. Valacyclovir is also compared with acyclovir and famciclovir. METHODS: All published literature containing the word "valacyclovir" was reviewed and summarized. RESULTS: Valacyclovir is the only oral antiviral agent approved for therapy of herpes labialis, the only antiviral drug approved for a 3-day course in the episodic treatment of recurrent genital herpes, as well as the only antiviral drug approved for once daily dosing for suppressive therapy. In herpes zoster, valacyclovir is more effective than acyclovir and equally effective as famciclovir at hastening the healing of zoster-associated pain and PHN. CONCLUSION: Valacyclovir is safe and effective in the therapy of patients with herpes simplex and herpes zoster and may be useful in other viral infections.     

Topical acyclovir in the treatment of initial genital herpes

In a double-blind randomised placebo-controlled trial of topical acyclovir in initial (first episode) genital herpes 18 patients received acyclovir ointment and 22 matching placebo ointment. Acyclovir significantly reduced the duration of viral shedding from external and all genital lesions, the duration of vesicles, the time to crusting, the time to complete healing of external and all genital lesions, new lesion formation, and the duration of pain, itching, and all symptoms combined for all patients. In female patients alone the time to crusting was not significantly different and the duration of pain only approached significance but the effects were otherwise the same as for all patients. No patients reported any adverse effects of treatment. Topical acyclovir is well tolerated and effective in treating initial genital herpes.     

Topical acyclovir in the treatment of initial genital herpes.

In a double-blind randomised placebo-controlled trial of topical acyclovir in initial (first episode) genital herpes 18 patients received acyclovir ointment and 22 matching placebo ointment. Acyclovir significantly reduced the duration of viral shedding from external and all genital lesions, the duration of vesicles, the time to crusting, the time to complete healing of external and all genital lesions, new lesion formation, and the duration of pain, itching, and all symptoms combined for all patients. In female patients alone the time to crusting was not significantly different and the duration of pain only approached significance but the effects were otherwise the same as for all patients. No patients reported any adverse effects of treatment. Topical acyclovir is well tolerated and effective in treating initial genital herpes.     

Oral shedding of herpes simplex virus type 2

OBJECTIVES: Herpes simplex virus (HSV) 1 and HSV-2 reactivate preferentially in the oral and genital area, respectively. We aimed to define frequency and characteristics associated with oral shedding of HSV-2. METHODS: Demographic, clinical and laboratory data of patients with documented HSV-2 infection and at least one oral viral culture obtained were selected from the University of Washington Virology Research Clinic database. RESULTS: Of 1388 people meeting the entry criteria, 44 (3.2%) had HSV-2 isolated at least once from their mouths. In comparison with the 1344 people who did not have HSV-2 isolated from their mouth, participants with oral HSV-2 were more likely to be male (OR = 1.9, 95% CI 1.0 to 3.7), HIV positive (OR = 2.9, 95% CI 1.4 to 6.0), and homosexual (OR = 2.2, 95% CI 1.1 to 4.2), and to have collected a larger number of oral specimens (median 32 v 4, p<0.001). Of the 58 days with oral HSV-2 isolation, 15 (25%) occurred during newly acquired HSV-2 infection, 12 (21%) during a recurrence with genital lesions, three (5%) during a recurrence with oral lesions, and three (5%) during a recurrence with oral and genital lesions; 25 (43%) occurred during asymptomatic shedding. Oral HSV-2 was found less frequently than oral HSV-1 (0.06% v 1%, p<0.001) in people with HSV-1 and HSV-2 antibody, and less frequently than genital HSV-2 (0.09% v 7%, p<0.001). CONCLUSIONS: Oral reactivation of HSV-2 as defined by viral isolation is uncommon and usually occurs in the setting of first episode of genital HSV-2 or during genital recurrence of HSV-2.     

Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir

OBJECTIVES: In prospective trials, episodic valaciclovir significantly increased the chance of preventing or aborting the development of painful vesicular genital herpes simplex virus (HSV) lesions compared with placebo. We explored the clinical outcome of aborted lesions and its association with early treatment in a study designed to compare 3 and 5 days' treatment with valaciclovir. METHODS: In a randomised controlled trial, valaciclovir 500 mg twice daily for 3 or 5 days was initiated at the first symptoms of a genital herpes outbreak. The primary end point was length of episode with pain, HSV shedding, and aborted lesions secondary end points. The effect of time from symptom recognition to treatment initiation on aborted lesions was assessed in a post hoc analysis. RESULTS: In 531 patients, no differences were observed between 3 and 5 days' treatment in episode duration (median 4.7 v 4.6 days), loss of pain/discomfort (2.8 v 3.0 days), or lesion healing (4.9 v 4.5 days). Vesicular lesions were aborted in 27% of patients treated for 3 days v 21% of patients receiving valaciclovir for 5 days. The odds of achieving an aborted episode were 1.93 (95% CI: 1.28 to 2.90) times higher for those initiating treatment with valaciclovir within 6 hours of first sign or symptom. CONCLUSIONS: There was no difference between 3 and 5 days' treatment in reducing episode duration or lesion abortion. Prompt treatment with valaciclovir can abort genital HSV reactivation episodes, preventing a vesicular outbreak. Maximum treatment benefit depends on prompt therapy after recognition of symptoms.     

Longitudinal study of herpes simplex virus type 2 infection using viral dynamic modelling

OBJECTIVES: Rates of reactivation of herpes simplex virus type 2 (HSV-2) change over time and these changes affect transmission and clinical management strategies. We conducted a longitudinal study of HSV-2 infection to quantify rates of change in HSV-2 reactivation, mucosal shedding and recurrences of genital lesions, using a newly available model of HSV within-host dynamics. METHODS: A cohort of 18 women was studied at two time periods spaced 2 years apart. The cohort provided daily mucosal swabs for HSV PCR analysis for 10 weeks during each time period and recorded recurrences in diaries. We fit the model of HSV dynamics to the mucosal shedding data using Bayesian methods to produce estimates of HSV reactivation, shedding and longitudinal rates of change. The model was validated using a separate group of 67 individuals. RESULTS: According to the viral dynamic modelling results, rates of HSV-2 reactivation from latency in the ganglia varied >10-fold among the women, and were estimated to be > or = 10% higher than rates of mucosal shedding episodes for many individuals. The mucosal shedding associated with each reactivation typically lasted 1-3 days. Reactivation frequency was estimated to be declining by three reactivations a year on average. The median number of recurrences, based on patient diaries, declined from 6.8 per year to 2.1 per year over the 2-year period. CONCLUSIONS: Rates of HSV-2 reactivation, shedding and recurrence generally decline over time but remain high in some individuals 4-5 years after primary infection. Viral dynamic modelling provides quantification of HSV infection that cannot be obtained by other methods.     

Screening to detect asymptomatic shedding of herpes simplex virus (HSV) in women with recurrent genital HSV infection.

To investigate the asymptomatic shedding of herpes simplex virus (HSV) from women with recurrent genital herpes infection, and to assess whether inapparent shedding could occur, eight such women were examined thrice weekly for one month. At each visit colposcopy was performed and multiple sites sampled for HSV. During the study four women had no recurrence of HSV infection, but four had at least one positive viral culture. One of these patients was asymptomatically shedding HSV on nine of her 11 clinic visits. Two episodes of urethral shedding were detected. In this group of patients the presence of inguinal lymphadenopathy was appreciably associated with the isolation of HSV from the urogenital tract.     

定量PCR对生殖器疱疹患者尿道隐性HSV排毒研究

目的:研究GH发作期和间歇期患者泌尿生殖道隐性HSV-2排毒情况和沙眼衣原体(Ct)、解脲脲原体(Uu)阴性的非淋菌性尿道炎(NGU)患者HSV-2感染情况。方法:发作期GH患者分别取皮疹和尿道拭子标本;间歇期GH患者每周1次取尿道拭子共4次,正常对照组及Ct、Uu阴性的NGU患者取尿道拭子标本,用定量PCR法检测标本中的HSV-2DNA。结果:GH、NGU患者及正常组之间尿道HSV-2隐性排毒阳性率有显著性差异(P<0.05)。GH患者尿道HSV-2总阳性率为(22%),明显高于NGU组(9.8%)及正常组(3.3%);现症发作期GH患者尿道HSV-2阳性率(21.7%)与复发间歇期患者尿道HSV-2阳性率(23%)无显著差异(P>0.05)。每年复发6次以上的GH患者尿道HSV-2阳性率(27.4%)明显高于复发6次以下者(15%),且有显著性差异(P<0.05)。结论:GH患者发作期及间歇期尿道均有HSV-2隐性排毒。年复发频率在6次以上的GH患者HSV-2隐性排毒多于年复发频率6次以下者。病程3年以内者尿道隐性排毒较3年以上者高;Ct、Uu阴性的NGU患者部分可由HSV-2感染所致。     

Herpes simplex virus shedding in genital secretions

Nine women and eight men with a history of genital herpes had cultures taken for 60 consecutive days to assess the frequency and duration of viral shedding in the absence of symptoms. Daily self-obtained specimens (cervical-vaginal swabs from women and urethral swabs from men) were submitted for viral isolation. Five of 972 samples were found to contain infectious virus; two of the positive specimens correlated with overt disease. The other three positive cultures, two from the same individual, were not clearly associated with a genital infection. Thus, the overall frequency of asymptomatic viral shedding was 0.31% and occurred in two of 17 individuals. It is concluded that prolonged continuous sampling may be necessary to assess the risk of asymptomatic shedding. Infectious virus was not present in the genital secretions of most individuals (15 of 17) in the absence of a lesion, even when cultured on a daily basis for 60 days.     

Chronic suppression for six months compared with intermittent lesional therapy of recurrent genital herpes using oral acyclovir: effects on lesions and nonlesional prodromes

Forty-seven patients with frequently recurrent genital herpes were treated with 200 mg of acyclovir or placebo capsules taken orally three times daily for six months; the drug was then withdrawn. Active lesional events were treated with open-labeled 200-mg acyclovir capsules five times daily for five days during the six months of suppression and for six months thereafter if the patient returned to the clinic for culture and treatment. During the six months of treatment, seven of 24 acyclovir recipients and none of 23 placebo recipients reported no lesions (P less than 0.01), while 17 of 24 acyclovir and none of 23 placebo recipients failed to return for lesion assessment (P less than 0.0001). The median time to first recurrence was 72 days in the acyclovir recipients vs. 14 days in placebo recipients (P less than 0.0001). Home-recorded prodromes without lesion development were common in both groups but occurred more often in the acyclovir-treated group (P less than 0.05). During follow-up all patients experienced lesional episodes, and no differences could be detected between the acyclovir- and the placebo-treated groups. Resistance to acyclovir was not encountered either before, during, or after suppression by this drug. Adverse events were not significantly different between the groups. We conclude that suppression by oral acyclovir of frequently recurrent genital herpes remains effective for at least six months. Nonlesional prodromes have undetermined significance but are more common during acyclovir suppression.     

Polymerase chain reaction for diagnosis of genital herpes in a genitourinary medicine clinic

BACKGROUND: Polymerase chain reaction (PCR) has well established advantages over culture for diagnosis of herpes viruses, but its technical complexity has limited its widespread application. However, recent methodological advances have rendered PCR more applicable to routine practice. Aim: To compare automated PCR with viral culture for diagnosis of genital herpes. METHODS: We studied 236 patients presenting with clinical features suggestive of genital herpes at an inner city genitourinary medicine clinic. Two swabs were taken from each patient. Cell culture and typing were performed by standard methods. Automated PCR was performed using the LightCycler instrument and the infecting viral type was determined by restriction endonuclease digestion of amplicons. RESULTS: 109 patients (46%) had a positive test for herpes simplex virus (HSV). In 88, both PCR and culture were positive; in 21 PCR only was positive. With both detection methods, lesion duration and morphology were associated with HSV detection. Compared with culture alone, use of PCR increased sensitivity by 13.3% in specimens from vesicular lesions, by 27.4% from ulcerative lesions, and by 20.0% from crusting lesions. CONCLUSIONS: We advocate adoption of automated PCR as an efficient HSV detection and typing method for diagnosis of genital herpes in routine clinical practice. PCR allowed rapid laboratory confirmation of the diagnosis and increased the overall HSV detection rate by 24%.     

Recurrent genital herpes in a population attending a clinic for sexually transmitted diseases.

Patients with recurrent genital herpes attending a sexually transmitted disease clinic were studied and transmission of the infection was elucidated by evaluating serostatus in their partners. Of 84 patients attending for recurrent genital herpes, 94% had a herpes simplex virus type 2 (HSV-2) infection and only 6% (5 patients) a type 1 infection. The mean age of the patients was 36 years and the duration of their infection was up to 37 years (median 4 years). In most patients the number of recurrences had not decreased between the first year and the last year. About half had experienced a more severe first episode infection. Of the patients, 64% were not aware of asymptomatic shedding and the risk of sexual transmission without clinical symptoms. Of 67 steady partners of patients with genital HSV-2, 15% had a history of genital herpes. By HSV serology, HSV-2 antibodies (indicating subclinical genital herpes) were demonstrated in more than half of the partners. The duration of the relationship or condom use did not seem to influence the frequency of transmission to the partner, which may indicate an individual susceptibility for acquiring a genital HSV-2 infection. Eleven per cent of the patients were on suppressive antiviral therapy, while 39% had no experience of antiviral therapy. Type-specific HSV serology was found to be of value in counselling partners of patients with genital herpes.