Three phase III randomized controlled trials of topical resiquimod 0.01-percent gel to reduce anogenital herpes recurrences.

Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days, P=0.7; trial 2, 54 and 48 days, P=0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days, P=not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days, P<0.001; trial 2, 19 compared to 13 days, P=0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days, P<0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.

Effectiveness of systematic articulation training program accessing computers (SATPAC) approach to remediate dentalized and interdental /s, z/: a preliminary study.

Traditional methods for treating speech distortion errors in older school-age children have tended to yield mixed success. The current study was a preliminary evaluation of an alternative approach called the Systematic Articulation Training Program Accessing Computers (SATPAC), which was tested for the remediation of /s/ and /z/. Procedures involved a sequence of phonetic placement and/or oral-motor placement cues as needed to establish the targets, followed by concentrated drill structured around a facilitating context nonsense word and then advanced to more natural contexts. Participants were 18 children aged 6 years, 9 months to 11 years, 10 months. Treatment involved once per week, individual, 10-min. sessions with an experienced speech-language pathologist. Group A (n = 9) received 15 weeks of treatment, while treatment was delayed for Group B (n = 9). Then the groups were reversed. During period one, Group A (treated) significantly improved their accuracy of /s, z/ in spontaneous speech, while Group B (untreated) showed no significant change. During period two, Group B improved significantly when treatment was applied. The majority of the participants retained proficiency two years later.

Inadequacy of plasma acyclovir levels at delivery in patients with genital herpes receiving oral acyclovir suppressive therapy in late pregnancy.

OBJECTIVE: Acyclovir therapy in late pregnancy among women with recurrent genital herpes is effective in decreasing genital lesion frequency and subclinical viral shedding rates at delivery, thereby decreasing the need for Caesarean section. Despite good adherence and increased dosing schedules, breakthrough lesions and viral shedding are still observed in some women at or near delivery. Anecdotal evidence suggests that low levels of herpes simplex virus replication at delivery may result in transmission to the neonate. Therefore, defining optimal acyclovir dosing during labour and delivery is warranted. Our objectives were to determine actual maternal and fetal acyclovir levels at delivery, and explore associations between acyclovir levels, duration of labour, and time since last acyclovir dose. METHODS: Twenty-seven patients were prescribed oral acyclovir 400 mg three times daily from 36 weeks' gestation. Cord blood (venous and arterial) and maternal venous blood samples were collected at delivery, and acyclovir levels measured using capillary electrophoresis. Correlations between duration of labour, and time since last acyclovir dose with acyclovir blood levels were calculated. RESULTS: Acyclovir levels were below the published mean steady-state trough value (180 ng/mL) in 52% of venous cord samples, 55% of arterial cord samples, and 36% of maternal samples. There was a significant inverse correlation between the time since last dose and venous cord levels (rs19 = -0.57, P < 0.015), arterial cord levels (rs16 = -0.63, P < 0.01), and maternal acyclovir levels (r10 = -0.69, P < 0.03). CONCLUSION: Oral dosing of acyclovir in women in late pregnancy may result in insufficient levels at delivery to prevent viral shedding. Alternative approaches that incorporate acyclovir dosing through labour, either through oral or intravenous administration, should be evaluated to assess effects on viral shedding.

Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: a randomized, controlled trial.

BACKGROUND: Resiquimod, an investigational immune response modifier and Toll-like receptor (TLR) 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 (Th1)--acquired immune response. In animal models, induction of Th1-specific responses modifies experimental herpes simplex virus (HSV) infection. METHODS: We conducted a randomized, double-blind, vehicle-controlled trial to assess the efficacy of resiquimod 0.01% gel for reducing human anogenital HSV-2 mucosal reactivation. Adults with genital HSV-2 applied resiquimod or vehicle topically to herpes lesions 2 times weekly for 3 weeks and then collected daily anogenital swabs for 60 days for HSV DNA polymerase chain reaction. Recurrences during the subsequent 7 months were treated with study gel. During the final treatment-free 60 days, participants again collected daily swabs to assess shedding. RESULTS: The median lesion and shedding rates were lower for resiquimod compared with vehicle recipients during the initial sampling period (10% vs. 16% [P=.03] and 10% vs. 17% [P=.08], respectively) and during the final sampling period (3% vs. 22% [P<.001] and 10% vs. 26% [P=.009], respectively). Resiquimod did not influence recurrence length. CONCLUSIONS: These findings suggest that the immunological control of HSV-2 reactivation and lesion clearance may differ and that TLR7 and TLR8 agonists can reduce the frequency of mucosal HSV-2 reactivation.

Cavo-atrial tumor resection under total circulatory arrest without a sternotomy.

Surgical management of intracardiac tumors arising in the inferior vena cava often requires total circulatory arrest for safe and adequate resection. Total circulatory arrest has traditionally been accomplished by accessing the great vessels through a sternotomy. Combination of a sternotomy and a large abdominal incision results in excellent exposure but also creates the potential for significant morbidity. We report here the resection of cavoatrial tumors by achieving total circulatory arrest through femoral arterial and venous cannulation without requiring a sternotomy. This minimal-access total circulatory approach has the potential to greatly diminish morbidity when managing tumors of the inferior vena cava.

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.

Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses.

Dendrimers are a novel class of polyanionic macromolecules with broad-spectrum antiviral activities and minimal toxicities. A new generation of amide dendrimer, SPL7013, was evaluated as a lead microbicide candidate against herpes simplex viruses (HSV). The plaque reduction assays showed that the 50% effective concentrations (EC(50)) determined by pre-treatment of cells were 2.0 microg/ml for HSV-1 and 0.5 microg/ml for HSV-2. Inhibitory effects were also observed on HSV-infected cells with EC(50)s of 6.1 microg/ml for HSV-1 and 3.8 microg/ml for HSV-2. These are the mean values from the test results of six batches of SPL7013. SPL7013 was also shown to be equally potent against HSV drug-resistant strains. SPL7013 completely inhibited viral adsorption to Vero cells at concentrations of higher than 3 microg/ml. Analyzed by a LightCycler assay after treatment of HSV-infected cells for 17 h, SPL7013 showed strong inhibition of HSV DNA synthesis with EC(50)s of approximately 6.2 and 2.0 microg/ml for HSV-1 and HSV-2, respectively. SPL7013 retained its anti-HSV activity even after treatment at acidic pHs 3.0 and 4.0 for 2 h. The presence of 10% human serum proteins did not affect the anti-HSV activity of SPL7013. SPL7013 was not toxic to Vero cells up to the highest concentration tested (10,000 microg/ml). Effects on cell proliferation were tested on two epithelial cell lines in both stationary and dividing phases. The 50% cytotoxic concentrations (CC(50)) in all cases were greater than 10,000 microg/ml. Our data indicate that SPL7013 is a promising candidate for development as a vaginal microbicide and a therapeutic agent.

Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial.

BACKGROUND: Famciclovir, the oral prodrug of penciclovir, is effective for the treatment of recurrent genital herpes. This randomized, clinic-initiated, double-blind trial compared the therapeutic efficacy and safety of treatment with famciclovir at dosages of 125 mg, 250 mg, and 500 mg twice daily for 5 days with placebo in immunocompetent adults with a recurrent episode of genital herpes. METHODS: Efficacy and tolerability were assessed in 308 patients with lesions present for no more than 6.5 h at the time of the first dose. Two assessments per day were performed to increase the precision of the determination of study end points. RESULTS: All doses of famciclovir were significantly more effective than placebo in reducing the time to cessation of viral shedding, complete lesion healing, and loss of all lesion-associated symptoms, particularly lesion tenderness, pain, and itching. Patients receiving treatment with famciclovir were significantly less likely to experience new lesions than were patients receiving placebo. All doses of famciclovir were tolerated as well as placebo was. There was no difference in efficacy or tolerability among the different doses of famciclovir; the lowest effective dose was 125 mg twice per day. CONCLUSIONS: In immunocompetent adults with recurrent genital herpes, a 5-day course of famciclovir at a dosage of 125 mg, 250 mg, or 500 mg twice per day was significantly more effective than was placebo in reducing the duration of viral shedding and symptoms and in accelerating lesion healing. These results support the use of treatment with famciclovir at a dosage of 125 mg for 5 days as an effective, well-tolerated treatment for episodes of recurrent genital herpes.

Docosanol: a topical antiviral for herpes labialis.

Recurrent herpes labialis is a painful and potentially disfiguring infection affecting an estimated 40 million people in the US alone. The majority of recurrences are caused by herpes simplex virus type 1. Various oral and topical formulations of nucleoside analogues have demonstrated efficacy for this indication. Over-the-counter treatments are palliative in nature and do not reduce time to healing. Docosanol is a compound with a unique mechanism of action involving viral fusion inhibition. In randomised, clinical trials, a 10% docosanol cream formulation, initiated within 12 h of symptoms onset, demonstrated efficacy in reduction of time-to-healing compared with a polyethylene glycol control. Despite its potential to be a mild irritant, this novel antiviral was well-tolerated in clinical trials. Docosanol is the first topical antiviral approved for over-the-counter use in recurrent herpes labialis.

The synergistic effects of betulin with acyclovir against herpes simplex viruses.

Betulin, a pentacyclic triterpenoid, was isolated from the bark of Betula papyrifera. The antiviral efficacies of betulin on herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) were evaluated using viral plaque reduction assays on Vero cells. The results indicate that betulin is active against both HSV-1 and HSV-2 infections with the 50% effective concentrations (EC(50)) of 0.40 and 4.15 microg/ml, respectively. The cytotoxicity of betulin was examined on Vero cells using a neutral red uptake assay. The 50% cytotoxic concentration (CC(50)) of betulin was 73.1 microg/ml. A synergistic antiviral effect between betulin and acyclovir (ACV) was determined by drug combination studies. Strong and moderate synergistic antiviral effects were observed for betulin and ACV against HSV-1 when the concentrations of ACV and betulin were higher than 0.068 and 0.4 microg/ml, respectively. At the concentrations lower than these, additive effect was found. Synergistic antiviral effects were also found against HSV-2 at higher concentrations than for HSV-1, i.e. 0.45 microg/ml of ACV combined with 8.4 microg/ml of betulin.

A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B.

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 x 10(6) copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log(10) copies/mL. After 28 days, the median HBV DNA log(10) change from baseline was -2.5, -2.7, -3.0, and -2.6 log(10). Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log(10) in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.

Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial.

Genital herpes is most often transmitted while the patient is asymptomatic, presumably during episodes of viral shedding. To determine whether famciclovir is effective in reducing asymptomatic shedding, women with frequent, recurrent genital outbreaks were enrolled in a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 112-day trial of suppressive treatment with famciclovir for anogenital viral shedding. Sixty women received 125 mg of famciclovir 3 times daily, 59 received 250 mg of famciclovir 3 times daily, and 58 received placebo. Patients recorded symptoms and self-obtained cultures daily. Famciclovir reduced asymptomatic shedding, compared with placebo (P < .0001). The onset of asymptomatic shedding was also delayed (P < .0001). Famciclovir reduced symptomatic shedding in a dose-dependent manner (0.72% for 125 mg 3 times daily vs. 0.19% for 250 mg 3 times daily [P < .0001] vs. 5.53% for placebo [P < .0001]). In conclusion, suppressive treatment with famciclovir reduced both asymptomatic and symptomatic viral shedding and delayed the onset of asymptomatic shedding in women with frequently recurring genital herpes. Studies to examine the effects of suppression by famciclovir on the transmission of genital herpes are warranted.

Quantitation of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in the liver of HBV-infected patients by LightCycler real-time PCR.

Antivirals for hepatitis B virus (HBV) reduce viral load and improve liver histology, however, their effect on covalently closed circular DNA (cccDNA), the HBV transcriptional template, has not been extensively examined. This study evaluated a newly designed LightCycler based quantitative cccDNA PCR assay. A linear range of 2.5 x 10(1) to 1 x 10(9) copies/assay using primers specific for HBV cccDNA and 2.5 x 10(1) to 2.5 x 10(9) copies/assay using primers specific for total HBV DNA (tDNA) was established. beta-Globin was used to estimate the number of cells in each PCR reaction. Enzymatic digestion with an ATP-dependent DNase improved the analytic specificity to a greater than 1:10000 ratio of cccDNA:RC DNA (relaxed circular DNA). One-tenth of the extracted DNA from 1mg of liver biopsy, was analyzed from six patients, three HBV-infected and three uninfected individuals, under blinded conditions; three were found positive and three negative for cccDNA and tDNA. Approximately 6 x 10(3) copies of cccDNA/mg of tissue were detected in a pre-transplant biopsy from an HBV-infected patient treated with lamivudine. Sequential post-transplant liver biopsies were negative for both HBV cccDNA and tDNA. An HBV-infected patient with cirrhosis who was antiviral therapy naïve had 3.7 x 10(4) copies of cccDNA/mg of liver tissue. Another treatment-naïve patient with a history of high HBV viral load had 1 x 10(5) copies of cccDNA/mg of tissue (4 x 10 (6) copies of tDNA/mg of tissue). Further studies are warranted but the high level of sensitivity, specificity, rapidity and accuracy provided by this novel assay with the LightCycler system indicate that it could be useful for monitoring antiviral therapy.

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Current treatment options to prevent perinatal transmission of herpes simplex virus.

Neonatal herpes is a potentially devastating consequence of perinatal transmission of the herpes simplex virus (HSV), with significant morbidity and mortality. Treatment options are available, but must begin early in disease with manifestations that are often protean. Thus, preventive measures need to be optimised. Antiviral suppression in late pregnancy of women with a history of recurrent genital herpes will decrease symptomatic recurrence at delivery and appears to reduce caesarian section rates. However, primary HSV Type 2 and primary HSV Type 1 episodes have the highest neonatal transmission rates and thus, effective prevention may require the identification and suppression of the discordant partner. Significant experience has been gained with the use of acyclovir in pregnancy and it is recommended for both episodic and suppressive therapy in pregnant women. Its use has been demonstrated to be cost-effective in suppressive therapy, although issues regarding compliance and the potential for neonatal neutropenia need to be addressed. The more conveniently dosed prodrugs valacyclovir and famciclovir are being evaluated for use in pregnancy.

A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery.

OBJECTIVE: The purpose of this study was to assess the efficacy of acyclovir in the reduction of herpes simplex virus culture and polymerase chain reaction positivity and cesarean delivery. STUDY DESIGN: Women with recurrent genital herpes simplex virus were randomized to acyclovir 400 mg three times daily or placebo from 36 weeks of gestation until delivery. A subset of daily specimens for herpes simplex virus culture and DNA polymerase chain reaction was self-collected. Analyses used chi(2), Fisher exact, and Mann-Whitney U tests. RESULTS: Lesions occurred at delivery among 11 of 78 women (14%) who received placebo and 4 of 84 women (5%) who received acyclovir (P =.08). Herpes simplex virus culture and polymerase chain reaction positivity near delivery occurred in 7% and 34% women in the placebo group and 0 and 2% in the acyclovir group (P =.03 and <.01, respectively). Cesarean delivery for herpes simplex virus occurred in 8 of the women (10%) in the placebo group and in 3 of the women (4%) in the acyclovir group (P =.17). Despite reductions in herpes simplex virus detection, 6% of the women who received acyclovir had herpes simplex virus detected by polymerase chain reaction on >20% of days. Neonatal outcomes were similar between groups. CONCLUSION: Acyclovir significantly reduced, but did not eliminate, herpes simplex virus lesions and detection in late pregnancy.

Therapeutic Options for Herpes Simplex Infections.

Herpes simplex viruses are responsible for a number of disease states in infected individuals. Capable of establishing latent infection, herpes simplex can reactivate, causing pain, discomfort, and psychosocial consequences. Because no cure is available, treatment modalities for herpes simplex infection are required, from both personal and public health standpoints. To date, therapy has centered around the use of antiviral drugs to control infection and suppress recurrences. To expand the scope of available treatments, efforts have focused on the development of vaccines against herpes simplex virus and new agents such as immune response modifiers. Recent data suggest that these new agents are promising in their therapeutic potential.

Oral famciclovir for the suppression of recurrent genital herpes: the combined data from two randomized controlled trials.

BACKGROUND: Genital herpes is a very common sexually transmitted disease. Safe and effective therapies are needed for patients with frequent recurrences. OBJECTIVE: The aim of our study was to determine the efficacy and safety of famciclovir for suppression of herpes simplex virus (HSV) infection in patients with history of clinically diagnosed recurrent genital HSV infection. METHOD: An analysis was conducted of the combined data from two randomized, double-blind, placebo-controlled studies of 52 weeks' duration involving a total of 469 patients (201 men, 268 women) from 47 university, hospital, or private referral centers in Europe and North America. The patients were 18 years or older with a history of six or more episodes of genital herpes during 12 of the 14-months prior to study entry and were not receiving suppressive therapy. They were randomized to receive oral famciclovir 250 mg twice daily or placebo for 52 weeks. The primary outcome measures were (1) the proportion of patients who remained free from clinical HSV recurrences, confirmed by viral culture, for at least 6 months after the start of study medication; (2) the time to first clinically confirmed lesional episode; and (3) the frequency of adverse events. RESULTS: A significantly greater proportion of famciclovir-treated patients (151/191, 79%) were free from HSV recurrences at 6 months compared with placebo recipients (48/184, 26%) (p<0.001); efficacy was maintained at 12 months. The median time for the first clinically confirmed lesional episode was significantly prolonged for famciclovir recipients (more than one year) compared with placebo recipients (59 days; p<0.0001). Famciclovir was well tolerated, with an adverse-experience profile comparable with placebo. CONCLUSIONS: Oral famciclovir 250 mg twice daily is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.