Valacyclovir for Herpes Simplex Virus Infection: Long-Term Safety and Sustained Efficacy after 20 Years Experience with Acyclovir

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1 S40 Valacyclovir for Herpes Simplex Virus Infection: Long-Term Safety and Sustained Efficacy after 20 Years Experience with Acyclovir Stephen K. Tyring, 1 David Baker, 2 and Wendy Snowden 3 1 University of Texas Medical Branch, Galveston; 2 State University of New York at Stony Brook; 3 GlaxoSmithKline Research and Development, Stevenage, United Kingdom An extensive clinical trial program combined with 5 years postmarketing experience with valacyclovir provides evidence of favorable safety and efficacy in herpes simplex virus (HSV) management. Valacyclovir enhances acyclovir bioavailability compared with orally administered acyclovir. Long-term use of acyclovir for up to 10 years for HSV suppression is effective and well tolerated. Acyclovir is also approved for use in children, is available in some countries over the counter in cream formulation for herpes labialis, and has been monitored in over 1000 pregnancies. Safety monitoring data from clinical trials of valacyclovir, involving over 3000 immunocompetent and immunocompromised persons receiving long-term therapy for HSV suppression, were analyzed. Safety profiles of valacyclovir ( 1000 mg/day), acyclovir (800 mg/day), and placebo were similar. Extensive sensitivity monitoring of HSV isolates confirmed a very low rate of acyclovir resistance among immunocompetent subjects (!0.5%). The incidence of resistance among immunocompromised patients remains low at about 5%. Five years after the licensing of valacyclovir and two decades after the introduction of acyclovir, a wealth of data has been generated on the clinical utility of this selective antiherpes agent and its prodrug. To date, it is estimated that acyclovir and valacyclovir have been prescribed to more than 80 million persons for a range of indications (GlaxoSmithKline, data on file). Valacyclovir is prescribed regularly for long-term (months to years) prophylaxis (suppression) of herpes simplex virus (HSV) mucocutaneous outbreaks, conditions that are not considered life threatening. Thus, an excellent therapeutic index is essential. Equally as important as efficacy and tolerability for an antiinfective agent widely used for HSV management is a lack of development of resistance. The clinical development program for valacyclovir has involved over 10,000 patients in clinical trials of up to 1 year in duration. Its initial development rationale was built on studies in which acyclovir was administered both orally and intravenously. Acyclovir was evaluated over periods of up to 10 years in patients with recurrent genital herpes. It was also studied in children and in a range of immunocompromised populations, and its use was formally monitored in pregnancy. Sensitivity monitoring for resistance initiated with acyclovir has been extended to the short- and long-term use of valacyclovir. Presented in part: 2nd European Congress of Chemotherapy and 7th Biennial Conference on Antiinfective Agents and Chemotherapy, Hamburg, Germany, May 1998 (abstract M175); 34th annual meeting, Infectious Diseases Society of America, New Orleans, September 1996 (Clin Infect Dis 1996; 23:879). Reprints or correspondence: Dr. Stephen K. Tyring, University of Texas Medical Branch, Rt. 1070, Galveston, TX (styring@utmb.edu). The Journal of Infectious Diseases 2002;186(Suppl 1):S by the Infectious Diseases Society of America. All rights reserved /2002/18608S-0005$15.00 Acyclovir is highly specific for herpesvirus-infected cells. Once inside the cell, acyclovir is selectively activated by the viral thymidine kinase in HSV- and varicella-zoster virus infected cells. In the active form, acyclovir acts specifically to inhibit viral replication by acting as a competitive substrate for viral DNA polymerase and as an obligate chain terminator, effectively preventing any further elongation of the viral DNA chain. The activity and selectivity of acyclovir is the result of this unique mode of action and is reflected in the clinical safety profile of acyclovir and valacyclovir. This review provides background information on the longterm use of valacyclovir for HSV infections. Safety data for valacyclovir and acyclovir in a range of patient groups are presented, focusing primarily on use for HSV indications. The findings of recent resistance monitoring initiatives indicate that HSV should remain sensitive to valacyclovir therapy, despite a long history of acyclovir usage. Experience with Acyclovir Long-term use in genital herpes. In 1984, 1175 otherwise healthy patients with frequently recurring genital HSV infection were enrolled in a study of oral acyclovir for suppression of outbreaks [1, 2]. The first year was double blind; patients were randomized to receive either acyclovir (400 mg twice/day) or placebo and were monitored frequently. Recurrences in both groups were treated with episodic acyclovir (200 mg 5 times/ day for 5 days). In the second year, an open-label design was used and patients could select either suppressive or episodic therapy or discontinue treatment and participation. For years 3 6, patients could elect to receive open-label continuous suppressive acyclovir therapy. In year 7, patients received episodic therapy with acyclovir (200 mg 5 times/day for 5 days) only.

2 JID 2002;186 (Suppl 1) Valacyclovir: Long-Term Safety S41 Patients who had 2 genital herpes recurrences during year 7 were offered continuous suppressive therapy with acyclovir (400 mg twice/day) for another 3 years. During the double-blind phase of the study, adverse experiences were similar in frequency for patients randomized to acyclovir or placebo. The most frequent adverse events were nausea, diarrhea, and headache. Nausea occurred in 4.8% of the patients randomized to suppressive therapy and in 2.4% of patients randomized to placebo in year 1, but thereafter was reported only at levels below 1%. For the rest of the study to year 10, acyclovir continued to be well tolerated. Adverse events were rare and mild and generally not thought to be related to treatment. There was no evidence of serious adverse drug reactions or cumulative toxicity (table 1). Acyclovir in pediatrics. Oral acyclovir, as a suspension, is approved for administration to otherwise healthy children with chickenpox in most countries including the United States and to immunocompetent and immunocompromised children with mucocutaneous HSV infections (most countries but not the USA). Oral acyclovir was well tolerated in clinical trials of these indications [3 5]. In 815 children (aged 2 12 years) treated for chickenpox (20 mg/kg/dose 4 times/day for 5 days), adverse events were similar in nature and frequency for acyclovir and placebo groups. The most commonly reported adverse events were gastrointestinal (GI). The only serious adverse event was cerebellar ataxia and disorientation in a placebo recipient and was considered secondary to disease. Mildly elevated aspartate transaminase values, leukopenia, and thrombocytopenia were observed in some patients, but there were no differences between treatment groups and no abnormal test results were attributed to the use of acyclovir [5]. In a placebo-controlled trial of 133 children aged 1 6 years with gingivostomatitis, half received acyclovir suspension (15 mg/kg 5 times/day for 7 days). Two children in each group had mild GI symptoms but no significant side effects were recorded in either group [3]. Oral acyclovir (300 mg/m 2 /dose 2 3 times/day) was investigated for the suppression of HSV recurrences after neonatal HSV infections on the skin, eyes, and mouth in an open-label study of 26 infants. Of the 26, 12 developed neutropenia, which resolved in 10 despite continued acyclovir. The 2 remaining cases resolved after discontinuation or dose reduction of acyclovir [6]. Acyclovir in pregnancy. The Acyclovir Pregnancy Registry was established in 1984 to record the outcome of fetuses exposed to acyclovir during pregnancy. Prospective data were collected by following up acyclovir exposure reported to the registry before any knowledge of the outcome was available. As of 31 July 1998, 1207 pregnancies had been prospectively reported to the registry [7]. There were 19 birth defects among 581 pregnancies involving exposure to acyclovir in the first trimester. The observed risk of birth defects was 3.3% (95% confidence interval, 2.0% 5.2%). This compares with a published risk of birth defects in the general population of 3% 5%. Among pregnancies in which exposure to acyclovir occurred in any trimester, 27 infants (2.2%) had birth defects. The rate of birth defects did not exceed that expected in the general population and the type of defects did not differ from those in untreated women. However, the size of the registry is insufficient to permit definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. As for all drugs considered for administration during pregnancy, the physician should assess the risk versus benefit for mother and fetus in each individual clinical situation. Acyclovir has been studied off-label in pregnant women in a number of clinical settings. It has been evaluated for HSV suppression in late pregnancy with the aim of preventing transmission to the neonate at delivery and for women with varicella who are at increased risk for developing varicella pneumonia [8 12]. Suppressive acyclovir therapy ( mg/day in 3 or 4 doses) administered for several weeks prior to the expected date of delivery reduced the frequency of symptomatic HSV recurrences at the time of labor and the requirement for genital herpes-related cesarean sections in several small studies [8 10]. Treatment was well tolerated in women with similar adverse events in acyclovir and placebo groups. No short-term side effects of acyclovir were observed in the infants, and no abnormal findings were seen in 19 children followed up at age 1 year after administration of acyclovir to their mothers. The risk of nephrotoxicity and neutropenia to the developing fetus is unknown and further studies are required to evaluate long-term safety of acyclovir in the fetus, neonate, and developing child. In 1995, case reports of valacyclovir exposures during pregnancy were added to the Acyclovir Pregnancy Registry and are summarized later in this review. In 1999, GlaxoWellcome was asked to discontinue the registry because the reporting rate of Table 1. Frequency of most common adverse events (%) among patients receiving continuous acyclovir suppressive therapy for 10 years [1, 2]. Year Therapy (n) Nausea Diarrhea Headache Rash Asthenia Dizziness Abdominal pain Vaginitis 1 S (586) E (589) S (698) E (85) S (430) S (152) NOTE. E, episodic therapy ( placebo suppression in year 1); S, suppressive therapy.

3 S42 Tyring et al. JID 2002;186 (Suppl 1) new exposures in pregnancy was clearly lower during the last 3 4 years of the registry than estimated by clinical usage, and cumulative data generated were considered insufficient to add further to the knowledge base. Experience with Valacyclovir Rationale. Acyclovir was the first specific, effective, orally bioavailable antiherpes agent. However, it has only limited oral bioavailability (10% 20%) [13] and dosing regimens up to 5 times a day are required to achieve efficacy in a range of indications. Valacyclovir was developed as an oral therapy for the treatment of infections caused by herpesviruses, including those that are less sensitive to acyclovir than HSV and, therefore, require greater exposure to achieve effective antiviral suppression, and also to reduce the dosing frequency. Valacyclovir is the l-valyl ester of acyclovir and is rapidly and extensively converted to acyclovir and l-valine [14]. Acyclovir bioavailability following oral valacyclovir is enhanced three- to five-fold compared with oral acyclovir [14]. Unlike acyclovir, which is poorly absorbed (bioavailability 10% 20% according to dose), acyclovir exposure after valacyclovir administration increases almost in proportion to the dose administered (bioavailability 50% in adults). Table 2 shows the relative exposures to acyclovir achieved with regimens of acyclovir and valacyclovir used in the management of HSV infections. Acyclovir pharmacokinetics after administration of valacyclovir are similar in immunocompetent and human immunodeficiency virus (HIV) infected patients and C max and AUC values approximate those estimated by simulation [15 18]. Results of preclinical toxicology studies indicate that valacyclovir has a similar safety profile to acyclovir [19]. Long-term safety in genital herpes. Three randomized controlled trials and 1 open-label study demonstrated the efficacy and long-term safety of oral valacyclovir for suppression of recurrent genital HSV infection (table 3) [16 18, 20]. In all, 3050 patients (1062 immunocompromised) were enrolled in the 4 studies and 2206 received valacyclovir mg/day for up to 1 year (table 3). In immunocompetent patients, 500 mg of valacyclovir daily in once or twice-daily dosing regimens Table 2. Acyclovir exposure after valacyclovir and oral acyclovir administration. Treatment C max (mm) Valacyclovir Daily AUC (mm/h) Acyclovir 400 mg 2 /day 2.6, a 2.9 b 33.4, b 37.3 a Valacyclovir 250 mg 2 /day 6.9 b 54.5 b Valacyclovir 500 mg 1 /day 10.9 b 45.5 b Valacyclovir 500 mg 2 /day 9.5, a 12.3 c 99.5, c a Valacyclovir 1000 mg 1 /day 17.2, a 22.6 b 79.8, b a NOTE. AUC, area under the curve. a Data are from [18] b Data are from [16] c Data are from [15]. significantly prevented or delayed recurrences compared with placebo and was comparable in efficacy to 400 mg of acyclovir twice a day [16, 17]. In HIV-infected patients (table 3, study 4), valacyclovir (500 mg twice/day) was more effective than valacyclovir (1000 mg once/day) in preventing or delaying HSV recurrences and showed a trend toward increased efficacy over acyclovir [18]. Subjects receiving valacyclovir, acyclovir, or placebo reported adverse events similar in nature and incidence (table 4). There was no apparent relationship between the total daily exposure to valacyclovir and the nature, severity, or frequency of the most common adverse events (data not shown). The most frequent adverse events among immunocompetent patients receiving valacyclovir or acyclovir were headache, infectious illness (e.g., influenza, common cold, rhinitis, sinusitis), and nausea. For HIV-infected patients, the most common adverse events were diarrhea, nausea, and infectious illnesses. Longterm therapy with valacyclovir was not associated with hematologic (hemoglobin, platelet count, white blood cell count) or clinical chemistry (creatinine, alanine aminotransferase [ALT], alkaline phosphatase) abnormalities. There were no substantial changes from baseline and no meaningful differences between valacyclovir, acyclovir, and placebo treatment groups. Valacyclovir was discontinued in 5 (0.3%) immunocompetent patients (1 each due to neutropenia, leukopenia, thrombocytopenia, elevated ALT, or other liver function test). In HIVinfected subjects, study drug was discontinued prematurely for Table 3. Patients treated in efficacy trials of valacyclovir for suppression of recurrent herpes simplex virus infection. Study, reference Subject population Total subjects No. of valacyclovir recipients Total daily valacyclovir dose, mg Variable compared (total daily dose) Trial duration 1 [17] Immunocompetent Placebo 16 weeks a 2 [16] Immunocompetent Acyclovir (800 mg) 1 year Placebo [20] Immunocompetent year 4 [18] HIV infected Acyclovir (800 mg) 1 year Total NOTE. HIV, human immunodeficiency virus. a In all, 313 patients continued with open-label valacyclovir to complete 1 year of therapy.

4 JID 2002;186 (Suppl 1) Valacyclovir: Long-Term Safety S43 Table 4. Most common adverse events reported in subjects receiving valacyclovir ( mg/day) or acyclovir (800 mg/day) for up to 1 year shown as percentage of events regardless of whether it could be attributed to drug and (in parentheses) percentages of subjects with an event attributed to drug. Event Subject type, reference (study no.) Immunocompetent [16, 17, 20] (1 3) HIV infected [18] (4) Valacyclovir (n p 1493) Acyclovir (n p 267) Placebo (n p 228) Valacyclovir (n p 713) Acyclovir (n p 349) Headache 32 (12) 37 (12) 25 (3) 18 (5) 17 (7) Rhinitis 20 (!1) 25 (!1) 15 (0) 12 (!1) 12 (0) Infection 15 (2) 21 (0) 11 (0) 18 (0) 13 (1) Nausea 10 (6) 12 (6) 8 (7) 12 (6) 14 (5) Pharyngitis 9 (1) 11 (0) 10 (!1) 11 (0) 13 (0) Diarrhea 8 (3) 12 (5) 10 (4) 20 (5) 19 (4) Abdominal pain 8 (3) 7 (3) 4 (3) 11 (3) 7 (2) Rash 6 (1) 6 (1) 7 (1) 15 (1) 14 (2) Depression 4 (1) 4 (1) 3 (1) 10 (1) 11 (0) Fever 2 (!1)!1 (0) 1 (0) 10 (0) 11 (!1) Any event 82 (32) 85 (31) 67 (24) 77 (28) 77 (25) 3 valacyclovir recipients (0.4%; increased creatinine, liver function abnormalities, increased ALT) and 4 (1.1%) acyclovir recipients (increased creatinine, liver function abnormalities, hyperkalemia, and leukopenia). Most adverse events were not considered attributable to treatment by the clinical investigators (table 4). Headache, nausea, and diarrhea were the most common adverse events attributed to drug. Rhinitis, pharyngitis, and infection were frequently listed as an adverse event but were rarely attributed to therapy. It is likely that these events were attributable to concurrent illnesses rather than to study medication. Similarly, rash, fever, diarrhea, depression, cough, asthenia, and vomiting in HIV-infected subjects could all be related to concomitant diseases, HIV infection itself, concurrent medications, or the increased sensitivity of HIV-infected subjects to drug-associated rash. Adverse events considered serious occurred in 2.4% of immunocompetent subjects and were thought to be possibly attributable to study medication for 3 (0.2%) valacyclovir recipients (leukopenia, hepatitis, and headache) and 2 (0.7%) acyclovir recipients (myasthenia and suicidal ideation). The death of 1 subject from bronchial asthma was not attributed to valacyclovir therapy. In HIV-infected subjects, serious adverse events were reported in 10.5% of the population, with possible attribution to study treatment in 8 (1.1%) valacyclovir recipients and 3 (0.9%) acyclovir recipients. These were most commonly associated with GI disturbances and headache. There were 8 deaths in valacyclovir recipients (AIDS progression, homicide, sepsis/septic shock, 2 subjects each; suicide, pneumonia, 1 subject each) and 2 deaths in acyclovir recipients (lactic acidosis, homicide, 1 each). Only 1 death was considered possibly related to study drug (the acyclovir recipient with lactic acidosis). Manifestations resembling thrombotic microangiopathy have been reported in clinical trials evaluating high doses of valacyclovir (8000 mg/day) administered for prolonged periods (months to years) for prophylaxis of cytomegalovirus (CMV) infection and disease, particularly in persons with HIV infection [21 23]. A number of factors may have contributed to the incidence of thrombotic microangiopathy in those trials including profound immunosuppression, underlying diseases (advanced HIV disease, graft-versus-host disease), and other classes of drug, particularly antifungal agents [20, 22 24]. There were no reports of thrombotic microangiopathy among the 3050 subjects in the 4 trials evaluating valacyclovir for suppression of recurrent genital herpes. Although 1 of the trials was in HIVinfected subjects, the patients did not have advanced HIV disease. The implication is that the occurrence of thrombotic microangiopathy is restricted to severely immunosuppressed persons receiving higher valacyclovir dosages than are required to control HSV infection. Potential for valacyclovir in children. Effective, convenient, and palatable antiherpetic agents are needed for children of all ages, from neonates to preteens. There is a particular need for HSV prophylaxis in immunocompromised children. Acyclovir is available in some countries as a suspension, which is palatable and easily swallowed by small children, but its low bioavailability necessitates frequent dosing. Valacyclovir should offer a simpler more convenient dosing regimen in this age group, but the physicochemical properties of the molecule so far have precluded production of an acceptable and stable liquid formulation [25], although extemporaneous syrups containing valacyclovir have been used for administration to children [25]. Such preparations are chemically and microbiologically stable for 21 days. The results of 3 preliminary studies in immunocompetent and immunocompromised children aged years suggest that the pharmacokinetics of acyclovir after valacyclovir administration are not substantially different from those in adults [26 28]. Bioavailability of acyclovir after valacyclovir in children is 45% 48% and results suggest that va-

5 S44 Tyring et al. JID 2002;186 (Suppl 1) lacyclovir may be substituted for intravenous acyclovir [26, 28]. There are no data on the safety of valacyclovir in children under age 12 years. Children 13 years were included in a study of valacyclovir (8 g/day) given for 90 days to prevent CMV disease after renal transplantation and the drug was generally well tolerated [29]. Valacyclovir use in pregnancy. The Acyclovir Pregnancy Registry has documented the pregnancy outcomes in 111 women exposed to valacyclovir. There was no increase in the number of birth defects compared with the general population, and there was no consistent pattern or uniqueness to the defects reported that would suggest a common cause. The pharmacokinetics of valacyclovir (500 mg twice/day) and acyclovir (400 mg 3 times/day) were examined in 20 pregnant women receiving antiherpes therapy in late pregnancy [30]. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery: 1.7 for valacyclovir; 1.3 for acyclovir). Valacyclovir was very well tolerated, and there was no clinical or laboratory evidence of drug toxicity in participants or their infants over a 6-month follow-up period. The number of pregnant women exposed to valacyclovir to date is small and there is a need for additional trials to further evaluate the safety and clinical utility of suppressive valacyclovir therapy during late pregnancy. HSV Resistance Figure 1. Sensitivity to acyclovir of herpes simplex virus (HSV) isolates from immunocompetent subjects receiving valacyclovir (250 mg once [black triangles] or twice/day [black diamonds] or 500 mg once/ day [inverted black triangles] or 1000 mg once/day [black squares]), acyclovir (400 mg twice/day [black circles]), or placebo (gray triangles) for up to 1 year for genital herpes suppression [41]. Mechanisms of resistance. Mutations in the HSV genome can result in a deficiency or alteration in viral thymidine kinase activity, preventing acyclovir from being phosphorylated and thus becoming resistant to therapy [31]. This is the most common mechanism for conferring acyclovir resistance and may also render the virus cross-resistant to other nucleoside analogues that are dependent on thymidine kinase for phosphorylation to the active form (e.g., penciclovir, ganciclovir). Occasionally, HSV strains are thymidine kinase altered and maintain the ability to phosphorylate the natural substrate, thymidine, but selectively lose the ability to phosphorylate acyclovir [31]. Others retain only a fraction of normal thymidine kinase activity (1% 15%) but are considered acyclovir resistant in susceptibility assays [31]. Mutation of the viral DNA polymerase gene resulting in failure to incorporate the acyclovir triphosphate in progeny DNA molecules is an alternative, but infrequent, mechanism that may result in HSV resistance to acyclovir [32, 33]. Sensitivity testing of HSV isolates to acyclovir. Despite the widespread use of acyclovir for two decades, resistance to acyclovir in immunocompetent patients is rare. Recent estimates of in vitro HSV resistance in immunocompetent persons in the United Kingdom and the United States suggest a prevalence of about 0.1% 0.4% [34, 35]. HSV isolates remained sensitive even after patients had acyclovir suppressive therapy for 6 years [36]. In immunocompromised patients, resistance is still uncommon (5% 6%) [34, 35, 37 39]. With the wider availability of topical antiviral preparations for herpes labialis, concern has been raised about the development of HSV-1 resistance. A recent study measured the antiviral sensitivity of 924 HSV isolates from herpes labialis lesions by use of a plaque reduction assay [40]. Only 1 HSV-1 isolate (0.1%) was resistant to acyclovir (IC mm); this isolate was also resistant to penciclovir (IC mm). Of the study subjects, 79% had previously used topical antivirals to treat their cold sores but prior antiviral use had no effect on susceptibility to acyclovir ( P p.160) or penciclovir (a). Sensitivity of HSV to acyclovir after valacyclovir. Sensitivity testing for HSV isolates to acyclovir has continued through various initiatives following the introduction of valacyclovir for management of genital herpes. There was no evidence of development of resistant HSV in the 4 trials of valacyclovir for

6 JID 2002;186 (Suppl 1) Valacyclovir: Long-Term Safety S45 genital herpes suppression (table 3; figure 1) [16 18, 20, 41]. In total, 22 isolates from genital HSV breakthrough lesions from 19 immunocompetent patients exposed to continuous valacyclovir for up to 48 weeks were tested in vitro for susceptibility to acyclovir, penciclovir, and foscarnet. All HSV-2 isolates demonstrated wild type sensitivity to the 3 antiviral agents; IC 50 values by plaque reduction assay fell within reference values of!3.9 mm for acyclovir,!41.7 mm for penciclovir, and!195.8 mm for foscarnet [42]. In addition, 2 isolates obtained from HIV-infected patients after 26 and 30 weeks of suppressive therapy with valacyclovir (1000 mg once/day) retained normal sensitivity to the antiviral agents tested. All 11 isolates from 8 HIVinfected patients taking episodic acyclovir or valacyclovir also had wild type sensitivity to acyclovir, penciclovir, and foscarnet. There were too few isolates to determine a statistically accurate estimate of the incidence of resistance to antivirals after valacyclovir administration. However, the lack of evidence of acyclovir resistance suggests that HSV strains in both immunocompetent and immunocompromised populations respond to acute valacyclovir treatment and are likely to continue to do so with chronic suppressive therapy. Summary The large number of patients studied has afforded considerable confidence in the safety of long-term suppressive therapy with valacyclovir at doses up to 1000 mg/day to prevent recurrent episodes of genital HSV infection in immunocompetent and HIV-infected subjects. Comparable safety profiles were observed for valacyclovir, acyclovir, and placebo in randomized controlled clinical trials. Acyclovir has been safe in long-term use in a wide range of patient groups, and the increased acyclovir exposures achieved with valacyclovir do not appear to have compromised the established safety heritage set by acyclovir in the management of HSV infection. HSV resistance surveillance continues with the completion of large surveys by the Task Force on Herpesvirus Resistance [34, 43]. To date, resistance to acyclovir in immunocompetent subjects is extremely rare (!0.5%) and occurs at low incidence ( 5%) in those who are immunocompromised. Thus, for acyclovir, and now for valacyclovir, efficacy and safety are sustained when the drugs are used either long term for HSV management or repeatedly in acute treatment courses over many years. Acknowledgments We acknowledge the contribution of the International Valacyclovir HSV Study Group for conducting the valacyclovir clinical trials. We thank A. T. Gibb for statistical analysis and G. B. Miller and J. D. 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