Valacyclovir in the Treatment of Facial Herpes Simplex Virus Infection

Transcription

1 S66 Valacyclovir in the Treatment of Facial Herpes Simplex Virus Infection A. Laiskonis, 1 T. Thune, 2 S. Neldam, 3 and E. Hiltunen-Back 4 1 Kaunas Medical University, Kaunas, Lithuania; 2 Haukeland Hospital, Bergen, Norway; 3 General Practice, Roedovre, Copenhagen, Denmark; 4 University Central Hospital, Helsinki, Finland The objective of this multicenter, randomized, double-blind, noninferiority trial was to investigate valacyclovir as treatment for facial herpes simplex virus (HSV) outbreaks. In total, 308 otherwise healthy outpatients self-initiated therapy with valacyclovir, either 1000 mg twice daily for 1 day or 500 mg twice daily for 3 days, for treatment of one facial HSV episode. Aborted lesions were the primary end point. Secondary end points included episode and pain resolution and lesion healing. By regimen (1 or 3 days), aborted lesions occurred in 42.2% versus 46.7% of patients, treatment difference, 4.5% (95% confidence interval, 16.3% to 7.4%; P p.49). Subgroup findings showed that about half the episodes aborted when therapy started during the prodrome/macule stages or within 6hoffirst symptoms. Episode and pain resolved rapidly, with results similar for both treatments. Adverse events were infrequent and similar for the two regimens. Most of the focus on improving the treatment of facial herpes simplex virus (HSV) infection, particularly herpes labialis, has been directed toward topical therapies, including those with a specific antiviral mechanism of action. Key contributing factors to this focus include the ease of access to such products in many countries, especially those that do not require a physician s prescription, the ability of most patients to recognize a pending facial herpes outbreak from an early age, and the readily visible anatomic sites affected for application of topical therapy. For many patients, however, topical treatments are not ideal. Application of medication to the affected site is sometimes difficult (e.g., if the lesion is on the nasal septum or extends from the lips to the inside of the mouth). Furthermore, topical treatments requiring frequent application are easily removed if applied to the lips and the subject then eats or drinks. Both acyclovir and penciclovir creams significantly reduce the duration of herpes labialis episodes, with faster lesion healing and pain resolution, although the benefits are modest [1 3]. One controlled trial of topical acyclovir also found an impact on aborting lesions, that is, prevention of the development of vesicular lesions and subsequent hard crust formation [1]. Studies of penciclovir cream and other studies of topical acyclovir failed to demonstrate a consistent benefit in aborting lesion development [2 4]. An aborted lesion in the treatment of recurrent facial HSV Institutional review boards at each site approved the study. All patients (or their legal representatives if minors) signed a written statement of informed consent. Grant support: GlaxoSmithKline Research and Development; Glaxo- SmithKline Europe. Reprints or correspondence: Dr. Alvydas Laiskonis, Infectious Diseases Clinic, Kaunas Medical University, Josvainiu St. 1, Kaunas 3021, Lithuania (infectkl@kma.lt). The Journal of Infectious Diseases 2002;186(Suppl 1):S by the Infectious Diseases Society of America. All rights reserved /2002/18608S-0008$15.00 infection may be considered the preferred clinical outcome. For the patient, the unsightly visible signs (lasting 1 week) with accompanying pain are prevented and the risk of autoinoculation reduced. For the community, the period of risk of HSV shedding from the facial lesion is also reduced. Estimates of background rates of aborted lesions in facial HSV infection vary from 16% to about 30% [3, 5, 6]. Controlled randomized trials of antivirals in facial HSV infection in which the reference (placebo) treatment is the vehicle control confound these estimates because the nature of the vehicle appears to be associated with a significant palliative effect [4, 7]. Several studies of oral acyclovir in nongenital HSV infection have shown similar modest treatment effects but lack of impact on aborted lesions [5, 8, 9]. A more profound effect was seen when oral acyclovir was used prophylactically [10 12]. Clearly for persons with frequent episodes or well-defined precipitating factors (e.g., sun exposure while skiing), suppressive oral therapy for prolonged or at-risk periods may be more appropriate. But for most persons, self-medication with episodic therapy at the onset of prodromal symptoms would be preferable. Such a therapeutic strategy would be economical and manageable by most adolescent and adult patients. A simple oral antiviral regimen would have several advantages over currently available topical therapies, including ease of use, discretion, and reduced risk of autoinoculation. The difficulty of treating herpes labialis has been attributed to the very rapid development of lesions after the trigger for HSV reactivation, with a strong secondary immune response resulting from the increased presence of virus-infected host cells that subsequently lyse to sustain high local virus load [5]. The impact of antiviral agents should be greater if treatment begins very early during the initial viral replication phase, before physical damage to the mucosal membranes occurs. The rationale for evaluating oral valacyclovir as therapy for facial herpes outbreaks is to address the limitations of the topical therapies

2 JID 2002;186 (Suppl 1) Valacyclovir in Facial HSV Infection S67 outlined above and to achieve high systemic acyclovir exposures. This should facilitate inhibition of HSV replication before the development of significant mucocutaneous damage, allow acyclovir to reach less accessible sites where application of topical treatments is difficult, and to ensure continued acyclovir exposure while eating and drinking. Valacyclovir accelerates lesion healing and pain resolution when used for episodic treatment of recurrent genital HSV outbreaks [13, 14], and early episodic treatment with valacyclovir also prevents vesicle and crust development by aborting episodes [13, 15]. Both topical and oral antiviral therapies have traditionally been evaluated with 5-day courses as episodic treatment, but valacyclovir () is similarly effective when given for 3 days [16]. The optimum duration of therapy for facial herpes has not been prospectively defined and may differ from that for genital herpes. With the availability of several antiviral treatments, it is impracticable to consider a placebo-controlled study in patients with recurrent facial HSV outbreaks. Thus, we used valacyclovir given as 500 mg twice a day for 3 days as the reference and compared it with a loading dose of 1000 mg of valacyclovir given twice a day for 1 day only. The hypothesis tested was that greater acyclovir exposure early in the episode before the development of any clinical signs of a lesion would be at least as effective as the twice a day 3-day course. In other words, this study aimed to establish that 1000 mg twice a day for 1 day was not worse than 500 mg of valacyclovir 3 times a day for 3 days. Methods Trial design. This study was a multicenter, randomized, double-blind comparison of two treatment regimens. At an initial screening visit, patients were randomized 1:1 to receive either valacyclovir 1000 mg (2 500-mg tablets) twice a day for 1 day followed by 2 days of placebo or 500-mg valacyclovir tablets twice a day for 3 days plus matching placebo tablets on the first day. Subjects self-initiated valacyclovir treatment at the first signs or symptoms of a facial HSV outbreak and then reported to the clinic for evaluation. Patient population. Eligible subjects were otherwise healthy males and females 12 years old who experienced 4 episodes of facial herpes per year with typical lesions. The diagnosis of facial herpes was based on prior evidence of HSV reactivation on the lips, face, or nose including the nasal septum. Previous facial HSV culture positivity, HSV-1 seropositivity, or a history of response to antiviral therapy was required prior to enrollment. Patients were excluded if they were pregnant, were nursing mothers, or were sexually active women of childbearing potential who were not using adequate contraceptive precautions. We excluded persons who had significant concomitant medical conditions or allergies and those who could not avoid use of other therapy for facial herpes (including other oral or topical antiviral drugs and systemic steroids) or would not agree to avoid mechanical disruption of the prodromal area or any lesion or were unable to recognize early prodromal symptoms of a recurrence. We also excluded subjects with a known history of intolerance to antiherpes drugs, persons with clinically significant lactose intolerance, significant renal insufficiency (estimated creatinine clearance!30 ml/min), those known or suspected to be immunocompromised, and those with a known medical or surgical condition that might alter their susceptibility to HSV reactivation and infections. Trial procedures. Patients underwent a screening evaluation and were then provided with study drug. They were instructed to initiate treatment as soon as possible after the onset of prodromal symptoms of a recurrent facial HSV outbreak and before the development of any visible clinical signs. Contact with the clinic by telephone or visit was required as soon as possible after treatment was started to provide the investigator with details of the recurrence and treatment initiation. A clinic visit was required as soon as possible after all signs and symptoms resolved, with an additional visit on day 4 if resolution had occurred earlier. Patients were required to keep a diary to record the date and time of administration of each study drug dose, the onset of the prodrome, the appearance of each sign and symptom, the times of lesion healing and pain resolution, plus assessments of lesion stage and symptom evaluation 3 times a day (prodrome, macule, papule, vesicle, crust, or healed). We assessed compliance with the treatment regimen by asking patients to return medication bottles along with any unused tablets after completion of the treated episode. All concurrent medications taken during the period in which the episode was treated were recorded in the diary. Evaluation of drug safety was by adverse event reporting. Efficacy end points. The primary end point was the proportion of patients with aborted lesions (i.e., where lesion development was blocked at or before the papule stage). Secondary end points included episode length (defined as total duration of symptoms and signs), time to lesion healing (for those who developed vesicular lesions), and time to resolution of pain or discomfort. Statistical methods. A sample size of 270 treated subjects was estimated to be sufficient to establish noninferiority of the 1000 mg twice a day (1 day) regimen, assuming that a difference of 15% would not be clinically meaningful. A one-sided confidence interval (CI) approach was used to establish noninferiority. It was assumed that 40% of subjects receiving 500 mg of valacyclovir twice a day for 3 days would achieve an aborted lesion; the sample of 270 subjects provides 80% power by use of the lower limit of the onesided 95% CI. The intent-to-treat population was defined as those patients randomized to treatment who returned to the clinic for evaluation of a treated HSV recurrence. The per-protocol population excluded subjects with major protocol violations defined as incorrect dosing, withdrawn subjects, subjects starting treatment during the papule stage or 12 h after the first symptom, and noncompliant subjects. We analyzed the primary end point by Fisher exact test. We explored the effects of the stage of the lesion at the time of start of treatment and the time from first symptoms or signs to treatment initiation on the proportion of patients with aborted episodes, although statistical testing was not prespecified. Secondary end points were analyzed by using the Cox proportional hazards methods, which included country as a covariate.

3 S68 Laiskonis et al. JID 2002;186 (Suppl 1) Table 1. Characteristics of the intent-to-treat population for facial HSV infection shown as percentages unless otherwise indicated. Characteristic Valacyclovir Demographics Age, median (range), years 36 (15 78) 38 (18 71) Female sex White race History of facial herpes Onset of disease, median (range), years 19 (2 44) 15 (0 45) Episodes in past year, median (range), no. 5 (1 20) 5 (2 15) Prodromal symptoms, always/mostly Classical lesions, always/mostly Site of HSV reactivation Lips Cheek 3!1 Chin 1 3 Nose 5 7 Forehead!1 0 Other 10 7 Current episode, treatment initiation (n p 296) n p 151 np 145 Prodrome/macule Papule Treatment within 6 h of symptom onset (n p 294) Compliance (n p 279): patients returning 0 tablets NOTE. Data are percentages, except where noted. Results Study population characteristics. In total, 429 patients were recruited at 31 sites in Denmark, Norway, Finland, and Lithuania, and 308 initiated treatment for a facial HSV recurrence. Table 1 lists demographic and baseline information for the intent-to-treat population by treatment group. There were no major differences in patient characteristics between treatment groups for the intent-to-treat population (or the whole randomized population; data not shown). In both treatment groups, 99% of subjects did not return any study medication. Aborted lesions. Of the 304 treated patients with data available, fully aborted lesions as defined according to the protocol occurred in 44% of subjects overall. Fewer than half (47%) developed classical lesions (vesicles and crusts) in either treatment group. The remaining episodes (9%) were considered partially aborted (development was blocked at the vesicle stage without crust formation). Table 2 shows detailed results for aborted lesions by treatment. The treatment difference for the intent-to-treat analysis (42.2% vs. 46.7% for the 1-day vs. 500 mg twice/ day 3-day regimens, respectively) was 4.5% (95% CI, 16.3% to 7.4%). When subjects with partially aborted lesions were included, the outcome of aborted lesions was achieved in 53% of patients in each treatment group (table 2). Since the lower 95% CI for the intent-to-treat analysis was 16.3%, noninferiority cannot be concluded. Furthermore, as the entire 95% CI does not fall below 15%, inferiority cannot be concluded. Therefore, it cannot be stated statistically that 1000 mg was worse or equivalent to 500 mg. For patients who started treatment within 6 h of the first symptoms, lesion abortion rates were similar to those of the intent-to-treat population at 45.9% and 48.5% for the 1-day loading and the twice daily 3-day regimens, respectively (table 2). In those whose treatment began at or before the macule stage, rates were marginally higher at 50.4% and 55.8%, respectively. For the subgroup ( n p 271, 89%) who initiated va- lacyclovir therapy within 6 h of symptom onset, the treatment difference in proportions with aborted lesions was 2.6% (95% CI, 15.3% to 10.1%; table 2). For the subgroup ( n p 228, 75%) who initiated valacyclovir therapy during the prodrome or macule stage, the treatment difference in proportions with aborted lesions was 5.3% (95% CI, 19.2% to 8.6%; table 2). Results for the per-protocol population ( n p 216, 71%) were consistent with those of the intent-to-treat population: a treatment difference of 3.7% (95% CI, 18.0% to 10.6%; table 2). Secondary efficacy end points. Overall, episode resolution and pain resolution were almost identical for the 2 treatment groups (table 3). Median lesion healing times for the 47% of patients with classic lesions ( n p 145) were 5.0 and 5.8 days for the 1000 mg twice a day 1-day and 500 mg twice a day 3- day regimens, respectively, and did not differ significantly. Similarly, median values for episode resolution were 3.1 days for both the 1- and 3-day regimens; for pain duration, median values were 1.5 days for both treatments. No significant differences were evident. Patients reported they were satisfied with the treatment in 90% of cases; 94% would use the treatment again. No notable difference in satisfaction between treatments was apparent (data not shown).

4 JID 2002;186 (Suppl 1) Valacyclovir in Facial HSV Infection S69 Table 2. Treatment population Primary efficacy analysis for facial HSV infection: aborted lesions. % Aborted lesions with valacyclovir regimen Intent to treat (n p 304) a Per protocol (n p 216) b Prodrome/macule at treatment onset (n p 228) c Papule at treatment onset (n p 68) Treatment within 6 h of symptom onset (n p 271) d Treatment after 6 h of symptom onset (n p 23) Includes partially aborted lesions e a Treatment difference estimate, 4.5% (95% confidence interval [CI], 16.3% to 7.4%); P p.49. b Treatment difference estimate, 3.7% (95% CI, 18.0% to 10.6%); P p.68. c Treatment difference estimate, 5.3% (95% CI, 19.2% to 8.6%). d Treatment difference estimate, 2.6% (95% CI, 15.3% to 10.1%). e Aborted lesion defined per protocol plus subjects with partially aborted lesions, i.e., whose lesions were blocked at the vesicle stage but with no crust formation. Adverse events. In all, 33 patients (11%) reported 38 adverse events most were considered mild or moderate in severity. Half of these events were considered as possibly drug related. Nausea and headache occurred in 2% and 1% of subjects, respectively, in both study arms. The common cold was reported as an adverse event in 1% of participants (4 subjects), although the colds were not attributed to study drug administration. Two subjects in the 1-day study group reported diarrhea. No obvious differences were evident between treatment groups. Discussion We believe this study is the first analysis of valacyclovir for episodic treatment of facial HSV infection including herpes labialis. The efficacy of valacyclovir has been established for episodic treatment of recurrent genital HSV infection [13, 14]. Our study sought to explore the potential of valacyclovir in recurrent HSV infection at a different anatomic site on the grounds that the sensitivity of acyclovir against HSV-1, as determined from in vitro IC 50 values, is not dissimilar to that against HSV-2 (HSV-1, mm; HSV-2, mm) [17]. The efficacy of oral acyclovir for this indication was shown in previous studies, albeit with only limited impact [5, 8, 9]; however, it is possible that facial HSV infection will require a different treatment regimen than for genital herpes and a placebo arm most likely will be necessary to establish efficacy. Our results do not demonstrate the equivalence of 1000 mg of valacyclovir twice a day for 1 day and 500 mg of valacyclovir twice a day for 3 days for treatment of facial herpes. Neither was the inferiority of the 1-day treatment course established. Further studies are required to determine the optimum dose and duration of valacyclovir therapy for the treatment of facial herpes. Our most important finding was that nearly half of the patients achieved an aborted lesion outcome with either valacyclovir regimen, an effect that was still apparent, as expected, in the slightly smaller subgroups who initiated treatment during the prodrome/macule stages or within 6 h of onset of a facial HSV episode. Although our study was not placebo controlled, it is worth considering this finding in relation to aborted lesion rates reported for other controlled trials. A rate of aborted lesions of 15% 16% was observed in a trial of penciclovir cream versus placebo conducted in a similar patient population [3], and rates of 26% and 10%, respectively, were seen in a trial of acyclovir cream versus placebo [1]. Trials with oral acyclovir have shown rates of aborted lesions of 30% and 29% for acyclovir and placebo, respectively [5]. Natural history studies in untreated subjects reported aborted lesion rates of up to 25% [18]. In the largest trial in recurrent genital HSV infection, valacyclovir significantly increased aborted lesions (30% with active treatment vs. 21% in the placebo group) [13]. The high rate of aborted lesions in our study would be a major contributor to the substantial reduction in the time for Table 3. Analysis of secondary efficacy end points in trial of acyclovir for facial HSV treatment. End point Median days to end point, by valacyclovir regimen Hazard ratio (95% CI) a Episode resolution ( ).92 Pain resolution ( ).70 Lesion healing ( ).14 a for 1 day vs. for 3 days. P

5 S70 Laiskonis et al. JID 2002;186 (Suppl 1) total HSV episode resolution in the overall study population. The median value of 3.1 days in both valacyclovir treatment groups is about half the value reported for control groups in other studies in which lesion healing was the primary efficacy end point (median, 6.0 days) [3, 13]. Likewise, pain resolution in valacyclovir recipients (median, 1.5 days) was at least twice as fast as that reported in any previous trial of acute HSV treatment (3.5 days for penciclovir cream; days for valacyclovir) [3, 13]. Lesion healing in our valacyclovir-treated patients who did not experience aborted lesions (median, 5.0 and 5.8 days) was, not surprisingly, similar to earlier reports in which mean/median values for patients receiving active treatment were about 5 days [3]. This preliminary study supports the further evaluation of valacyclovir as episodic therapy of facial HSV infections, including herpes labialis. The results raise a number of important questions that should be addressed in future studies: the optimal duration of therapy, whether a 1-day course can provide sufficient efficacy, and whether a loading dose regimen can be designed so as to significantly enhance the probability of facial herpes lesions aborting, thus preventing the development of painful vesicles and the pain associated with formation and loss of hard crusts. Participating Investigators Denmark. P. Andersen, U. Thybo Johansen, and K. Okholm, Aarhus; L. Brincker, Slagelse; P. Hauschildt Christiansen, Tranbjerg; C. Colstrup, Næstved; U. Gjede, Thisted; P. Hein, Fredericia; S. Neldam, K. Kornø-Rasmussen, and P. Elmegaard-Rasmussen, Copenhagen; S. Rungø, Svendborg. Finland. E. Hiltunen-Back, Helsinki; T. Jarvinen, Oulu; M. Kousa, Jyvaskyla; M. Mortenhumer, Kokkola; T. Rantanen, Lahti. Norway. D. Aandahl, A. Granholt, A. Ording Helgesen, J. Langeland, T. Langeland, and M. Nyrud, Oslo; T. Holst, Tønsberg; K. Tambs, Sandvika; P. Madsen, T. Thune, and S. Helland, Bergen; J. Sandven, Øystese. Lithuania. A. Laiskonis, Kaunas. Acknowledgments We thank Elke Löschel and Trine Nielsen for coordinating the study, Lisbet Groes for statistical analysis, and Jane Crooks and Judy Barber for critical review of the manuscript. References 1. Fiddian AP, Yeo JM, Stubbings R, Dean D. Successful treatment of herpes labialis with topical acyclovir. Br Med J (Clin Res Ed) 1983;286: Raborn GW, Martel AY, Grace MGA, McGaw WT. Herpes labialis in skiers. Randomized clinical trial of acyclovir cream versus placebo. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84: Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R. Penciclovir cream for the treatment of herpes simplex labialis: a randomized, multicenter, double-blind, placebo-controlled trial. JAMA 1997;277: Boon R, Goodman JJ, Martinez J, Marks GL, Gamble M, Welch C. 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