Ron Boon

Famciclovir for the Suppression of Symptomatic and Asymptomatic Herpes Simplex Virus Reactivation in HIV-Infected Persons: A Double-Blind, Placebo-Controlled Trial

Persistent genital herpes simplex virus (HSV) infection was one of the first opportunistic infections described in persons with AIDS [1]. Although 60% to 80% of the general population has serum antibodies to HSV-1, HSV-2, or both [2-4], up to 95% of HIV-positive persons are seropositive for either HSV-1, HSV-2, or both [5-11]. This makes HSV one of the most common viral infections complicating HIV infection. Anecdotal reports indicate that clinical reactivations usually persist for an extended period, may involve many cutaneous and mucosal sites, and seem to increase with progression of HIV disease [12, 13]. In addition, long-term antiviral therapy is commonly used to suppress frequent HSV reactivations. Although the efficacy of such therapy is well established in immunocompetent persons [14-16], no published trials have quantitated the efficacy of suppressive antiviral therapy on HSV-1 or HSV-2 reactivation in HIV-infected persons. Famciclovir is a nucleoside analogue recently licensed for the treatment of herpes zoster and recurrent genital HSV infection [17]. To determine the efficacy of famciclovir for the suppression of HSV reactivation in HIV-infected persons, we did a double-blind, placebo-controlled, crossover trial in 48 persons with HIV infection. Methods Study Participants and Design Persons infected with both HIV and HSV were recruited into our study through advertisements in local newspapers and referrals from private physicians. The study was approved by the University of Washington institutional review board. We screened 123 persons and enrolled 48. Reasons for exclusion were lack of HSV antibodies (14%), inability to complete or lack of interest in completing 4 consecutive months of daily home culture (80%), and unwillingness to go without therapy during a recurrence of HSV (6%). At enrollment, each participant completed a standardized interview designed to record history of previous HSV reactivation, frequency of previous antiherpesvirus therapy, and extent of HIV disease. We excluded persons if they were younger than 18 years of age, were currently infected or had previously been infected with acyclovir-resistant HSV, had known gastrointestinal disorders affecting absorption, or had received suppressive antiviral therapy with acyclovir in the 6 months before enrollment. Patients were paid

Postherpetic Neuralgia: Impact of Famciclovir, Age, Rash Severity, and Acute Pain in Herpes Zoster Patients

300 for completion of the protocol; those who completed only the first arm of the protocol were paid

Safety of famciclovir in patients with herpes zoster and genital herpes.

150. At study entry, each participant was randomly assigned to receive either famciclovir tablets, 500 mg twice daily, or placebo tablets (identical in appearance to the famciclovir tablets) twice daily, for 8 weeks. This 8-week period was followed by a 7-day washout period, during which no pills were taken, and then by a second 8-week period during which participants received whichever regimen they had not received during the first phase of the trial. We chose this study design because it controlled for the variability between individual persons in CD4 cell count (which can affect the frequency of HSV reactivation [13]) and because a 7-day washout period had been shown not to influence subsequent HSV reactivation [18]. Famciclovir and placebo were dispensed in 28-day supplies (56 pills). During the entire 119-day study period, patients obtained once-daily cultures of the oropharynx, genitals (urethra and penile shaft in men; cervicovaginal area and labia in women), and rectum. Participants returned to the clinic at 28-day intervals so that we could review their daily symptom diaries, monitor compliance, distribute more study medication and culture supplies, and assess safety. All participants were also asked to return to the clinic during episodes of genital herpes. At these visits, we performed genital examinations to confirm the presence of lesions and obtained additional cultures of the lesions. Both participants and investigators were blinded to culture results until the conclusion of the study. Neither open-label oral acyclovir nor topical anti-HSV products for treatment of an HSV recurrence were allowed. Collection of Daily Cultures The methods used to collect swabs for HSV isolation have been described elsewhere [16, 18]. Each participant collected one specimen daily from each of four anatomic sites, using a separate Dacron swab for each culture. Oral-pharyngeal cultures were obtained by inserting a swab into the mouth and vigorously rubbing it along the gum line and over the palate. Men obtained urethral cultures by rubbing a swab over the urethral opening and obtained penile cultures by rubbing a separate swab along the entire ventral and dorsal shaft of the penis. Women obtained labial cultures by rubbing a swab over the entire labia majora and minora. Cervicovaginal cultures were obtained by rubbing a swab over the exocervix and posterior vaginal fornix. Rectal cultures were obtained by inserting the swab approximately 2 to 4 cm into the anus and gently rotating it. Each swab was placed in a separate vial that contained viral transport media, was labeled with site and date, and was stored in the refrigerator. Participants were instructed to obtain the cultures at the same time each day, preferably upon awakening. Cultures were picked up by a courier within 36 hours of collection and were transported to the virology laboratory of the University of Washington, where they were immediately inoculated into tissue culture. Participants also filled out daily diary cards that recorded the site-specific presence or absence of symptoms (pain, tingling, numbness or itching, presence of lesions) and the number of pills taken each day. The cards were collected monthly and reviewed by the study clinician. Unused cards of medication were collected, and pill counts were done to confirm compliance records. Laboratory Studies Serologic and T-Cell Analysis Seropositivity for HIV was confirmed by using standard enzyme-linked immunoassays and Western blot assays. CD4 cell subset analysis was done by using flow cytometry. Tests for antibodies to HSV were performed with Western blot analysis on serum specimens obtained at study entry [11, 19]. Patients were classified into three groups: those who were seropositive for HSV-1 only, those who were seropositive for HSV-2 only, and those who were seropositive for both HSV-1 and HSV-2. Herpes Simplex Virus Culture and Sensitivity Testing For isolation of HSV, each sample was inoculated in triplicate into 48-well microtiter plates that contained human diploid fibroblasts [20]. Each well was examined three times weekly for evidence of cytopathic changes of HSV infection. Cultures that showed cytopathic effects were confirmed and typed by using HSV-specific monoclonal antibodies. The initial culture supernatant from each clinical isolate that was obtained while patients were receiving famciclovir was inoculated into human diploid fibroblast cells [21]. Cell-associated virus (1:200 dilution in MEM [minimal essential media]-10% fetal calf serum) was inoculated in duplicate onto freshly confluent diploid fibroblast cells in 24-well plates. Plates were rocked at 30 tilts per minute for 60 minutes; penciclovir (Smith-Kline Beecham Pharmaceuticals, Philadelphia, Pennsylvania) containing medium was then added at 11 serial log2 dilutions from 40.96 to 0.04 g/mL. Control wells with no penciclovir were also established. When controls without penciclovir demonstrated 4+ cytopathic effect, the Hybriwick kit (Diagnostic Hybrids, Athens, Ohio) was used to measure HSV DNA [22] according to the manufacturers directions. The IC50 value was estimated as the lowest concentration of drug that caused a 50% or greater reduction of mean cycles per minute hybridization of HSV-specific DNA probe to cell lysates. Values for IC50 were calculated with a computer algorithm that used a Michaelis-Menten model and nonlinear least-squares curve fitting. Definition of Terms Total HSV shedding was defined as the total number of days on which HSV was isolated by culture (regardless of anatomic site) divided by the total number of days on which cultures were obtained. Asymptomatic HSV shedding was defined as the total number of days on which a participant reported no symptoms or lesions at an anatomic site from which HSV was isolated divided by the total number of days on which cultures were obtained. Symptomatic HSV shedding was defined as the total number of days on which a lesion or symptom was reported by the participant in the symptom diary at an anatomic site from which HSV was isolated divided by the total number of culture days. A recurrence of genital herpes was defined as lasting from the onset of lesions to the complete healing of lesions. Statistical Analysis Treatment effect was initially evaluated with intention-to-treat analyses that included all randomly assigned participants before crossover. Survival analysis was used to handle data censoring caused by early withdrawals. Time to first isolation of HSV (either HSV-1 or HSV-2) by culture, time to HSV-1 isolation, and time to HSV-2 isolation were examined. Differences in Kaplan-Meier survival curves between the famciclovir and placebo groups in the first treatment period were assessed by using the log-rank test. The relative risk for shedding was estimated by using the Cox proportional-hazards regression model with first-period treatment as the only predictor variable. To determine the effect of famciclovir on reduction of HSV-1 and HSV-2 shedding rates and days with symptoms, we used crossover analysis methods to further analyze participants who successfully completed both arms of the study. Successful completion was defined as more than 28 days with cultures in each treatment arm. Because HSV shedding and symptom rates were not normally distributed, nonparametric tests were used. Wilcoxon rank-sum tests for carryover (residual) and period effects compared the sums and differences, respectively, of rates during placebo and famciclovir administra

A randomized, double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients

New and previously reported analyses of the data from a placebo-controlled trial of famciclovir are reviewed in light of recently proposed recommendations for the analysis of pain in herpes zoster trials. The analyses examined the effect of famciclovir treatment on the duration of postherpetic neuralgia (PHN), which was defined as pain persisting after rash healing, pain persisting > 30 days after study enrollment, or pain persisting > 3 months after study enrollment; the baseline characteristics of patients in the famciclovir and placebo groups who developed PHN; the impact of famciclovir treatment on the duration of PHN, while controlling for significant covariates; and the prevalence of PHN at monthly intervals from 30 to 180 days after enrollment. The results of these analyses indicated that greater age, rash severity, and acute pain severity are risk factors for prolonged PHN. In addition, they demonstrated that treatment of acute herpes zoster patients with famciclovir significantly reduces both the duration and prevalence of PHN.

Surveillance for antiviral-agent-resistant herpes simplex virus in the general population with recurrent herpes labialis.

Safety reporting from individual ongoing and completed clinical studies has demonstrated that famciclovir, the well-absorbed oral form of the antiherpesvirus agent penciclovir, has been well tolerated by more than 3,000 individuals worldwide. An integrated safety evaluation has been performed and includes over 1,600 patients from 11 completed, randomized, double-blind clinical trials and 2 open trials. The famciclovir population consisted of 816 herpes zoster patients (four trials), 409 patients with acute genital herpesvirus infections (seven trials), and 382 patients from two genital herpes suppression studies. Overall, the famciclovir-treated patient population was 57.7% female and ranged in age from 15 to 102 years (mean, 42.6 years), with 31.2% aged 50 years or more and 15.7% aged 65 years or more. The mean duration of exposure to famciclovir was 28.8 days (5.8 days excluding suppression studies). The total daily doses ranged from 125 mg to 2.25 g. The most common adverse experiences reported as related to study medication (famciclovir and placebo) were headache, nausea, and diarrhea. The frequencies of adverse experiences and laboratory abnormalities (hematology, clinical chemistry, and urinalysis parameters) were similar in both famciclovir and placebo recipients. Thus, safety data from the analysis of 13 completed clinical studies demonstrate that famciclovir is tolerated well by patients with either herpes zoster or genital and has a safety profile comparable to that of placebo.

Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials

In this randomized, double-blind, multicenter, acyclovir-controlled study, the efficacy and safety of famciclovir were evaluated for the treatment of herpes zoster in patients who were immunocompromised following bone marrow or solid organ transplantation or oncology treatment. A total of 148 patients, 12 years or older with clinical evidence of localized herpes zoster, received either oral famciclovir, 500 mg three times daily, or acyclovir, 800 mg five times daily, for 10 days. Famciclovir was equivalent to acyclovir with respect to the numbers of patients reporting new lesion formation while on therapy (77% vs. 73%, respectively). There were no significant differences between the groups in the time to cessation of new lesion formation, full crusting, complete healing of lesions, or loss of acute phase pain. Treatment with famciclovir was well tolerated, with a safety profile comparable to that of acyclovir. Thus oral famciclovir is a convenient, effective, and well-tolerated regimen for immunocompromised patients with herpes zoster.

Susceptibility of Herpes Simplex Virus Isolates to Nucleoside Analogues and the Proportion of Nucleoside-Resistant Variants after Repeated Topical Application of Penciclovir to Recurrent Herpes Labialis

ABSTRACT In a general population survey in the United States, the prevalence of antiviral-agent-resistant herpes simplex virus was very low among more than 1,000 isolates from individuals with an episode of recurrent herpes labialis not treated with topical antiviral agents. Two isolates had borderline resistance to acyclovir (0.2%), and all were susceptible to penciclovir.

Penciclovir Susceptibilities of Herpes Simplex Virus Isolates from Patients Using Penciclovir Cream for Treatment of Recurrent Herpes Labialis

Summary. A susceptibility testing program was established to determine the prevalence of resistance to penciclovir among herpes simplex virus isolates collected from patients participating in 11 world-wide clinical trials involving penciclovir (topical or intravenous formulations) or famciclovir, the oral prodrug of penciclovir. These trials represented nine randomised double blind, placebo or aciclovir-controlled studies and two open-label studies. Groups surveyed included immunocompetent or immunocompromised patients receiving 2 to 12 months chronic suppressive therapy for genital herpes, immunocompetent patients with recurrent herpes labialis treated for four days, and immunocompromised patients with mucocutaneous herpes simplex virus (HSV). Another subset of patients had been identified as non-responders to aciclovir or to valaciclovir. This program assessed the susceptibility profile for a total of 2145 herpes simplex virus isolates from 913 immunocompetent and 288 immunocompromised patients treated with penciclovir, famciclovir, aciclovir or placebo (depending on trial design). HSV isolates were tested for susceptibility to penciclovir using the plaque reduction assay (PRA) in MRC-5 cells. Resistance was defined as an IC50≥2.0 µg/ml or an IC50> 10-fold above the wild type control virus IC50 within that particular assay. Penciclovir-resistant HSV was isolated from 0.22% immunocompetent patients, and 2.1% of immunocompromised patients overall and therefore the frequency of penciclovir-resistant herpes simplex virus in the immunocompetent population approximates that of aciclovir-resistant herpesvirus reported previously. Penciclovir-resistant HSV isolates were more common in isolates from immunocompromised patients, consistent with aciclovir clinical experience. Treatment with penciclovir (intravenous formulation) was associated with the development of resistant HSV in only one severely immunocompromised patient (day 7 isolate IC50 = 2.01 µg/ml), although treatment was effective and resulted in the complete clearance of the lesion by day 8. No patients receiving topical penciclovir developed treatment-associated penciclovir-resistant HSV, and a single immunocompromised patient developed resistant HSV upon treatment with oral famiciclovir.

Penciclovir Cream for the Treatment of Herpes Simplex Labialis: A Randomized, Multicenter, Double-blind, Placebo-Controlled Trial

Subjects received topical penciclovir for 4 days during successive episodes of recurrent herpes labialis. Isolation of herpes simplex virus (HSV) was attempted from lesions obtained before initiation of treatment and on each day of therapy. Isolates remained sensitive to penciclovir when tested by a plaque reduction assay, and there was no significant change in sensitivity during any treatment course or between successive treatments. The proportion of nucleoside-resistant variants present within a subset of these isolates was further investigated using a more-sensitive plating efficiency assay. Although the proportion of antiviral-resistant HSV variants increased on successive days, it invariably remained a minor subpopulation. Moreover, isolates from successive episodes obtained before treatment showed no change in the proportion of resistant HSV variants. We conclude that antiviral-resistant variants, which are readily detected in HSV isolates from peripheral lesions, do not accumulate in the sensory ganglia of immunocompetent patients receiving multiple courses of nucleoside analogues.

Oral Famciclovir for the Suppression of Recurrent Genital Herpes: A Randomized Controlled Trial

ABSTRACT The antiherpesvirus agent penciclovir (PCV) shares an identical activation pathway and a similar mode of action with acyclovir (ACV). However, since PCV represents a relatively recent treatment option, the clinical resistance profile to PCV is less well known. A susceptibility program was established to assess the resistance profile for serial herpes simplex virus isolates from immunocompetent patients with recurrent herpes labialis obtained throughout a 4-day period of treatment with topical PCV (1% cream) or a placebo. Two isolates (2 of 1,035 [0.19%]), representing 0.34% of the patients (2 of 585), were confirmed to be PCV-resistant (Pcvr) herpes simplex virus type 1 by a plaque reduction assay in MRC-5 cells. These two viruses were highly resistant to PCV (50% inhibitory concentrations [IC50s], >55 μg/ml) and were isolated less than 17 h after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from these patients were completely susceptible to PCV (IC50s, <2.0 μg/ml). Thus, it is not clear whether the resistance to PCV for these two early-treatment isolates was directly associated with the 17 h of PCV treatment; several possible explanations are discussed. In an analysis of the distribution of IC50 differences between the first and last isolates, there were three patients with minor IC50 increases in the PCV-treated population and one in the placebo-treated group, although statistically, only the latter was an outlier. No patients were found to have Pcvr virus at the end of acute treatment, regardless of treatment group. Overall, the prevalence of Pcvr was found to be similar to the 0.3% Acvr reported for immunocompetent, untreated populations.