Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals

Objective: To compare the efficacy and safety of 7 days' treatment with famciclovir 500 mg twice a day versus acyclovir 400 mg five times a day, for mucocutaneous herpes simplex virus (HSV) infection in HIV-infected individuals.

Design: Randomized, double-blind, parallel-group study to demonstrate equivalence for the primary efficacy parameter.

Setting: Forty-eight hospital-based or specialist public-health clinics in 12 countries.

Cited Here...: Two-hundred and ninety-three HIV-positive patients with recurrent HSV infection (orolabial or genital) starting treatment within 48 h of first appearance of herpetic lesions.

Main outcome measures: Proportion of patients developing new lesions during treatment (primary outcome measures); Time to complete healing of lesions, time to cessation of viral shedding, time to loss of lesion-associated symptoms, number of withdrawals due to treatment failure (secondary outcome measures).

Cited Here...: Equivalence was defined prospectively and famciclovir was equivalent to acyclovir in preventing new lesion formation: new lesions occurred in 16.7% and 13.3% of patients, respectively [difference, 3.4%; 95% confidence interval (CI), -4.8-11.5]. The groups were comparable in time to complete healing (median 7 days for both groups; hazard ratio, 1.01; 95% CI, 0.79-1.29;P  = 0.95), cessation of viral shedding (median of 2 days [hazard ratio = 0.93; 95% C.I. 0.68, 1.27;p  = 0.64]), and loss of lesion-associated symptoms (median 4 days; hazard ratio, 0.99; 95% CI, 0.75-1.30;P  = 0.93). Similar numbers in each group withdrew because of treatment failure. There were no differences between groups in the incidence of adverse events.

Conclusions: Famciclovir given twice a day is as effective and well tolerated as high-dose acyclovir for mucocutaneous HSV infections in HIV-infected individuals, and has the convenience of less frequent dosing.

Introduction

Infection with herpes simplex virus (HSV) is common in patients infected with HIV; seroprevalence studies have found evidence of prior infection with either HSV-1 or HSV-2 in more than 90% of HIV-infected individuals ^[1]. Studies have indicated that a characteristic feature of HSV infection in this population is an increased frequency and severity of recurrent disease over time ^[2], associated with deterioration in the patients' immune status ^[3]. Early in the course of HIV disease, the herpetic lesions heal spontaneously over a period of approximately 2 weeks ^[2] but as the disease progresses, the lesions may persist for several weeks or months if untreated. Individuals with advanced HIV disease are also more likely to shed HSV-2 clinically and subclinically than patients with less advanced disease: men with CD4 cell counts < 200 × 10⁶/l were shown to be twice as likely to shed HSV-2 compared with men with CD4 cell counts > 500 × 10⁶/l ^[4]. Highly active antiretroviral therapy, which is associated with a subsequent recovery of CD4 cell counts, may lead to less frequent subclinical shedding and lesional recurrences, although less than 10% of HIV-infected individuals in the world currently receive such therapy ^[5].

There is some evidence that HSV infection induces HIV expression and has a cofactorial role in the pathogenesis of AIDS ^[6,7]. There is also evidence indicating that HIV is shed from genital herpes lesions, which suggests that such lesions may be an important co-factor for HIV transmission ^[8]. These findings concerning the transmission and expression of HIV and HSV indicate the importance of treating herpes simplex infections in HIV-infected individuals.

Acyclovir has been the standard treatment for HSV infection in immunocompromised patients but its short intracellular half-life in vitro and low and variable oral bioavailability ^[9] mean five times daily dosing is necessary. According to published literature ^[10,11] and a sponsor commissioned survey of clinical usage of acyclovir in Europe conducted in 1991 (unpublished data), the usual regimen for treatment of recurrent HSV infections in patients with HIV varied from 200 mg five times daily to 800 mg five times daily with a duration of 5-10 days. Therefore, a dose of acyclovir, 400 mg five times daily, was chosen as best reflected clinical practice for comparison with famciclovir, 500 mg twice a day for 7 days. Famciclovir (Famvir®, SmithKline Beecham), the well absorbed oral form of penciclovir (77% bioavailable ^[12]), is a nucleoside analogue with a similar spectrum of antiviral activity against the herpes viruses, and comparable potency and selectivity, to those of acyclovir ^[13-15]. Penciclovir, like acyclovir, requires viral encoded thymidine kinase for its conversion to the monophosphate. It is then phosphorylated by cellular enzymes to the active form, penciclovir-triphosphate ^[16], which inhibits viral DNA polymerase and, therefore, viral replication ^[17]. However, the triphosphate of penciclovir formed in virus-infected cells is considerably more stable than that of acyclovir. For example, the half-life of penciclovir triphosphate in HSV-2-infected human lung fibroblasts (MRC-5 cells) in vitro is 20 h, compared with 1 h for acyclovir ^[18]. Furthermore, it has been shown that the in vitro inhibition of viral replication by penciclovir continues for several hours after the compound is removed from the culture medium, whereas viral replication restarts immediately after removing acyclovir ^[13]. It may be possible, therefore, to administer famciclovir less frequently than acyclovir and yet continuously inhibit HSV replication without maintaining blood concentrations at or above the level needed for viral inhibition ^[19].

Published studies have demonstrated that famciclovir is an effective and well-tolerated treatment for recurrent genital herpes infections in immunocompetent patients ^[20,21]. Famciclovir has been prescribed more than 4 million times worldwide. To date, no clinically significant interactions have been identified. Based on the metabolism of famciclovir, no pharmacokinetic interactions with drugs commonly administered to HIV-infected individuals are anticipated. Neither famciclovir nor its antiviral product penciclovir inhibit any of the known cytochrome p450 enzymes. Furthermore, the oxidative conversion of the prodrug famciclovir to penciclovir involves aldehyde oxidase rather than cytochrome p450. As zidovudine and penciclovir are eliminated by the same renal pathways (i.e. tubular secretion and passive filtration) a formal interaction study was performed in HIV-infected individuals and no clinically significant pharmacokinetic interactions were identified ^[22].

This paper describes the results of treating mucocutaneous HSV infection in HIV-infected individuals for 7 days with famciclovir 500 mg twice a day, and acyclovir 400 mg five times a day.

Materials and methods

This was a randomized, double-blind, double-dummy, parallel-group study with centres in Australia, Belgium, Canada, France, Germany, Hungary, Ireland, Italy, Mexico, New Zealand, Spain and the UK. The study was performed in accordance with Good Clinical Practice and the Declaration of Helsinki as amended in Hong Kong (1989), as well as the requirements of the relevant national regulatory authorities. Both the protocol and the statement of informed consent were approved by the ethics committee at each study centre.

Patients

Male and female patients, 18 years of age or over were eligible for inclusion in the study if they were HIV seropositive (determined by enzyme linked immunosorbent assay and confirmed by an additional recognized method), had a clinically diagnosed recurrent mucocutaneous HSV infection (orolabial or genital) with a minimum of 2 lesion-free weeks since the previous episode and were able to start study medication within 48 h of the onset of lesions. Key exclusion criteria included: women who were pregnant, breast feeding, planning a pregnancy or not using adequate contraception; patients with a first episode of HSV infection, crusted lesions, clinical evidence of disseminated or visceral disease arising from a herpes virus infection that warranted intravenous acyclovir therapy, clinically significant renal or hepatic disease, impaired gastrointestinal absorption, known acyclovir hypersensitivity or infection with HSV known to have reduced sensitivity to acyclovir, patients who had used any antiviral agent other than zidovudine, 2′,3′-dideoxyinosine or dideoxycytidine within 2 weeks of entering the study, or changed the regimen of any of these drugs within the previous 4 weeks, were using topical steroids in the area of their lesions and patients with any other disorder or infection that would interfere with lesion assessment. Patients were permitted to participate in the study only once. Patients were enrolled between 1993 and 1996.

Treatments

This paper reports the results of treatment with either famciclovir, 500 mg twice a day, or acyclovir, 400 mg five times daily. Patients were randomized in a double-blind, double-dummy manner. (A 250 mg twice a day famciclovir treatment arm was originally included but recruitment to this arm was discontinued after 59 patients had been randomized to facilitate patient recruitment and study completion. The efficacy data from the low-dose famciclovir arm were not analysed as there were insufficient data from which to draw conclusions.)

As famciclovir was provided as tablets and acyclovir as capsules, each patient received one tablet (famciclovir or placebo) twice daily and one capsule (placebo or acyclovir) five times daily. Patients were given treatment packs comprising seven blister cards (one per day) with the time for each dose indicated. The first dose of study medication was taken at the clinic to ensure that all patients received active treatment immediately. To measure treatment compliance, patients were given a diary to record the date and time at which each dose was taken.

Assessments

At the initial screening visit, patients who were eligible for inclusion in the study and who gave informed consent underwent a full medical history and examination. The anatomical location and stage of all herpetic lesions were noted, and the number of individual eruptions (papule, vesicle, ulcer or crust) was scored on a scale of none (0), one (1), few (2-5) or many (> 5). In addition, swabs were taken from the lesions for viral culture; a blood sample was taken for clinical chemistry, haematology and CD4/CD8 count; and a urine sample was taken for dipstick urinalysis and pregnancy testing where appropriate. Thereafter, patients were required to attend the clinic every day for the first 5 days of treatment and then on alternate days until all lesions had healed completely (healing was defined as the point at which all lesions had lost their crust and re-epithelialization had occurred, such that only erythema remained). At each visit, the patients' symptoms and the condition of their lesions were assessed, and swabs were taken for viral culture unless two consecutive HSV-negative cultures had been obtained. Patients were also asked about the occurrence of any adverse events. Blood and urine samples were taken for assessment of clinical laboratory parameters at the end of the treatment phase and either on day 14 or at the time of complete healing, whichever occurred first. All concomitant medications administered during the study were recorded.

Statistical analyses

The primary endpoint was the proportion of patients developing new lesions during treatment. Secondary endpoints were time to complete healing of all lesions, time to cessation of viral shedding, duration of lesion-associated symptoms and the number of withdrawals due to treatment failure. In addition, subgroup analyses for the key efficacy parameters of new lesion formation and time to complete healing were performed for CD4 lymphocyte count (≥ 200 × 10⁶/l versus < 200 × 10⁶/l) and location of lesions (anogenital versus orolabial).

The study was designed to demonstrate equivalence with respect to the proportion of patients developing new lesions while on study medication. The treatments would be regarded as equivalent if the upper limit of the two-sided 95% confidence interval (CI) for the difference (famciclovir minus acyclovir) was less than 15%^[23,24]. If famciclovir was at least as effective as acyclovir, a sample size of 112 patients per treatment group would allow demonstration of equivalence with 80% power, assuming that the incidence of new lesion formation was the same in both groups (expected to be 20%). For the secondary endpoints, the treatment difference for proportional data was considered statistically significant if the 95% CI lay entirely above or below zero. Time-to-event data were analysed using Cox proportional hazard methodology ^[25] and treatment difference was considered statistically significant if the 95% CI for hazard ratios lay entirely above or below 1. Patients who continued to report the event at the last assessment were censored in the analysis.

The intent-to-treat population, which included all patients who received at least one dose of study medication, was the principal population for the efficacy and safety analyses. Overall significance levels where P  ≤ 0.05 for two-tailed tests were considered to be statistically significant.

Results

Patient demographics

A total of 293 patients were randomized and received at least one dose of study medication. The baseline demographic characteristics were similar for the two treatment groups (Table 1). Using the Centers for Disease Control classification of HIV status (1986, revised 1987), approximately half (49.1%) of all randomized patients were classified as Group II/III (asymptomatic infection and/or generalized lymphadenopathy), and the other half (50.9%) were classified as Group IV (HIV-associated conditions; primarily secondary infectious diseases). However, a slightly greater proportion of patients classified as Group IV was randomized to famciclovir treatment (56.0%) than to acyclovir treatment (45.5%). CD4 lymphocyte counts were comparable between treatment groups, and the proportions of patients with CD4 counts above and below 200 × 10⁶ cells/l were similar (52.9% and 47.1% respectively, for all randomized patients). Approximately 42% of patients started study medication within 24 h of lesion outbreak, and there were no differences between treatment groups in the time of initiation of therapy following lesion appearance. The predominant lesion stages present in all patients at baseline were vesicles (57.3% for famciclovir, 59.4% for acyclovir) and ulcers (44.7% for famciclovir, 43.4% for acyclovir). Anogenital lesions (50.9% of patients) were more common than orolabial lesions (37.5%). Analysis of viral cultures performed at baseline found that 57.4% of patients swabbed were culture-positive, with HSV-2 infection (54.6% of patients) more common than HSV-1 (36.2%) overall.

Table 1

Of the 293 patients randomized, 262 (89.4%) completed the study. The reasons for withdrawal were lost to follow-up (10 patients), adverse experience (seven patients), lack of compliance (five patients), lack of efficacy (three patients), protocol violation (three patients), concurrent disease (one patient) and other reasons (two patients). The majority of patients who were lost to follow-up (eight patients) or withdrawn due to lack of compliance (four patients) were from the famciclovir group, while withdrawals for adverse events and lack of efficacy were comparable between the two treatment groups.

Primary efficacy measure

The proportion of patients with new lesion formation during treatment was similar in the two groups and statistical equivalence was achieved (16.7% famciclovir versus 13.3% acyclovir; 95% CI, -4.8-11.5). As the upper limit of the two-sided 95% CI for the difference was < 15%, famciclovir 500 mg twice a day was equivalent to acyclovir 400 mg five times daily in preventing new lesion formation while patients were receiving treatment.

Secondary efficacy measures

The median time to complete healing of all lesions was 7 days in both treatment groups with a hazard ratio of 1.01 (95% CI, 0.79-1.29;P  = 0.95). The Kaplan-Meier estimates of the proportion of patients who had healed completely on each day of the study is shown in Fig. 1. The median time to cessation of viral shedding from all lesions was 2 days for both famciclovir and acyclovir (hazard ratio, 0.93; 95% CI, 0.68-1.27;P  = 0.64); the median time to loss of all lesion-associated symptoms was 4 days in both groups (hazard ratio, 0.99; 95% CI, 0.75-1.30;P  = 0.93). Only three patients (one treated with famciclovir and two treated with acyclovir) were withdrawn due to treatment failure.

Fig. 1

Subgroup analyses

There was no evidence to suggest a difference between treatment with famciclovir and acyclovir in new lesion formation or in time to complete healing, when patients were subgrouped according to CD4 lymphocyte count (< 200 × 10⁶/l versus ≥ 200 × 10⁶/l) or lesion location (anogenital versus orolabial).

Tolerability

The most frequently occurring adverse events (affecting ≥ 5% of patients) for the famciclovir and acyclovir groups are summarized in Table 2. The occurrence of adverse events was similar for the two treatment groups: at least one adverse event was reported by 54.0% of patients treated with famciclovir and by 57.3% of patients treated with acyclovir. Overall, the most common adverse events, headache, nausea and diarrhoea, were reported by similar proportions of patients in each group. There were no reports of either haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura. Seven patients withdrew because of adverse events (four patients treated with famciclovir and three treated with acyclovir). These events were considered serious in three patients (two patients treated with famciclovir and one patient treated with acyclovir), and in one case was also fatal. All of the events leading to withdrawal were considered by the investigators to be unrelated or probably unrelated to study medication. Altogether, four patients died during the study period (one treated with famciclovir and three treated with acyclovir) but all deaths resulted either from underlying conditions or HIV-related secondary infections and the investigator considered them unrelated or probably unrelated to study medication.

Table 2

Evaluation of clinical laboratory data failed to identify a consistent pattern for any clinically important laboratory abnormalities in the famciclovir treatment group, bearing in mind the immunocompromised status of the study population. Furthermore, the incidence of abnormalities in laboratory parameters was comparable between the famciclovir and acyclovir groups.

Discussion

For the past decade, acyclovir has been the mainstay of treatment for HSV-1 and HSV-2 infections in both immunocompetent and immunocompromised patients. The bioavailability of oral acyclovir is low and variable ^[9], necessitating frequent dosing, which may in turn reduce compliance with treatment ^[26]. Furthermore, clinical and virological breakthrough are not uncommon in immunocompromised patients receiving acyclovir prophylaxis against HSV infection ^[26-29]. There is a need, therefore, for an oral antiviral agent with reliable pharmacokinetics and a convenient dosing regimen, which is effective and well tolerated for both the treatment and prophylaxis of HSV infections in immune deficient individuals.

The present study compared the efficacy and safety of 7 days' treatment with famciclovir 500 mg twice a day, and acyclovir 400 mg five times daily, in HIV-infected individuals with mucocutaneous HSV infection. The treatments were comparable when evaluated across a range of efficacy parameters, including the proportion of patients developing new lesions during treatment, and the times to cessation of viral shedding, complete healing and loss of lesion-associated symptoms. Furthermore, subgroup analyses based on CD4 lymphocyte counts and the location of lesions showed that the efficacy of famciclovir was not influenced by these factors.

The present study also showed that famciclovir 500 mg twice a day, was generally well tolerated in HIV-infected patients compared with acyclovir, although no placebo-controlled group could ethically be included. This is consistent with the excellent safety profile of famciclovir demonstrated in immunocompetent individuals ^[20,21]. The most frequently reported adverse events during treatment with both acyclovir and famciclovir were headache, nausea and diarrhoea, and the incidence of these events was comparable between the two treatment groups. In addition, no clinically relevant changes in any laboratory parameters were found.

Taken together, the results of the present study demonstrate that the efficacy and tolerability of famciclovir 500 mg twice a day, for the treatment of orolabial and genital HSV infections in HIV-infected individuals are comparable with those of acyclovir 400 mg five times daily. Based on these results, famciclovir has received licensure for the treatment of mucocutaneous HSV infections in HIV-infected individuals in several international markets, including the USA.

The importance of effective treatment for recurrent HSV infections in HIV-infected patients is highlighted by the suggestion that these infections may influence HIV expression and the pathogenesis of HIV ^[6,7]. Furthermore, as HIV is shed from genital herpes lesions ^[8], and people who acquired HIV infection through sexual activity are also likely to be infected with HSV-2 ^[30], it is possible that herpetic lesions facilitate HIV transmission.

In clinical practice, the less frequent dosing regimen of famciclovir may lead to improved treatment compliance. This is of particular importance in HIV-infected individuals, who are taking multiple medications. In addition, adverse event and laboratory data profiles show famciclovir to be well tolerated by these individuals and there is no evidence to suggest that famciclovir shows any clinically significant pharmacokinetic interactions with other drugs involved in the treatment of individuals with HIV.

In conclusion, the present double-blind, multicentre study has demonstrated that twice-daily famciclovir is an effective and well-tolerated therapy for orolabial and genital HSV infections in HIV-infected individuals and provides patients with a convenient dosing regimen.