Abstract

To determine the efficacy and safety of valacyclovir (500 mg twice daily) for the suppression of recurrent genital herpes simplex virus infections in human immunodeficiency virus (HIV)–infected subjects, a randomized, double-blind, placebo-controlled, multicenter international trial was conducted. A total of 293 HIV-seropositive subjects receiving antiretroviral therapy were enrolled. The proportion of subjects who did not have a recurrence of genital herpes at 6 months was 65% among valacyclovir recipients versus 26% among placebo recipients (relative risk, 2.5; 95% confidence interval, 1.8–3.5). The time to first genital herpes recurrence was significantly shorter in the placebo group (median, 59 days) than in the valacyclovir group (median, >180 days). Valacyclovir was well tolerated; the incidence of adverse events for the 2 treatment groups was similar when the duration of treatment was considered. There were no episodes of thrombotic microangiopathy. Valacyclovir was safe and effective for the suppression of recurrent genital herpes infection in HIV-infected individuals

Despite the high frequency and severity of herpes simplex virus (HSV) infections often observed in persons infected with human immunodeficiency virus (HIV), few studies have investigated the effect of anti-HSV suppressive therapy in this population, and no antiherpetic drug has been specifically approved by the US Food and Drug Administration for this indication. Suppressive regimens for HSV infections in patients with HIV infection have been extrapolated from recommendations on the basis of other experience in immunocompromised populations. In profoundly immunocompromised patients, intravenous therapy with acyclovir has been shown to be effective for the treatment of mucocutaneous herpes [1]. Subsequently, oral acyclovir was shown to suppress genital herpes in a healthy population [2]. The results of small studies and anecdotal reports have suggested that immunocompromised patients may require higher oral doses of acyclovir for adequate suppression [3]

Valacyclovir was developed to improve the bioavailability of acyclovir and to reduce the need for frequent dosing regimens [4]. In immunocompetent individuals, 500 or 1000 mg of valacyclovir once daily significantly delayed or prevented at least 70% of recurrences, compared with placebo, in a 1-year study [5]. The results of a 48-week study that compared valacyclovir with acyclovir for HSV infection in HIV-infected individuals who had a history of 1 genital HSV recurrence within 1 year of study and ⩾100 CD4+ cells/μL suggested that valacyclovir (500 mg twice daily) suppressed episodes of recurrent genital herpes at a rate comparable to acyclovir (400 mg twice daily) [6]. Therefore, we conducted a placebo-controlled study to investigate the efficacy and safety of valacyclovir administered twice daily for 6 months to people with HIV infection and recurrent genital herpes

Materials and Methods

DesignThis was an international, randomized, double-blind trial of valacyclovir (500 mg twice daily) compared with placebo. The study was conducted between May 1999 and January 2002. Subjects who met inclusion criteria were randomized in a 2:1 allocation (valacyclovir:placebo) to receive either oral valacyclovir (500 mg) or matching placebo twice daily, for up to 6 months. At the randomization visit, subjects initiated the assigned treatment and were instructed to return to the clinic monthly and at their first recurrence of genital herpes. Subjects with a clinically confirmed recurrence discontinued the assigned study drug and were treated with valacyclovir (1 g twice daily) for 5 or 10 days until they were healed. After treatment of the recurrence, subjects resumed suppressive therapy with open-label valacyclovir (500 mg twice daily) for the remainder of the 6-month study period

Study populationMen and women aged ⩾18 years with a history of HIV infection, a stable antiretroviral regimen for at least 2 months, and a history of symptomatic recurrent genital herpes in the genital, perianal, or buttocks area were eligible. Subjects must have had ⩾4 recurrences of genital herpes in the preceding 12 months or in the year before initiating long-term suppressive antiherpetic therapy. Subjects receiving suppressive antiherpetic therapy must have discontinued therapy at the randomization visit. Exclusion criteria included significant hepatic or renal impairment, malabsorption, or vomiting; a history of thrombotic microangiopathy; and hypersensitivity to acyclovir, valacyclovir, famciclovir, or ganciclovir. Informed consent was obtained from patients prior to enrollment into the study, in accordance with International Conference on Harmonization guidelines, Good Clinical Practice guidelines, the human experimentation guidelines of the US Department of Health and Human Services, and relevant local authorities. Institutional review board or ethics committee approval was obtained at each study site

ProceduresAfter informed consent was obtained, subjects were examined, and the history of herpes and HIV infections was reviewed. Blood and urine samples were collected for baseline values of HIV and HSV-2 serological testing, routine hematologic testing and clinical chemistry tests, CD4+ and CD8+ cell counts, plasma HIV RNA levels, a urine pregnancy test for women, and dipstick urinalysis. Subjects completed diary cards with information about dates of recurrences of genital or oral herpes, concomitant medication, missed doses of study drug, and adverse events. Blood samples for hematologic testing, chemistry tests, and HIV RNA levels were obtained at each monthly visit; CD4+ and CD8+ cell counts were done only at month 3 and the end of study

In the event of a recurrence of genital herpes, subjects were instructed to obtain a swab of the suspected lesion and to return to the clinic within 24 h of the onset of signs or symptoms. If a subject had a prodrome but no lesions, the subject was instructed to return for reevaluation the following day. If the clinician observed a herpetic lesion, the assigned treatment was discontinued, and open-label treatment with oral valacyclovir (1 g twice daily) for 5 days was initiated. An additional virus culture was obtained from the lesion, and blood was collected for HIV RNA testing. Subjects returned on day 5 to evaluate healing, and a second 5-day treatment course was dispensed as needed. Those whose lesions were not healed by day 10 were managed at the discretion of the investigator. For subsequent recurrences of herpes during the 6-month study, subjects could initiate treatment with valacyclovir (1 g twice daily) during the prodrome stage and after clinical evaluation

HSV-2 isolates from genital specimens obtained during recurrences were sent to ViroMed Laboratories for the evaluation by plaque reduction assay of the in vitro sensitivity of HSV-2 isolates to acyclovir [7]. The HIV RNA polymerase chain reaction (PCR) assay used in our study was the HIV RNA PCR Amplicor Standard 1.0 assay (Roche Diagnostics). The linear range of quantification for this standard assay is 400–750,000 copies/mL. HIV infection was documented by antibody testing. HSV-2 confirmation was determined at the time of initial screening via Western blot and/or MRL HerpeSelect Immunoblot (Focus Technologies) [8]

Statistical analysisThe sample size of 288 subjects was based on a proportions analysis of the primary end point (recurrence of genital herpes) to provide 90% power. If it was assumed that 25% of placebo-treated subjects and 45% of valacyclovir-treated subjects would be classified as recurrence-free at 6 months, a total of 288 subjects in a 2:1 allocation (192 valacyclovir:96 placebo) would provide 90% power to detect a difference between valacyclovir and placebo for the recurrence of genital herpes [9]. The sample-size calculation was based on α=0.05 and a 2-sided test statistic

All statistical tests were 2-sided and were stratified by center grouping. It was prospectively determined to group together by country any centers that recruited <12 subjects. Data were analyzed from the population of subjects who received at least 1 dose of study drug (intent-to-treat [ITT]) and the per protocol population (patients without any major protocol deviations). Because the results of the analyses were similar between these populations, the results presented here are from the ITT population

The primary efficacy end point was the proportion of subjects who did not have a recurrence of genital herpes at 6 months in the valacyclovir group, compared with that in the placebo group. Subjects who withdrew before 6 months without a recurrence were assumed to have had a recurrence. The response rates were compared between the treatment arms using the Cochran-Mantel-Haenzel test, adjusted for center grouping

The primary end point was further explored, considering the time to the first recurrence of genital herpes. The time to first genital herpes recurrence was measured as the time from randomization until the onset of a macular or papular lesion. The time to first recurrence was compared between treatment groups using the log-rank test, stratified by center grouping. Subjects who did not reach the end point had censored event-free times equal to the last day that the absence of the end point was confirmed by the investigator. Similarly, the time to the first culture-positive recurrence of genital herpes (the secondary end point) and the time to the first recurrence of oral herpes were compared between treatment groups using the log-rank test, stratified by center grouping

An exploratory analysis of the time to the first recurrence of genital herpes was done using Cox’s proportional-hazards model to consider the effect of the following covariates: sex, age, recurrence history (⩽8 or >8 recurrences), baseline HIV RNA copies/mL, race (white or other), baseline Centers for Disease Control and Prevention (CDC) classification of HIV disease (A, B, or C), baseline CD4+ cell count, time since primary episode (<5 or ⩾5 years), and previous suppressive therapy (yes or no)

In addition to these prespecified analyses, a post hoc analysis was done on the proportion of subjects who did not have culture-positive recurrences and those who did not have oral recurrences during the study. The response rates were compared between the treatment arms using the Cochran-Mantel-Haenzel test, adjusted for center grouping

Summary statistics of log10 HIV RNA levels and CD4+ cell counts by study visit were presented as actual values and as the change from randomization. CD4+ cell counts and stage of HIV disease (CDC classification) were summarized by study visit. The reported safety measures were adverse events and laboratory data

Results

Participant characteristicsTwo hundred and ninety-three subjects were randomized at 25 study sites in the United States, Canada, and the United Kingdom: 99 in the placebo group and 194 in the valacyclovir group. The demographics and baseline clinical characteristics were similar between valacyclovir and placebo recipients (table 1). The majority of the subjects were white (64%) and male (88%), which is consistent with the demographics of HIV infection in developed countries. Nearly half (49%) of all subjects had received long-term suppressive antiherpetic therapy during the year before randomization. Among these subjects, the median number of genital herpes recurrences per year prior to initiating suppressive therapy was 5 in both treatment groups (range, 4–40). For all other subjects, the median number of recurrences during the preceding 12 months was 4 in the placebo group (range, 4–9) and 5 in the valacyclovir group (range, 4–20)

Table 1

Demographic characteristics of patients randomized to receive placebo or valacyclovir

Table 1

Demographic characteristics of patients randomized to receive placebo or valacyclovir

The treatment groups were comparable for severity of HIV infection. The median baseline plasma HIV RNA level was 2.6 log10 copies/mL in each treatment group (range, 2.6–5.9 log10 copies/mL), with 43% of the population enrolled having detectable HIV RNA loads (⩾400 copies/mL). Twenty-five percent of all subjects had a CD4+ cell count <200 cells/μL at entry (median, 313 and 336 cells/μL for the placebo and valacyclovir groups, respectively). Thirty-eight percent of subjects enrolled were classified as having CDC category C HIV disease at baseline, and these were similarly distributed among treatment groups. At baseline, 94% and 93% of subjects receiving placebo and valacyclovir, respectively, were also receiving ⩾3 antiretroviral medications

Of the 293 subjects randomized, 231 (79%) completed the study and 62 (21%) discontinued prematurely. Seventeen percent of subjects in each treatment group discontinued during the double-blind phase. The most common reason for discontinuation was loss to follow-up (8% in the placebo group and 9% in the valacyclovir group). Only 3% of each treatment group withdrew because of an adverse event during the double-blind phase

Suppression of HSV recurrencesA total of 89 subjects had a recurrence of genital herpes during the double-blind phase of the study (56/99 [57%] in the placebo group and 33/134 [17%] in the valacyclovir group). The proportion of subjects who had no recurrence of genital herpes at 6 months was significantly higher in the valacyclovir group than in the placebo group (65% vs. 26%; relative risk, 2.5; 95% confidence interval [CI], 1.8–3.5) (table 2)

Table 2

Efficacy of oral valacyclovir for the suppression of genital herpes in human immunodeficiency virus–seropositive patients

Table 2

Efficacy of oral valacyclovir for the suppression of genital herpes in human immunodeficiency virus–seropositive patients

The time to the first recurrence of genital herpes was significantly shorter in the placebo group (median, 59 days) than in the valacyclovir group (median, >180 days) (hazard ratio [HR], 5.0; 95% CI, 3.30–7.7) (table 2; figure 1A). A similar result was observed for the time to the first culture-positive recurrence (HR, 16.7; 95% CI, 7.7–33.3) (table 2; figure 1B). Thirty-eight percent (38/99) of placebo recipients, compared with 4% (8/194) of valacyclovir recipients, reported a culture-positive recurrence during the study

Figure 1

A Kaplan-Meier plot of the time to the first recurrence of genital herpes. B Kaplan-Meier plot of the time to the first culture-positive recurrence of genital herpes. C Kaplan-Meier plot of the time to the first recurrence of oral herpes

Figure 1

A Kaplan-Meier plot of the time to the first recurrence of genital herpes. B Kaplan-Meier plot of the time to the first culture-positive recurrence of genital herpes. C Kaplan-Meier plot of the time to the first recurrence of oral herpes

At baseline, 36% of placebo recipients, compared with 29% of valacyclovir recipients, reported a history of HSV infections in the lips/facial region. The time to the first recurrence of oral herpes was also significantly shorter in the placebo group (HR, 5.3; 95% CI, 2.0–14.3) (table 2; figure 1C). Fifteen percent (15/99) of subjects who received placebo, compared with 4% (8/194) of subjects who received valacyclovir, reported a recurrence of oral herpes during the study

None of the covariates we examined (sex, age, recurrence history, baseline HIV load, race, baseline CDC classification, baseline CD4+ cell count, time since primary episode, and previous suppressive therapy) was predictive of the time to the first recurrence of genital HSV (data not shown). Of the 144 subjects who had received previous suppressive therapy (53 in the placebo group and 91 in the valacyclovir group), 12 (23%) and 60 (66%), respectively, had not had a recurrence of genital HSV at 6 months. Of the 149 patients who reported no suppressive therapy during the previous year (46 in the placebo group and 103 in the valacyclovir group), 14 (30%) and 66 (64%), respectively, had not had a recurrence of genital HSV at 6 months

The median plasma HIV RNA level was 2.6 log10 copies/mL at baseline in each treatment group. For the subjects who remained in the double-blind phase at 6 months, HIV load results were available for 32 placebo recipients and 140 valacyclovir recipients. This difference reflects the number of placebo recipients who discontinued the double-blind phase because of a recurrence of genital herpes. At month 6, the median virus load was unchanged from baseline and remained at 2.6 log10 copies/mL for both treatment groups. Furthermore, for the 40 placebo and 19 valacyclovir recipients with HIV load samples collected on the first day of a genital herpes recurrence, the median virus load was unchanged from the level at the randomization visit. Similarly, there was no clinically significant change in CD4+ cell count or CDC classification at 6 months for subjects who remained in the double-blind phase of the study

SafetyDuring the double-blind phase, subjects received placebo for a median of 59 days (range, 1–195 days) and valacyclovir for a median of 172 days (range, 3–236 days). Eighty percent of subjects assigned to receive valacyclovir completed 6 months of treatment. Eighty-seven subjects received open-label valacyclovir recurrence as either episodic or suppressive therapy; the median duration of open-label treatment was 133 days (range, 11–193 days)

The proportion of subjects who experienced an adverse event during the double-blind phase was 58% for the placebo group and 75% for the valacyclovir group, regardless of a causal association with treatment. Because subjects ceased double-blind therapy once they had a recurrence of genital herpes, the total period of double-blind monitoring was shorter in the placebo group than in the valacyclovir group, which may explain the increased number of adverse events seen in the valacyclovir group during the double-blind phase. To explore whether differences in adverse event rates reflected differences in the duration of exposure to placebo or valacyclovir, adverse event rates per exposure day were calculated for both treatment groups. Adverse event rates per day were similar between treatment groups during the double-blind phase: 2.2% for placebo and 2.0% for valacyclovir. In addition, a Kaplan-Meier plot of the time to the first adverse event demonstrated a similar incidence of adverse events over time (data not shown)

The most frequently reported adverse events for valacyclovir versus placebo were headache (13% vs. 8%), diarrhea (12% vs. 12%), upper respiratory tract infection (9% vs. 7%), vomiting (3% vs. 9%), fatigue (8% vs. 5%), influenza (8% vs. 3%), nasopharyngitis (8% vs. 2%), nausea (8% vs. 8%), and rash (8% vs. 1%). Although rash was reported more often in valacyclovir than placebo recipients, an analysis of all reports of rash (e.g., unspecified rash, generalized or genital rash, allergic dermatitis, erythema, or urticaria) did not reveal any uniform clinical presentation, consistent time to rash onset, or other trend in the data to suggest a causal relationship between the administration of valacyclovir and rash. Study medication was withdrawn for only 1 subject receiving valacyclovir who reported rash during the double-blind phase of the study

Three percent of subjects in each treatment group reported a serious adverse event during the double-blind phase of the study. The most commonly reported serious adverse events involved gastrointestinal disorders (appendicitis, pancreatitis, nausea, and vomiting). Only 3 serious adverse events, all in the same subject, were considered by the investigator to be attributable to valacyclovir. This subject had a history of abnormal liver function test results and had elevated aspartate transaminase and alanine transaminase levels (388 and 692 U/L, respectively) ∼1 month after the initiation of double-blind study medication (valacyclovir). Valacyclovir was stopped for ∼3 weeks, highly active antiretroviral treatment (HAART) was also interrupted, and the transaminase abnormalities were resolved 2 weeks later. Approximately 3 and 5 weeks after resuming study medication, the subject experienced pyrexia and vomiting, respectively; both events were considered by the investigator to be possibly related to valacyclovir

There were no reports of thrombotic microangiopathy, thrombocytopenic purpura, or hemolytic-uremic syndrome. No deaths were reported during the study. Hematologic and clinical chemistry values across treatment groups were similar over time

HSV resistance testingFifty HSV-2 isolates from 48 subjects who had a recurrence of genital herpes were obtained during the study. No pretreatment isolates were collected. No HSV-1 was isolated from genital specimens. Acyclovir-resistant isolates (IC50, >2 μg/mL) were identified in 3 subjects (6.0%), all of whom had CDC stage C HIV disease. Two subjects randomized to the valacyclovir group had a recurrence of genital herpes caused by a resistant isolate after 3 and 10 weeks, respectively, of valacyclovir (IC50, 34.71 and 12.37 μg/mL, respectively). One of these subjects had received suppressive antiherpetic therapy, for ∼1 year prior to entry. The third subject, who had been randomized the to placebo group, had a recurrence of genital herpes caused by a sensitive isolate after 4 weeks of double-blind medication (IC50, 0.06 μg/mL) and a second recurrence caused by a resistant isolate after ∼18 weeks of open-label valacyclovir (IC50, 30.3 μg/mL). This subject had received suppressive antiherpetic therapy for ∼4 years prior to study entry. All 3 subjects responded clinically to a 5-day course of valacyclovir (1000 mg twice daily) and did not have any further recurrences during the study

Discussion

Ours is the first multicenter, placebo-controlled study to demonstrate the efficacy of suppressive antiherpes therapy in a heterogeneous population of individuals with HIV infection. Our study population included some individuals with advanced HIV infection, despite concurrent antiretroviral therapy with HAART. Twenty-five percent of the study population had CD4+ cell counts <200 cells/μL, 43% had plasma HIV RNA levels ⩾400 copies/mL, and 38% of subjects had CDC stage C HIV disease at baseline

Twenty-six percent of subjects who received placebo and 65% of subjects who received valacyclovir had not had a recurrence by 6 months, with a median time to first recurrence of 59 days for placebo recipients and >180 days for valacyclovir recipients. Subjects who received valacyclovir were 2.5 times more likely to be free of recurrence at 6 months than those who received placebo, and, at any given time, subjects who received placebo were 5 times more likely to have a recurrence than those who received valacyclovir. In addition, subjects who received placebo were 17 times more likely to have a culture-positive recurrence than those who received valacyclovir and were 5 times more likely to have a recurrence of oral herpes at any time

A previous 48-week study of valacyclovir for genital herpes suppression in HIV-infected persons enrolled subjects with a history of 1 recurrence within 1 year of study entry [6]. It is believed that most physicians and patients will be reluctant to initiate long-term suppressive therapy for a low recurrence rate of 1 or 2 outbreaks per year. A rate of ⩾3 recurrences per year would probably more resemble the use of long-term suppressive therapy in clinical practice. To increase the probability of reaching an end point in our 6-month study, subjects were required to have had a history of ⩾4 recurrences during the previous year. In addition, when considering patients for suppressive therapy in clinical practice, the decision should not be based on the frequency of recurrences alone. The severity of recurrences and the potential for the activation of HIV in this patient group are also important factors

The population was heterogeneous with regard to the use of suppressive antiherpes therapy prior to study entry. The proportion of subjects who reported the use of prior suppressive antiherpes therapy was fairly well balanced between the treatment groups. It is possible that the HSV recurrence history data provided by subjects who received prior suppression was less reliable than the data provided by the treatment-naive patients, which potentially introduced selection bias into the results. The multivariate analysis of the time to the first recurrence of genital herpes was not influenced by the presence of prior suppressive therapy

Famciclovir, another antiherpetic nucleoside analogue, is available in the United States for the episodic treatment of mucocutaneous herpes recurrences in patients with HIV but is not approved for suppressive therapy in this population [10]. Famciclovir has been studied in HIV-infected subjects in an 8-week placebo-controlled crossover trial in 48 patients. Treatment reduced the number of days of symptoms and viral shedding; 29 subjects completed the 8-week trial [11]

In a study completed prior to the introduction of HAART, HSV reactivation was associated with higher plasma HIV RNA levels, and the suppression of HSV was associated with a decrease in plasma HIV RNA levels [12]. In our study, there were no clinically important differences between groups or over time in HIV RNA levels, CD4+ cell counts, or HIV stage. The concomitant use of HAART in subjects in the present study may explain the lack of effect seen in plasma HIV RNA loads. Another limitation of the study was the use of the Amplicor assay to measure HIV load. It is possible that changes could have occurred in the range of 50–400 copies/mL, which more sensitive assays might have detected

When the duration of study medication exposure was considered, there was no evidence of an increased incidence of adverse events in the valacyclovir group than in the placebo group. Rash was reported more often in the valacyclovir group; however, there was no apparent causal relationship to valacyclovir, and treatment modifications generally were not required. In addition, there were no reports of deaths or thrombotic microangiopathy. Thrombotic microangiopathy has been seen in previous studies of severely immunocompromised HIV-infected patients (CD4+ cell count <50 cells/μL) receiving high doses of valacyclovir over long periods of time (median, 54 weeks; range, 8–77 weeks) [13, 14]. The absence of thrombotic microangiopathy–like syndrome during our 6-month suppression study supports the safety of valacyclovir (500 mg twice daily) for the suppression of genital herpes in HIV-infected individuals. Data beyond 6 months at this dose level in this population are not available

The development of HSV resistance to acyclovir or other antiherpetic agents is rare in the immunocompetent population. However, acyclovir resistance is more frequent in immunocompromised subjects. In one study, the incidence of resistant HSV isolates was reported to be 6.3% among immunocompromised subjects, including patients with cancer; bone marrow, heart, and/or lung transplant recipients, and HIV-infected subjects [15]. A CDC surveillance study reported an incidence of acyclovir-resistant HSV strains of 5.3% in HIV-infected individuals [16]. Because of the possible emergence of drug resistance to acyclovir after the use of valacyclovir for genital herpes suppression in the HIV-infected subjects, we evaluated acyclovir resistance. The resistance rate in our study (6%) was similar to that reported in the literature. In addition, none of the patients with acyclovir-resistant isolates in the present study developed clinical disease that was refractory to therapy

In summary, we have established an important treatment option for the management of genital herpes in HIV-infected patients. A convenient, twice-daily regimen of valacyclovir suppressive therapy was well tolerated in HIV-infected individuals and effectively reduced the risk of genital and oral HSV recurrences

Valacyclovir International HSV Study Group members

Study group members include Stephen L. Becker and William Lang (ViRx, San Francisco, CA); Marcus A. Conant (Conant Medical Group, San Francisco, CA); Susan J. Jacobson (Alta Bates Medical Center, Berkeley, CA); Peter W. Kraus (Kraus Medical Partners, Los Angeles, CA); Peter Wolfe (Pacific Oaks Research, Beverly Hills, CA); Michael Denker (Advanced Biomedical Research, Hackensack, NJ); Jeffrey Dinsmore (Infectious Disease Consultants, Altamonte Springs, FL); Marc S. Kaufman (Palm Beach Research Center, West Palm Beach, FL); Gerald Pierone (Treasure Coast Infectious Disease Center, Vero Beach, FL); Alvan E. Fischer (ClinCare, Providence, RI); John Gnann (University of Alabama at Birmingham); Joseph G. Jemsek (Jemsek Clinic, Huntersville, NC); Anne Marie Rompalo (Johns Hopkins University, Baltimore, MD); Thomas Rushton (Marshall University School of Medicine, Huntington, WV); Clement Olivier and Eric Lefebvre (Clinique Medical Actuel, Montreal, Quebec, Canada); Anita R. Rachlis (Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada); Barbara Romanowski (Edmonton, Alberta, Canada); Margaret Johnson (Royal Free Hospital, London, UK); Barry S. Peters (Guy’s and St. Thomas’ Hospital, London, UK); and Celia J. Skinner (Royal London Hospital, London, UK)

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Presented in part: 40th annual meeting of Infectious Diseases Society of America, Chicago, 24–27 October 2002 (abstract 653)
Financial support: GlaxoSmithKline
Conflict of interest: A.W. has received research support from and was a consultant for GlaxoSmithKline. T.W. has disclosed a financial relationship with GlaxoSmithKline
Study group members are listed after the text