Mar 27, 1982 - SHEENA SUTHERLAND. Department of Virology, Middlesex Hospital Medical School, London. A. PAUL FIDDIAN. Department of Clinical ...
Saturday 27 March
INTRAVENOUS ACYCLOVIR TREATMENT FOR PRIMARY GENITAL HERPES ADRIAN MINDEL
MICHAEL W. ADLER
Academic Department of Genito-urinary Medicine, Middlesex Hospital Medical School, London W1
SHEENA SUTHERLAND
Department of Virology, Middlesex Hospital Medical School,
London
marked systemic reaction. In addition, we considered that such a preparation was the most appropriate for establishing baseline information about the drug, because its use circumvents problems associated with gastrointestinal tract absorption. We conducted a randomised, double-blind, placebo-controlled trial of intravenous acyclovir in 30 patients having their first attack of genital HSV. This report is concerned only with the first attack. The information on recurrences will be presented in a future paper. Patients and Methods
A. PAUL FIDDIAN
Department of Clinical Immunology and Chemotherapy, Wellcome Research Laboratories, Beckenham, Kent
patients with a severe first attack of genital herpes were treated with intravenous acyclovir in a randomised, double-blind, placebo-controlled trial. The medians for healing time, duration of vesicles, new lesion formation, viral shedding, and all symptoms were significantly shorter in patients treated with acyclovir than in the controls. No important side-effects were noted. Intravenous acyclovir seems to be a safe and effective therapy for patients having their first attack of genital herpes. Summary
30
Introduction GENITAL infection with herpes simplex virus (HSV) is a major and increasing cause of morbidity in many countries. 10 800 such cases were reported from sexually transmitted disease clinics in the U.K. in 1980, a rise of 60% over the previous five years.’ The primary infection may be severe enough to warrant hospital admission, and recurrences may be frequent and may create profound morbidity and sexual dysfunction.2,3 There is also the possible association with carcinoma of the cervix4 and with neonatal infection, which can be fatal. Inability to treat genital herpes is reflected in the diversity and number of remedies that have been used.The recent introduction of acyclovir, an antiviral agent of low toxicity with high specificity against herpesviruses, has raised hopes for an effective therapy against genital HSV. 7,8 The parenteral form of acyclovir has been effective in the treatment of disseminated herpetic infections in in immunocompetent and immunocompromised patients9 8 with varicella zoster.8 patients The aim of the present study was to find out whether acyclovir decreased the length and severity of the primary attack of genital herpes. We decided to use an intravenous preparation since the infection is often accompanied by
1982
Study Population Patients with a first attack of genital herpes infection severe enough to warrant hospital admission, who presented to the department of genito-urinary-medicine, Middlesex Hospital, within 6 days of the first appearance of genital sores were invited to participate in the trial. Informed consent was obtained from all patients. Criteria for exclusion were a history of previous genital herpes, age less than 16 years, renal impairment, or specific antiviral therapy in the previous 14 days. Females were excluded if they were pregnant or were not using adequate contraceptive measures (oral contraception or intrauterine device).
Patient Management All patients were admitted for 7 days or longer if clinically indicated. On admission blood was taken for full and differential blood count, erythrocyte sedimentation rate, urea and electrolytes, creatinine, and liver function tests (LFTs). These tests were repeated on the 4th and 7th days of the hospital stay. Specimens were taken for Neisseria gonorrhoeae, Trichomonas vaginalis, and Candida albicans, and serological tests for syphilis were done. Patients’ clinical status was assessed by the use of a standardised recording schedule on admission and daily for 7 days, and then twice weekly until healing occurred. All the clinical assessments were done by one person (A. M.). Patients were prescribed frequent saline baths and analgesia as required. Fluid balance was monitored
continuously. After complete healing had occurred patients were requested to return to the clinic if they had recurrences and, in any event, 6 months after the initial episode. On each follow-up visit a full history was taken and an examination performed.
Drug Administration Except for the first 4 patients who received the drug or placebo as injection, the rest were given slow (45-60 min) infusions through an indwelling intravenous cannula every 8 h for 15 doses, each dose being 5 mg/kg body weight. The placebo used was mannitol. The drug and placebo were packaged in indistinguishable a
bolus
vials with individual code numbers, blind.
so
that the trial
8274
was
double
698 TABLE I-PATIENT DEMOGRAPHY
were due to dihydrocodeine. 7 patients (4 and 3 placebo) had abnormal LFTs during the acyclovir abnormalities were mild and short-lived These study period. and did not differ between the two groups. 1 of the patients who received acyclovir in a bolus had a transient rise in urea and creatinine which returned to normal in 48 h. All subsequent patients received acyclovir or placebo by slow intravenous infusion.
symptoms
Healing Virology obtained on admission and on days 12 and 28 for herpes antibody estimation. Complement fixing antibody to HSV was assayed in microtitre plates by the use of the method of Bradstreet and Taylor. 10 Patients whose first serum specimen had antibody titres of < 1/2 were classified as having primary infections; all others were considered to have initial infections of the genital Serum
was
tract.
Swabs for viral culture were taken from all lesions and, in females, from the cervix even if no infection was evident. These were repeated daily for the first 7 days and then twice weekly until complete healing occurred. Swabs were sent to the laboratory in transport medium and inoculated into cultures of human embryo lung fibroblasts which were incubated at 37°C and examined daily for 5 days. The first isolate from each patient was submitted to neutralisation tests for the identification of herpes simplex virus. Further isolates were identified by their cytopathic effects.
Time
(Table II)
The times taken for healing in different anatomical sites (external lesions, internal lesions, and all lesions combined) were compared for the acyclovir and placebo group. The median healing time for all lesions was significantly shorter in the acyclovir group (7 days) than in the placebo group (14 days). In half of the patients treated with acyclovir all lesions had healed by the 7th day compared with less than 10% who received placebo (fig. A). The median healing times for internal lesions was 5’5days in the treated group, compared with 10 days in the control group. However, there was 110 significant difference in the
duration of external lesions between the two groups. In females acyclovir was associated with a shorter healing time for internal lesions and all lesions combined, but not for external ones.
Analysis of Results
New Lesion Formation, Duration
A one-tailed log rank test was used for all variables to compare the group with the placebo group. 1 Medians were used because many of the variables had a skewed distribution.
The median duration of new lesion formation was 0 days in the acyclovir group, compared with 2 days in the placebo group. No new lesions appeared in the acyclovir group after the second day (fig. B), but they continued to appear for up to 15 days in the controls. In females the duration of new lesion formation was also shorter in the acyclovir-treated patients than in the controls. Vesicles lasted a median of 3 days in patients treated with acyclovir compared with 5 days in the placebo group. Vesicles persisted for up to 8 days in patients treated with acyclovir, and up to 16 days in placebo-treated patients (fig. C). Among females there was no significant difference in the duration of vesicles between the two groups. Improvement in symptoms was less -impressive. The median duration of pain in the treated and control groups was identical, whether all patients or females alone were considered; however, pain lasted longer in placebo-treated patients than in those receiving acyclovir (fig. D). Among females alone there was little difference between the acyclovir and control groups in the duration of all symptoms, but when all patients were considered the median duration of all symptoms in the acyclovir-treated patients was 6’5days compared with 8 -5days in the placebo group. In addition all acyclovir-treated patients were symptom-free by the 1Oth day and this contrasts with placebo-treated patients, whose symptoms persisted for up to 20 days (fig. E).
acyclovir
Results Patient Characteristics
(Table I) drug
15 Patients received the
and 15 placebo. Their infections were classified as primary or initial. 20 patients had primary infections and their reciprocal complement fixing antibody titres rose from
