James D. Connor

A CONTROLLED TRIAL COMPARING VIDARABINE WITH ACYCLOVIR IN NEONATAL HERPES SIMPLEX VIRUS INFECTION

BACKGROUND Despite the use of vidarabine, herpes simplex virus (HSV) infection in neonates continues to be a disease of high morbidity and mortality. We undertook a controlled trial comparing vidarabine with acyclovir for the treatment of neonatal HSV infection. METHODS Babies less than one month of age with virologically confirmed HSV infection were randomly and blindly assigned to receive either intravenous vidarabine (30 mg per kilogram of body weight per day; n = 95) or acyclovir (30 mg per kilogram per day; n = 107) for 10 days. Actuarial rates of mortality and morbidity among the survivors after one year were compared overall and according to the extent of the disease at entry into the study (infection confined to the skin, eyes, or mouth; encephalitis; or disseminated disease). RESULTS After adjustment for differences between groups in the extent of disease, there was no difference between vidarabine and acyclovir in either morbidity (P = 0.83) or mortality (P = 0.27). None of the 85 babies with disease confined to the skin, eyes, or mouth died. Of the 31 babies in this group who were treated with vidarabine and followed for a year, 88 percent (22 of 25) were judged to be developing normally after one year, as compared with 98 percent (45 of 46) of the 54 treated with acyclovir (95 percent confidence interval for the difference, -4 to 24). For the 71 babies with encephalitis, mortality was 14 percent with vidarabine (5 of 36) and with acyclovir (5 of 35); of the survivors, 43 percent (13 of 30) and 29 percent (8 of 28), respectively, were developing normally after one year (95 percent confidence interval for the difference, -11 to 39). For the 46 babies with disseminated disease, mortality was 50 percent (14 of 28) with vidarabine and 61 percent (11 of 18) with acyclovir (95 percent confidence interval for the difference, -20 to 40); of the survivors, 58 percent (7 of 12) and 60 percent (3 of 5), respectively, were judged to be developing normally after one year (95 percent confidence interval for the difference, -40 to 50). Both medications were without serious toxic effects. CONCLUSIONS In this multicenter, randomized, blinded study there were no differences in outcome between vidarabine and acyclovir in the treatment of neonatal HSV infection. The study lacked statistical power to determine whether there were sizable differences within the subgroups of those with localized HSV, encephalitis, or disseminated disease.

Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak.

Enteroviruses are common causes of localized and systemic infection in patients of all ages and are the most frequent cause of epidemic aseptic meningitis in the United States. We have developed a polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) for rapid diagnosis of enteroviral meningitis. This assay was applied to 257 CSF specimens during a large community outbreak of enterovirus disease; 109 (97%) of 112 enterovirus culture-positive CSF samples contained enterovirus RNA. In addition 35 (66%) of 53 samples from patients with suspected central nervous system disease with negative or no CSF viral cultures were positive by enterovirus PCR. The enterovirus PCR detected 13 different enterovirus serotypes. PCR results are available within 24 hours compared with a mean of 6.8 days for enterovirus culture. The clinical characteristics of 141 patients with enterovirus central nervous system disease are presented. This study demonstrates the usefulness of enterovirus PCR for the rapid diagnosis of enterovirus central nervous system disease and the potential for PCR tests to shorten hospitalization.

Intravenous acyclovir for the treatment of primary genital herpes.

Thirty-one patients with first episodes of genital herpes were randomized in a double-blind fashion to intravenous treatment with saline placebo or acyclovir, 5 mg/kg body weight at 8-hour intervals, for 5 days. The median duration of viral shedding from genital lesions after the onset of therapy was significantly shorter for patients given acyclovir (2 days) than for those given placebo (13 days), p less than 0.001. Viral shedding from the pharynx, cervix, urethra, and urine were also shorter in acyclovir-treated patients. (p less than or equal to 0.01 for each comparison). Local and systemic symptoms were shortened by a mean of 5 days and healing of genital lesions by a mean of 12 days in acyclovir-treated patients. (p less than 0.01). Complications during treatment, such as extragenital lesions or urinary retention requiring catheterization, developed in four patients given placebo and in none given acyclovir. (p less than 0.05). Intravenous acyclovir substantially decreases the symptoms, duration of lesions, and complications of primary genital herpes.

Treatment of cytomegalovirus pneumonia with high-dose acyclovir

Cytomegalovirus pneumonia is a serious complication of marrow transplantation, with a 90 percent fatality rate. Acyclovir, a new antiviral agent with variable in vitro activity against cytomegalovirus, was administered to eight marrow transplant patients with biopsy-proven cytomegalovirus pneumonia; one patient survived. Doses were between 400 and 1200 mg/m2 and peak plasma levels between 47 and 316 microM were attained. Possible marrow toxicity occurred in three patients, and mild neurotoxicity occurred in one. High-dose acyclovir had mild toxicity but was not effective as treatment for cytomegalovirus pneumonia after marrow transplantation.

Vidrabine therapy of varicella in immunosuppressed patients

In order to assess further the clinical usefulness of vidarabine therapy of chicken pox, a double-blind, placebo-controlled trial was performed in immunocompromised patients. Thirty-four patients entered the trial; 19 received vidarabine and 15 the placebo. All patients had disease less than or equal to 72 hours in duration and 23 had lymphoproliferative malignancies. Both patient populations were balanced for underlying disease, preceding chemotherapy, and duration of chicken pox. No patient received zoster immune globulin. Drug therapy accelerated cessation of new vesicle formation (P = 0.015) and decreased median daily lesion counts (P = 0.06 on days 2 and 3). Fever (greater than or equal to 37.8 degrees C orally) resolved more rapidly in the drug-treated group. By day five, 70% of drug-treated subjects were afebrile in contrast to 35% of placebo recipients (P = 0.066). One drug recipient developed mild pneumonitis during the study which resolved with therapy, whereas eight placebo recipients developed varicella-related complications which led to death in two patients (P less than 0.01). These results were achieved with minimal evidence of laboratory or clinical toxicity related to drug administration. The findings indicate that vidarabine has a good therapeutic index (efficacy/toxicity) for treatment of chicken pox in immunocompromised patients when given early in the course of the infection.

Antiretroviral Concentrations in Breast-Feeding Infants of Women in Botswana Receiving Antiretroviral Treatment

BACKGROUND The magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown. METHODS We measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)-infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants. RESULTS Twenty mother-infant pairs were enrolled. Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion). Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum. The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine. The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis. CONCLUSIONS HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion. Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants.

Toxicity of Combined Ganciclovir and Zidovudine for Cytomegalovirus Disease Associated with AIDS: An AIDS Clinical Trials Group Study

OBJECTIVE To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease. DESIGN Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. SETTING Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). PATIENTS Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed. INTERVENTIONS Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. MEASUREMENTS AND MAIN RESULTS Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. CONCLUSION The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion.

Central nervous system tuberculosis in children: a review of 30 cases.

The medical records of 30 children with central nervous system tuberculosis (CNS tuberculosis) who were treated between March, 1976, and February, 1989, were reviewed. All had cranial computerized tomography scans at presentation. The mean cerebrospinal fluid leukocyte count was 200/mm3, protein 239 mg/dl, glucose 25 mg/dl and CSF/serum glucose ratio 21%. Mantoux skin tests with 5 tuberculin units were ≥10 mm induration in 50%, and chest radiographs were positive in 40% of patients. Hydrocephalus was demonstrated by cranial computerized tomography in all 30 patients (100%). Cranial computerized tomography scan demonstrating hydrocephalus is a sensitive radiographic finding in children with central nervous system tuberculosis and should be part of the early evaluation of children with suspected central nervous system tuberculosis.

Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections☆

Sixty-nine patients with first episodes and 111 with recurrent episodes of genital herpes simplex virus (HSV) infection were enrolled in a double-blind trial comparing a 5 percent topical acyclovir ointment versus placebo, polyethylene glycol (PEG). Among acyclovir recipients with first episodes of genital herpes, the mean duration of viral shedding from genital lesions, 2.0 days, mean duration of local pain or itching, 3.6 days, and mean time to healing of lesions, 11.2 days, were less than in placebo recipients 4.6, 6.7, and 15.8 days, respectively (p less than 0.05 for each comparison). Among patients with recurrent genital herpes, the mean duration of viral shedding from genital lesions was 0.8 days in acyclovir recipients compared with 1.7 days in placebo recipients (p less than 0.001). Among men with recurrent genital herpes, the mean time to crusting and healing of lesions was 3.5 and 7.5 days in acyclovir recipients compared with 5.0 and 9.7 days in placebo recipients, p = 0.03 and 0.07, respectively. No significant differences in the duration of symptoms or healing times were noted between acyclovir- and placebo-treated women with recurrent genital herpes. Acyclovir therapy was not associated with a decrease in frequency of clinical recurrences or an increase in the time of the next recurrence in patients with either first or recurrent genital herpes. Topical acyclovir appears effective in shortening some of the clinical manifestations of genital HSV infections.

Pharmacokinetics and Safety of Indinavir in Human Immunodeficiency Virus-Infected Pregnant Women

ABSTRACT Human immunodeficiency virus-infected women (n = 16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.