Original Article
A Controlled Trial Comparing Vidarabine with Acyclovir in Neonatal Herpes Simplex Virus Infection
N Engl J Med 1991; 324:444-449February 14, 1991
- Abstract
- Abstract
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. (N Engl J Med 1991; 324:444–9.)
Media in This Article
Figure 1
Survival of Babies with Neonatal HSV Infection, According to Treatment and the Extent of Disease.Figure 2
Cessation of Viral Shedding at Any Site during Treatment of Neonatal HSV Infection.Article Activity
- Article
NEONATAL herpes simplex virus (HSV) infection is associated with substantial morbidity and mortality, and its incidence is increasing in the United States.1 2 3 Since 1973, the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group has performed therapeutic trials that demonstrated decreased mortality and morbidity with intravenous vidarabine therapy.4 , 5 Nevertheless, overall, only 53 percent of surviving children were developing normally one year after treatment. The development of acyclovir provided an opportunity to improve outcome by administering a selective and specific inhibitor of viral replication.6 , 7 The current study of babies with neonatal HSV infection compared mortality and morbidity after treatment with either acyclovir or vidarabine. We also examined whether there is a difference in the therapeutic indexes of these drugs in the management of neonatal HSV infection.
Methods
Study Population
Newborns (babies less than one month of age) with virologically confirmed HSV infection were eligible for enrollment in this study. Babies were enrolled from 27 institutions from February 1981 to January 1988. Newborns were enrolled in the study irrespective of gestational age, birth weight, or concomitant medical problems.
Enrollment and Randomization
Informed consent was obtained from the newborn's parents or legal guardians and was required for entry. The study was controlled and blinded. The assignment of study medication was determined by a randomization schedule stratified according to center by the closed-envelope technique. A block randomization was employed to ensure a balanced allocation of treatment assignment after every four consecutive patients enrolled at a center. Vidarabine was administered by continuous intravenous infusion over a 12-hour period at a dosage of 30 mg per kilogram of body weight per day and at a concentration no greater than 0.7 mg per milliliter in standard intravenous fluid. The dosage of acyclovir was 30 mg per kilogram per day divided into three doses that were given every eight hours in a minimal volume of 50 ml of standard intravenous fluid over a one-hour period. Therapy was continued for 10 days. Study medications were kindly provided by Warner-Lambert/Parke-Davis (vidarabine) and Burroughs Wellcome (acyclovir).
Clinical Observations
All HSV-infected newborns were placed in one of three categories according to the extent of disease on the basis of clinical and laboratory findings at both admission and the conclusion of the study or on the basis of autopsy findings.4 , 5 First, newborns were classified as having disseminated infection if they had visceral-organ involvement, as manifested by hepatitis (defined as an aspartate aminotransferase level ≥2.5 times normal), HSV pneumonitis, or disseminated intravascular coagulopathy. Central nervous system disease was not considered disseminated involvement. Second, newborns were classified as having central nervous system infection if they had neurologic and cerebrospinal fluid abnormalities, such as pleocytosis (≥50×106 white cells per liter for preterm babies and >20×106 white cells per liter for term infants) and proteinosis (>1.2 g per liter for preterm babies and ≥0.90 g per liter for term infants), indicative of brain infection, with or without involvement of the skin, eyes, or mouth (mucous membranes). Clinical findings included hypotonia, seizures, and abnormal computed tomographic scans and electroencephalograms. Other diseases of the central nervous system, such as intraventricular hemorrhage, were recorded to prevent misclassification. Third, babies were classified as having infection confined to the skin, eyes, or mouth if they did not have evidence of other organ involvement.
During a minimum of 14 days of hospitalization (unless the subject died), newborns were assessed daily, and findings were recorded on standardized case-record forms.4 , 5 Evidence of progression of disease was evaluated, including the formation of new lesions, neurologic deterioration, pneumonia, eye disease, or other infectious complications. Associated diseases (respiratory distress syndrome and intraventricular hemorrhage) were recorded. Other medications administered during the study were documented.
A general assessment was made and neurologic status, including ascertainment of developmental milestones achieved, was determined 3, 6, 12, and 24 months after enrollment in the study. The presence of recurrent skin and ocular lesions was recorded at each visit. Morbidity was defined as follows. Normal or mild impairment included only ocular sequelae, as manifested by recurrent HSV keratoconjunctivitis. Moderate neurologic impairment included hemiparesis or a persistent seizure disorder and no more than a three-month developmental delay, as adjusted for gestational age. Severe neurologic sequelae included microcephaly, spastic quadriplegia, chorioretinitis or blindness, and a serious developmental delay of at least three months, according to the Denver Developmental Assessment Scale.
Laboratory Observations
Specimens for HSV isolation were obtained from skin vesicles, if present, nasopharynx or oropharynx, conjunctivae, urine, stool, cerebrospinal fluid, and in some cases, central nervous system tissue. These specimens were inoculated into cell cultures suitable for viral growth and isolation.4 , 5 Attempts to isolate the virus were repeated every five days during hospitalization. Isolates of HSV were typed with monoclonal antibodies.8
Sensitivity testing of randomly selected HSV isolates obtained before and after acyclovir or vidarabine therapy was performed.9 Toxicologic monitoring was performed on admission (pretreatment) and every 7 days thereafter for 28 days. In addition to the clinical assessment, laboratory tests were conducted, including complete blood counts, urinalysis, and measurement of blood urea nitrogen, serum creatinine, total bilirubin, aspartate aminotransferase, and gamma-glutamyltransferase.
Sample Size and Primary End Points
The number of babies required for the trial was determined before the study began with the use of standard procedures but was adjusted when we learned that the frequency of disease affecting the skin, eyes, or mouth increased twofold, whereas the frequency of disseminated infection decreased by the same factor as compared with previous trials.10 The total number of babies enrolled in the trial had the ability to detect a 25 percent difference between the two treatments at a significance level of 5 percent and a power of more than 90 percent. Primary response variables for evaluating drug efficacy were mortality and the morbidity of surviving patients.
Statistical Analysis
The method of Kaplan and Meier was used to calculate survival curves and actuarial estimates of the 12-month mortality and morbidity rates. A log-rank test and the rank regression procedure were used to compare the outcome of the two treatments, with stratification for the extent of disease and additional covariate adjustments.11 Chi-square tests, t-tests, and nonparametric tests were also used. All P values were calculated with a two-tailed test.
Results
Population Characteristics
A total of 210 babies with virologically proved neonatal HSV infection were entered in the study. Eight babies had disease at birth (chorioretinitis, skin lesions or scarring, and hydrocephalus) and were excluded from efficacy analyses.12 Ninety-five babies were randomly assigned to receive vidarabine, and 107 to receive acyclovir (Table 1Table 1
Characteristics at Enrollment of Mothers and Their Newborns Treated with Vidarabine or Acyclovir.*). There were neither demographic nor clinical differences (sex, race, gestational age, birth weight, age at enrollment, duration of disease before enrollment, stratification of duration of disease, type of virus, or maternal findings) between randomization groups. However, the distribution of infants according to the extent of disease was significantly different for the two treatments (P = 0.02). Notably, 28 of the 95 vidarabine recipients (29 percent) had disseminated disease as compared with 18 of the 107 acyclovir-treated babies (17 percent). Similarly, babies with skin, eye, or mouth disease accounted for 31 of the 95 vidarabine recipients (33 percent) as compared with 54 of 107 acyclovir-treated babies (50 percent).There were no differences in relevant population characteristics between treatment groups for each classification, as shown in Table 2Table 2
Characteristics of Newborns Treated with Vidarabine or Acyclovir, According to Extent of Disease.*. Overall, babies with either disease localized to the skin, eyes, or mouth or disseminated infection were enrolled in the study at a younger age than babies with encephalitis (mean [±SE] age, 11.0±0.5 vs. 16.2±0.9 days; P<0.0001). Three observations that could have influenced the outcome warrant note. First, the duration of disease before treatment according to the extent of disease averaged four to five days. Second, the frequency of prematurity ranged from 20 to 29 percent according to the extent of disease. Third, the frequency of a maternal history compatible with HSV infection was similar in both treatment groups, ranging from 33 to 48 percent for each subgroup.Mortality
Figure 1Figure 1
Survival of Babies with Neonatal HSV Infection, According to Treatment and the Extent of Disease. contrasts survival data according to the extent of disease for the first 12 months after enrollment. There were no significant differences in survival between treatment groups (P = 0.27) after adjustment for the imbalance in the extent of disease with use of a stratified analysis based on the rank regression procedure. No baby with disease localized to skin, eyes, or mouth died. The mortality rate of babies with encephalitis was 14 percent in both treatment groups. Babies with disseminated infection had a higher mortality rate: 50 percent of the vidarabine recipients died, as compared with 61 percent of the acyclovir recipients (95 percent confidence interval for the difference, –20 to 40). There was a wide confidence interval because of the small number of patients in this subgroup. Efficacy determinations were further adjusted for other important covariates, including the level of consciousness, disseminated intravascular coagulopathy, prematurity, type of virus, and extent of disease.13 The overall difference in survival remained insignificant even after the multivariate adjustments (P = 0.273). In the group with disseminated infection, all 11 deaths in the acyclovir-treated patients and 7 of the 14 deaths in the vidarabine recipients occurred during the first week of therapy.Morbidity
Morbidity was assessed after one year of life for each of the disease categories (Table 3Table 3
Assessment of Morbidity after 12 Months in Infants with Neonatal HSV Infection Treated with Vidarabine or Acyclovir.). There were no significant differences in morbidity between the two treatment groups (P = 0.83) after adjustment for the extent of disease with a stratified analysis. For vidarabine-treated babies with disease confined to the skin, eyes, or mouth, 88 percent (22 of 25) were judged to be developing normally. One vidarabine recipient had severe sequelae, one had moderate impairment, and one had a mild delay in motor development. Among the acyclovir recipients, 98 percent (45 of 46) were judged to be developing normally; 1 child had a moderate developmental delay (95 percent confidence interval for the difference, –4 to 24). The results of cerebrospinal fluid examinations and electroencephalography were normal in the four neurologically impaired children both at enrollment and after the completion of therapy.Among babies with central nervous system infection, 43 percent of those receiving vidarabine (13 of 30) were judged to be developing normally, as compared with 29 percent of those receiving acyclovir (8 of 28) (95 percent confidence interval for the difference, –11 to 39). These children had normal electroencephalograms, and none had seizures. Of the vidarabine recipients, 11 (37 percent) had severe impairment, 1 had a seizure disorder with moderate developmental delay, 4 had evidence of moderate motor impairment (17 percent), and 1 (3 percent) had mild motor impairment. Nine of the acyclovir recipients (32 percent) had severe impairment.
Finally, among the babies with disseminated disease, 58 percent of those receiving vidarabine (7 of 12) were developing normally, as compared with 60 percent of those receiving acyclovir (3 of 5) (95 percent confidence interval for the difference, –40 to 50). Five babies had severe sequelae (four of the vidarabine recipients and one of the acyclovir-treated babies), and one child from each treatment group had a three-month delay in motor development.
Overall, 67 of the 76 surviving vidarabine-treated babies and 79 of the 91 acyclovir recipients were available for follow-up after 12 months. Among surviving vidarabine recipients, 42 (63 percent) were normal, 16 (24 percent) had severe impairment, and 9 (13 percent) had visual impairment, seizures, motor impairment, or hemiparesis. Among surviving acyclovir recipients, 56 (71 percent) were judged to be developing normally, 10 (13 percent) had severe impairment, and 13 (16 percent) had visual impairment, seizures, motor impairment, or hemiparesis. According to the rank regression procedure in a multivariate data analysis, there were no statistical differences in morbidity (P = 0.9441) after adjustment for the extent of disease and the other important prognostic variables.13
Recurrent Disease
The disease progressed in four infants (2 percent) during therapy. In two babies, one from each treatment group, it progressed from central nervous system infection to disseminated disease. Two other acyclovir recipients entered with skin, eye, or mouth disease and were later found to have encephalitis. In addition, in six babies with disseminated infection, four treated with vidarabine and two receiving acyclovir, the disease spread to an additional organ after the beginning of therapy, usually the brain or the lungs.
Eight percent of the surviving babies (7 of 87) with encephalitis or disseminated disease appeared to have a recurrence of the disease within one month after completing therapy. Six babies received vidarabine, and one received acyclovir. All seven babies had relapse of central nervous system disease, as manifested by recurrent seizures and a more abnormal cerebrospinal fluid profile, with retrieval of HSV from the fluid.
Recurrent skin lesions were common within one month after therapy was completed. Eight of 42 babies who received vidarabine (19 percent) had recurrent skin lesions, as compared with 17 of 49 acyclovir-treated babies (35 percent). There were no differences in the frequency of recurrent skin lesions according to the extent of disease or treatment group. Six months after therapy the rate of recurrence had increased to 46 percent in both groups.
Adverse Reactions
Four cases of adverse clinical reactions were attributed to vidarabine and three to acyclovir. These consisted of rash (one case in each group), diarrhea (one in the vidarabine group), tremulousness (two in the vidarabine group and one in the acyclovir group), and vomiting (one in the acyclovir group).
Laboratory Data
Thirty vidarabine recipients (32 percent) and 35 acyclovir-treated babies (33 percent) had infection caused by HSV type 1. A higher proportion of vidarabine recipients than acyclovir recipients continued to shed virus during treatment (P<0.001) (Fig. 2Figure 2
Cessation of Viral Shedding at Any Site during Treatment of Neonatal HSV Infection.). Four vidarabine recipients had HSV isolated after 10 days of treatment; all were found to be developing normally on follow-up. Randomly selected viral isolates obtained before and after treatment from the same baby (20 from each treatment group) remained sensitive to acyclovir (0.2 to 0.45 μg per milliliter) and vidarabine (8 to 10 μg per milliliter).No life-threatening adverse effect of either drug on bone marrow, liver, or renal function was observed. Overall, according to the disease classification, the mean levels of hemoglobin and bilirubin, blood urea nitrogen, creatinine, and aspartate aminotransferase were not significantly different in either of the two treatment groups at any sampling interval up to 28 days after enrollment. However, the mean values for platelet and white-cell counts on days 7 and 14 were more abnormal in the vidarabine recipients than in the acyclovir recipients. Deviations from normal laboratory values were assessed for any child at any time during the study. Abnormalities were defined as a platelet count of less than 100×109 cells per liter, a white-cell count of less than 2.5×109 cells per liter, an aspartate aminotransferase level of more than 250 U per liter, a blood urea nitrogen level of more than 17.85 mmol per liter, and a creatinine level of more than 265.2 μmol per day. There was a higher rate of laboratory aberrations in vidarabine recipients (Table 4Table 4
Abnormal Laboratory Values in Infants with HSV Infection Treated with Vidarabine or Acyclovir.). No abnormal laboratory value was associated with a clinical complication.Discussion
This large multicenter, controlled trial compared acyclovir with vidarabine for the treatment of neonatal HSV infection. Overall, we detected no differences in outcome after adjusting for the extent of disease; however, the statistical power was insufficient to determine whether sizable differences existed within disease categories. Regardless, the overall number of babies who appeared to be developing normally was increased (from approximately 50 percent to 70 percent) in comparison with previous studies. Early recognition of babies with disease confined to the skin, eyes, or mouth and the early institution of therapy probably decreased the incidence of progression to more serious disease, since these factors have been shown to be important for vidarabine therapy.14 Although we were unable to establish the superiority of acyclovir for the treatment of neonatal HSV infection, considerable knowledge has emerged regarding the natural history, mortality, and morbidity of this infection, providing insight for future therapeutic strategies.
The outcome varied significantly according to the extent of disease. None of the babies with skin, eye, or mouth involvement died, and over 90 percent of these babies appeared to be developing normally on follow-up. However, severe morbidity was observed in some infants. It must be noted that neurologic impairment developed in these infants despite the presence of completely normal findings on cerebrospinal fluid and neurologic examinations both at the onset and after the completion of antiviral therapy. A widely distributed skin rash may be evidence of viremia and may lead to the seeding of target organs such as the brain, with subsequent insidious reactivation after treatment. Mortality was lower in infants with brain infection than in those with disseminated disease. However, the proportion of surviving children who appeared to function normally was similar in the two disease categories. A definitive evaluation of outcome will ultimately be based on school performance.
From these observations, we must consider how outcome can be improved. Intravenous therapy might be continued for 21 days, perhaps with the subsequent administration of oral acyclovir to prevent apparent subtle recurrences.15 , 16 Whether such an approach would have prevented the apparent relapse in 8 percent of treated babies will be difficult to prove. These babies had disease about four days before treatment, an unacceptably long period in the management of other life-threatening infections. Thus, diagnostic and therapeutic efforts should lead to the introduction of antiviral therapy earlier in the course of the disease, with the appearance of the first clinical symptoms indicative of infection.16 If therapy is instituted early in infants whose infection is confined to the skin, eyes, or mouth, the outcome is usually excellent.
Future efforts should emphasize the prevention of this disease, as discussed in the article by Whitley et al.13 in this issue of the Journal. Currently, vidarabine and acyclovir appear to be equally effective for the management of neonatal HSV infection. Because of its ease of administration, we recommend acyclovir as the treatment of choice in a dosage of 30 mg per kilogram per day for 10 days. It is our intent to define further the therapeutic usefulness of higher dosages of acyclovir for prolonged periods.
Supported by a contract (N01-AI-62554) with the Development and Applications Branch of the National Institute of Allergy and Infectious Diseases and by grants from the General Clinical Research Center Program (RR-032) and the state of Alabama.
*Members of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group include C. Laughlin, National Institutes of Health, Bethesda, Md.; R. Whitley, C. Afford, J. Benton, S.-J. Soong, A. Lakeman, S. Stagno, G. Caddell, and N. Watson, University of Alabama at Birmingham; L. Corey and S. Burchett, University of Washington, Seattle; A. Arvin, C. Prober, and A. Yeager (deceased), Stanford University, Stanford, Calif.; A. Nahmias and H. Keyserling, Emory University, Atlanta; D. Powell, M. Hilty, and M. Brady, Ohio State University, Columbus; J. Connor, S. Spector, and R. Straube, University of California, San Diego; S. Stan, R. Fleisher, S. Plotkin, and J. Puck, University of Pennsylvania, Philadelphia; P. Wright, K. Edwards, W. Gruber, C. Porch, and R. Bradley, Vanderbilt University, Nashville; C. Sumaya, S. Lipton, and V. Novelli, University of Texas, San Antonio; P. Shackelford, Washington University, St. Louis; V. San Joaquin and M. Marks, University of Oklahoma, Norman; R. Steele and R. Jacobs, University of Arkansas, Little Rock; M. Levin, University of Colorado, Denver; R. Andersen and J. Bale, University of Iowa, Iowa City; F. Hayden and J. Kattwinkel, University of Virginia, Charlottesville; F.Y. Aoki and G.W. Hammond, University of Manitoba, Winnipeg, Canada; L. Dunkle, S. Toce, W. Keenan, S. Nagvi, R. Lusk, G. Gale, and D. O'Connor, St. Louis University, St. Louis; M. Kleiman, K. Fife, and J. Gaebler, University of Indiana, Bloomington; R. Pollard, University of Texas, Galveston; R. Alexander, Centers for Disease Control, Atlanta; G. Ray, V. Fulginiti, and Z. Shehab, University of Arizona, Tucson; M. Myers, C. Harrison, L. Stanberry, and D. Bernstein, University of Cincinnati, Cincinnati; J. Modlin, Johns Hopkins University, Baltimore; M. Hirsch and R. Schooley, Massachusetts General Hospital, Boston; A. Chow and D. Scheifele, University of British Columbia, Vancouver, Canada; R. Clemons, Burroughs Wellcome Company, Research Triangle Park, N.C.; and R. Buchanan and S. Thornton, Warner-Lambert, Morris Plains, N.J.
Source Information
From the Departments of Pediatrics, Microbiology, Medicine, and Biostatistics, University of Alabama at Birmingham, Birmingham (R.W., C.A., S.-J.S.); the Department of Pediatrics, Stanford University, Stanford, Calif. (A.A., C.P.); the Department of Medicine, University of Washington, Seattle (S.B., L.C.); the Department of Pediatrics, Ohio State University, Columbus (D.P.); the Department of Pediatrics, University of Pennsylvania, Philadelphia (S.P., S.S.); the Department of Pediatrics, University of California, San Diego (J.C.); the Department of Pediatrics, University of Arkansas, Little Rock (R.J.); and the Department of Pediatrics, Emory University, Atlanta (A.N.).
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