Stuart E. Starr

Predictors of Morbidity and Mortality in Neonates with Herpes Simplex Virus Infections

BACKGROUND In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates. METHODS Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection. RESULTS AND CONCLUSIONS There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences.

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.

Ganciclovir Treatment of Symptomatic Congenital Cytomegalovirus Infection: Results of a Phase II Study

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

COMBINATION THERAPY WITH EFAVIRENZ, NELFINAVIR, AND NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS IN CHILDREN INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS TYPE 1

BACKGROUND Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.

Oka/Merck varicella vaccine in healthy children: final report of a 2-year efficacy study and 7-year follow-up studies

A large double-blind, randomized, placebo-controlled trial of live attenuated Oka/Merck varicella vaccine was conducted among healthy children, 1-14 years of age. During the first varicella season, the efficacy of the vaccine among susceptible children was 100%1. During the second varicella season, 22 children were diagnosed with varicella; 21 cases in placebo recipients and one in a vaccine recipient. The overall efficacy of the vaccine through two varicella seasons was 98%. After the code for the study was broken, the original group of vaccine recipients continued to be followed for development of varicella. The estimated proportion of vaccine recipients who remained varicella-free at the end of 7 years was 95%. The 23 cases of varicella that occurred in vaccine recipients over the 7-year period were considerably milder than natural varicella. The average number of lesions was 53, 50% of the children had non-vesicular rashes, and 14% of the children had a temperature greater than or equal to 38.9 degrees C (102 degrees F), oral. The persistence of antibody in a subset of vaccine recipients followed for 6 years was 100%.

Effect of Towne Live Virus Vaccine on Cytomegalovirus Disease after Renal Transplant: A Controlled Trial

OBJECTIVE To test the efficacy of vaccination with the Towne live attenuated cytomegalovirus vaccine. DESIGN A double-blind, randomized, placebo-controlled trial in candidates for renal transplantation. The cytomegalovirus serologic status of both recipients and donors were determined, and the recipients were followed for periods of 6 months to 7 years after transplant. SETTING A university transplant center. PATIENTS The analyses were made on 237 patients who were given either vaccine or placebo, received renal transplants, and were followed for at least 6 months. INTERVENTION Subcutaneous inoculation with Towne live attenuated virus or with placebo. MAIN OUTCOME MEASURES The presence of cytomegalovirus infection was defined by virus isolation and antibody tests. If infection occurred, a prearranged scoring system for cytomegalovirus disease was used to objectify disease severity. RESULTS The vaccine was well tolerated, and there were no discernible long-term adverse effects. Recipients who were originally seropositive did not clearly benefit from vaccination. Protective efficacy was analyzed in the group at highest risk for cytomegalovirus disease; recipients who were seronegative at the time of vaccination and who received a kidney from a seropositive donor. Compared with placebo recipients, vaccinated patients in this group had significantly less severe cytomegalovirus disease, with a significant reduction in disease scores (P = 0.03) and 85% decrease in the most severe disease (95% CI, 35% to 96%), although infection rates were similar. Graft survival at 36 months was improved in vaccinated recipients of cadaver kidneys (8 of 16) compared with unvaccinated recipients (4 of 16) (P = 0.04). CONCLUSIONS Previous vaccination of seronegative renal transplant recipients with live cytomegalovirus results in reduction of disease severity mimicking the action of naturally derived immunity.

A non-X-linked syndrome with susceptibility to severe epstein-barr virus infections

Three siblings developed severe (two) or fatal (one) infectious mononucleosis. This family differed from previously described kindreds with a susceptibility to overwhelming Epstein-Barr virus infections in that: (1) both males and females were affected; (2) they had a history of the recurrent bacterial infections; (3) they produced the full spectrum of antibodies to EBV in the expected range of titers; and (4) survivors recovered completely. Two of these youths, but not their parents or an unaffected sibling with mild IM, had a deficiency of natural killer activity that did not respond to preincubation of their peripheral blood mononuclear cells with interferon. NK activity may have an important role in controlling infections with EBV.

A Canarypox Vector–Expressing Cytomegalovirus (CMV) Phosphoprotein 65 Induces Long-Lasting Cytotoxic T Cell Responses in Human CMV-Seronegative Subjects

The major matrix phosphoprotein 65 (pp65) of cytomegalovirus (CMV) is an important target of HLA-restricted cytotoxic T cells (CTL) after natural infection. A canarypox-CMV pp65 recombinant was studied for its ability to induce CMV pp65-specific CTL, helper T lymphocytes, and antibodies in a phase I clinical trial. Twenty-one CMV-seronegative adult volunteers were randomized to receive immunizations at months 0, 1, 3, and 6 with either canarypox-CMV pp65 or placebo. In canarypox-CMV pp65-immunized subjects, pp65-specific CTL were elicited after only 2 vaccinations and were present at months 12 and 26 in all subjects tested. Cell-depletion studies indicated that the CTL were phenotype CD8(+). Peripheral blood mononuclear cells proliferated in response to stimulation with purified pp65, and antibodies specific for pp65 also were detected. Canarypox-CMV pp65 is the first recombinant vaccine to elicit CMV-specific CTL responses, which suggests the potential usefulness of this approach in preventing disease caused by CMV.

An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children.

Objective:The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Methods:Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. Results:The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C→T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. Conclusions:HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial

BACKGROUND Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.