Yvonne J. Bryson

Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects.

Abstract We performed a double-blind placebo-controlled trial of oral acyclovir in the treatment of first episodes of genital herpes simplex virus infections in 48 young adults (31 women and 17 men...

Combination Treatment with Zidovudine, Didanosine, and Nevirapine in Infants with Human Immunodeficiency Virus Type 1 Infection

BACKGROUND In infants and children with maternally acquired human immunodeficiency virus type 1 (HIV-1) infection, treatment with a single antiretroviral agent has limited efficacy. We evaluated the safety and efficacy of a three-drug regimen in a small group of maternally infected infants. METHODS Zidovudine, didanosine, and nevirapine were administered in combination orally to eight infants 2 to 16 months of age. The efficacy of antiretroviral treatment was evaluated by serial measurements of plasma HIV-1 RNA, quantitative plasma cultures, and quantitative cultures of peripheral-blood mononuclear cells. RESULTS The three-drug regimen was well tolerated, without clinically important adverse events. Within four weeks, there were reductions in plasma levels of HIV-1 RNA of at least 96 percent (1.5 log) in seven of the eight study patients. Over the 6-month study period, replication of HIV-1 was controlled in two infants who began therapy at 2 1/2 months of age. Plasma RNA levels were reduced by 0.5 to 1.5 log in five of the other six infants. CONCLUSIONS Although further observations are needed, it appears that in infants with maternally acquired HIV-1 infection, combined treatment with zidovudine, didanosine, and nevirapine is well tolerated and has sustained efficacy against HIV-1.

Clearance of HIV Infection in a Perinatally Infected Infant

BACKGROUND We describe a child who was identified shortly after birth as infected with the human immunodeficiency virus type 1 (HIV-1), but whose infection appears to have completely cleared. Asymptomatic HIV-1 infection was diagnosed in the mother during the fourth month of pregnancy. The infant was delivered vaginally at 36 weeks, received no blood products, and was not breast-fed. METHODS AND RESULTS HIV-1 was detected by culture of the infants peripheral-blood mononuclear cells at 19 and 51 days of age. Plasma from the infant was also culture-positive for HIV-1 at 51 days of age by DNA polymerase chain reaction (PCR). Nucleotide-sequence analysis of HIV-1 DNA showed extremely close homology of the cultures obtained 32 days apart, and forensic markers of genetic identity for the two cultures were identical. Hence, inadvertent viral contamination or error in the collection of specimens was highly unlikely. At 12 months of age the infant was seronegative for HIV-1, and numerous subsequent cultures and tests by PCR have also been negative for HIV-1. The child is five years of age at this writing, is HIV-seronegative, and remains well, with normal growth and development and no laboratory or clinical evidence of HIV-1 infection. CONCLUSIONS The infant we describe was infected perinatally with HIV-1, but the infection subsequently cleared and the infant remained without detectable HIV-1 infection five years later.

Treatment of Cytomegalovirus Retinopathy with Ganciclovir

Ganciclovir is an experimental antiviral drug with activity against human cytomegalovirus (CMV). Forty patients with acquired immune deficiency syndrome (AIDS) and CMV retinopathy were treated with ganciclovir on a compassionate protocol basis. Initial treatment doses ranged from 5.0 to 14.0 mg/kg/day for 9 to 26 days. Signs of drug response were a halt to enlargement of lesions, decreased opacification of retinal tissue, and resolution of hemorrhage and vasculitis. Complete response was seen in 88% of patients and incomplete response was seen in 9%. Vision improved or remained stable in 88% of patients. Initial treatment did not eradicate live virus from the eye. To prevent reactivation of disease, 26 patients received low-dose maintenance therapy ranging from 1.5 to 7.5 mg/kg/day, once or twice daily, 3 to 7 days per week. Reactivation of disease developed for unknown reasons in 50% of patients on continuous, uninterrupted maintenance therapy for longer than 3 weeks. Reversible neutropenia, requiring cessation of treatment, developed in 30% of patients on initial treatment and in 38% of patients on maintenance therapy. Rhegmatogenous retinal detachment was a late complication in seven patients. By reducing or delaying visual loss, ganciclovir appears to be useful in the management of CMV retinopathy in patients with AIDS.

The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: Phase I Acquired Immunodeficiency Syndrome Clinical Trials Group study (protocol 082)

OBJECTIVES: We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. STUDY DESIGN: Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. RESULTS: The total body clearance (26.3 ± 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 ± 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. CONCLUSIONS: In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.

Deficiency of immune interferon production by leukocytes of normal newborns

Abstract The maturity of the newborns immune system was assessed by measuring proliferative responses and interferon production of isolated mononuclear cells from cord blood ( N = 19), newborns 1 to 7 days of age ( N = 19), and adult controls ( N = 18). Ficoll-Hypaque-separated mononuclear cells were stimulated with phytohemagglutinin (PHA), allogeneic leukocytes in a mixed leukocyte culture (MLC), or Newcastle disease virus (NDV), pulsed with thymidine after 3 to 7 days in culture, and thymidine incorporation into DNA measured and used to calculate a proliferative index. The supernatants were h-arvested at optimal times for assay of classical and immune interferon (IF) production. IF was assessed by a microtiter assay using human diploid cells after encephalomyocarditis virus challenge. The proliferative responses of cord and newborn cells were equivalent or greater than those of adult controls. PHA-induced immune IF was produced in only 1 of 19 cord bloods and 3 of 19 newborns, whereas immune IF was produced in all adults (225 ± 2 units). No IF was produced in MLC in newborns, cords, or adults. NDV-induced classical IF was produced in normal amounts by newborn (373 ± 2IU), cord (457 ± 2IU), and adult cells (170 ± 3IU). These results indicate an abnormality of cellular immunity in newborns not detected by T-cell numbers or proliferative responses and parallels similar defects in T-cell-mediated cytotoxicity, another specialized T-cell function. These results suggest a possible mechanism for viral infection in newborns with concomitant bacterial infections and in patients undergoing graft-versus-host reactions.

A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection

BACKGROUND Serious bacterial infections are common in children infected with the human immunodeficiency virus (HIV). Studies performed before zidovudine became standard therapy found that intravenous immune globulin decreases the number of serious bacterial infections in these children. We designed a multicenter study to evaluate the efficacy of intravenous immune globulin in children with advanced HIV infection who were receiving zidovudine. METHODS In a double-blind trial 255 children between 3 months and 12 years of age who had the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were randomly assigned to receive either intravenous immune globulin (400 mg per kilogram of body weight) (n = 129) or placebo (0.1 percent albumin) (n = 126) every 28 days. All children received 180 mg of zidovudine per square meter of body-surface area orally four times daily. Treatment assignment was stratified according to whether the patients had a history of one or more serious bacterial infections, had previously been treated with zidovudine, or were currently receiving prophylaxis with trimethoprim-sulfamethoxazole. The median length of follow-up was 30.6 months. RESULTS The estimated two-year rates of serious bacterial infections with confirmed pathogens were 16.9 percent for the immune globulin group and 24.3 percent for the placebo group (relative risk, 0.60; 95 percent confidence interval, 0.35 to 1.04; P = 0.07). The treatment effect was seen primarily among the 174 children who were not receiving trimethoprim-sulfamethoxazole prophylaxis at entry; the estimated two-year rates of infection were 11.3 percent for the immune globulin group and 26.8 percent for the placebo group (relative risk, 0.45; 95 percent confidence interval, 0.22 to 0.91; P = 0.03). For the 81 children who were receiving trimethoprim-sulfamethoxazole prophylaxis initially, the rates were 27.7 percent in the immune globulin group and 17.7 percent in the placebo group (relative risk, 1.26; 95 percent confidence interval, 0.44 to 3.66; P = 0.67). The two-year survival was similar in the two groups: 79.2 percent among immune globulin recipients and 75.4 percent among placebo recipients (P = 0.41). CONCLUSIONS In children with advanced HIV disease who are receiving zidovudine, intravenous immune globulin decreases the risk of serious bacterial infections. However, this benefit is apparent only in children who are not receiving trimethoprim-sulfamethoxazole as prophylaxis.

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.

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.

Treatment of Human Immunodeficiency Virus 1-Infected Infants and Children with the Protease Inhibitor Nelfinavir Mesylate

An open-label study was conducted of nelfinavir mesylate, given with reverse transcriptase inhibitors to human immunodeficiency virus 1 (HIV-1)-infected infants and children 3 months to 13 years of age. Doses of nelfinavir mesylate of 20-30 mg/kg yielded drug exposures comparable to those seen in adults. The drug was well tolerated; mild diarrhea was the primary toxic effect observed. Seventy-one percent (39) of the 55 evaluable subjects had an initial decrease in plasma HIV-1 RNA, of at least 0.7 log10 copies/mL; suppression of plasma HIV-1 RNA levels to < 400 copies/mL was observed in 15. Children who began taking at least one new reverse transcriptase inhibitor near the time when nelfinavir mesylate was started, and those with a > or = 24% proportion of CD4 lymphocytes, had a greater chance of achieving and maintaining a decline in plasma HIV-1 RNA to < 400 copies/mL. Suppression of viremia was achieved in children as young as 3 months of age.