First-in-human study of the pharmacokinetics and antiviral activity of IDX375, a novel nonnucleoside hepatitis C virus polymerase inhibitor.

IDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only). IDX375 was well absorbed and well tolerated by all of the study participants. A single-day 200-mg BID dose resulted in exposure-related anti-HCV activity with maximal 0.5 to 1.1 log(10) reductions in plasma HCV RNA. These observations support further clinical investigations of IDX375.

Risk factors for Guillain-Barré syndrome.

In 100 cases of Guillain-Barré syndrome (GBS) reported from 10 metropolitan areas to the Centers for Disease Control (CDC) after the 1976-77 influenza vaccination campaign and matched associate or spouse controls, we searched for risk factors for GBS other than A/New Jersey/1976 influenza vaccination and acute respiratory infection. The 47 vaccinated cases recalled influenza vaccination in past years less frequently than did controls (p less than 0.025). Cases and controls did not differ in the number of previous vaccinations or in interval from last vaccination. Cases also gave a history of allergy less frequently than controls. There were no other significant differences.

HLA antigens in Guillain-Barré syndrome.

We compared Guillain-Barré syndrome (GBS) cases reported from cities in the United States in 1976-1977 with spouse or associate controls to detect possible HLA associations. HLA-A11 was somewhat less common among 92 cases than among 100 controls (p = 0.04). The 38 patients and 42 controls vaccinated against A/NJ/76 differed slightly in overall distribution of B locus antigens (p = 0.06), but the individual HLA-B antigen associations were more easily explained by chance. The 54 unvaccinated cases showed no apparent relation to HLA type. These findings should encourage further immunogenetic study of etiologically related GBS cases.

Impact of chickenpox on households of healthy children.

There is little information available regarding the impact of varicella among healthy children. A group of 137 households, identified by the County of Los Angeles Department of Health Services, were interviewed by telephone and yielded 247 cases of varicella. There were no hospitalizations for complications. Rates for physician visits and telephone calls to health care providers were 0.5 and 1.0 per case, respectively. School days lost by cases and work days lost by well adults in the households were 8.7 and 0.5 per case, respectively. Varicella had a measurable impact of economic significance on our survey population. Our observations need to be extended and included in cost-benefit analyses of varicella vaccine.

Hyperpyrexia due to air-conditioning failure in a nursing home.

During the period August 9--13, 1976, 21 of 89 residents of a nursing home in southeastern Florida had sudden onset of fever--temperature greater than 38.1 degrees C (100.6 degrees F) with no accompanying symptoms. Five residents, whose temperatures ranged from 39.4 degrees C (103 degrees F) to 41.3 degrees C (106.4 degrees F), died. No viral or bacterial pathogens were isolated. None of the nursing home's 123 employees and volunteers had similar illness. The air-conditioning system was shut down for repairs from August 9 through August 12, a time when recorded peak temperatures outdoors ranged from 30.6 degrees C (87 degrees F) to 32.2 degrees C (90 degrees F). The only recorded temperature inside the nursing home for that period was 31.7 degrees C (89 degrees F). Laboratory and epidemiologic data were consistent with the theory that the illness was due to hyperpyrexia, secondary to environmental conditions, rather than to an infectious agent. The episode was considered analogous to the nonspecific increased mortality of elderly and chronically ill persons during an urban heat wave. The episode points up the need for prompt recognition and intervention when there is the potential for heat stress in elderly and chronically ill patients. Buildings housing such patients must be designed so that alternative ventilation can be provided when the central air-conditioning system fails.

Presentation of neonatal herpes simplex virus infections: implications for a change in therapeutic strategy.

To identify clinical signs of disease that might lead to more rapid recognition in treatment, we reviewed the time from onset of illness to diagnosis of 42 consecutive cases of neonatal herpes simplex virus (HSV) infection seen between 1965 and 1984. The first signs of illness included mucocutaneous lesions in 14, central nervous system signs in 20, fever in 6 and respiratory insufficiency in 2 infants. The median time from onset of illness to presentation to medical personnel was 1 day. The median time from presentation to medical personnel to obtaining viral cultures was 3 days (range, 1 to 11) and was similar in infants who did and did not have mucocutaneous lesions. Viral cultures were performed within 24 hours of admission on 8 of 13 noncongenitally infected infants born between 1982 and 1984 compared to 5 of 24 seen between 1965 and 1981 (P less than 0.03). However, a greater than 72-hour delay between presentation to medical personnel and obtaining viral diagnostic studies occurred in 33, 40 and 14% of infants born in the years 1965 to 1977, 1978 to 1981 and 1982 to 1984. Involvement of additional organ systems by HSV was noted in 57% of infants between the time from presentation to medical personnel and diagnosis. Neonatal HSV infection was often severe by the time patients presented to medical personnel, and the disease usually progressed rapidly. To achieve a better therapeutic outcome for infants with neonatal herpes, consideration should be given to the initiation of antiviral therapy on presumptive clinical and epidemiologic grounds. Future strategies for therapy of neonatal herpes should be directed at preventing the acquisition of disease.

Surveillance of Reye syndrome in the United States, 1977.

Between December 1, 1976, and November 30, 1977, 454 cases of Reye syndrome were reported to the Centers for Disease Control by 43 states. Analysis of data about these cases revealed that Reye syndrome primarily affected white children under age 18 years, with a mean age of 7.7 years and bimodal incidence peaks in infancy and at age 6-7 years, was temporally and geographically associated with influenza B for about 75% of cases, but also occurred sporadically and not in association with influenza B activity. Although Reye syndrome was reported infrequently for non-white children aged one year or older, there was a high incidence in minority infants, and the case-fatality ratio in infants of all races was significantly higher than that of the older children. Favorable outcome was associated with prolonged interval between onset of prodromal illness and hospitalization, admission to hospital at a milder stage of illness, and treatment in hospitals with established pediatric training programs.

Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976--1977.

Because of an increase in the number of reports of Guillian-Barre syndrome (GBS) following A/New Jersey influenza vaccination, the National Influenza Immunization Program was suspended December 16, 1976 and nationwide surveillance for GBS was begun. This surveillance uncovered a total of 1098 patients with onset of GBS from October 1, 1976, to January 31, 1977, from all 50 states, District of Columbia, and Puerto Rico. A total of 532 patients had recently received an A/New Jersey influenza vaccination prior to their onset of GBS (vaccinated cases), and 15 patients received a vaccination after their onset of GBS. Five hundred forty-three patients had not been recently vaccinated with A/New Jersey influenza vaccine and the vaccination status for 8 was unknown. Epidemiologic evidence indicated that many cases of GBS were related to vaccination. When compared to the unvaccinated population, the vaccinated population had a significantly elevated attack rate in every adult age group. The estimated attributable risk of vaccine-related GBS in the adult population was just under one case per 100,000 vaccinations. The period of increased risk was concentrated primarily within the 5-week period after vaccination, although it lasted for approximately 9 or 10 weeks.

Reye syndrome in Ohio, 1973-1977.

Some major epidemiologic features of Reye syndrome have been elucidated since the first description of this clinical entity. Multiple studies have shown an association with epidemic influenza B and endemic varicella. Little population data are available on age, sex, race, geographic distribution, and secular trends. A five-year retrospective population-based study of 190 Ohio residents diagnosed with Reye syndrome from January 1, 1973-December 31, 1977, is reported here. The temporal relationships between the occurrence of Reye syndrome and influenza B and varicella were confirmed; however, a high number of blacks and city dwellers with Reye syndrome were found in this study.