45-year follow-up of hepatitis C virus infection in healthy young adults.

BACKGROUND: The sequelae during the first two decades after acute hepatitis C virus (HCV) infection have been well studied, but the outcome thereafter is unknown. OBJECTIVE: To conduct an extended study of the natural history of HCV infection by using archived serum specimens originally collected between 1948 and 1954. DESIGN: Retrospective cohort study. SETTING: A university, a Veterans Affairs medical center, and a medical follow-up agency that had access to the serum specimens and accompanying demographic and medical records. PARTICIPANTS: 8568 military recruits who were evaluated for group A streptococcal infection and acute rheumatic fever between 1948 and 1954. Blood samples were taken from the recruits and, after testing, were stored frozen for almost 45 years. MEASUREMENTS: The presence of antibodies to HCV was determined by enzyme-linked immunoassay, supplementary recombinant immunoblot assay, and polymerase chain reaction for HCV RNA. Morbidity and mortality were also assessed. RESULTS: Of 8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay and recombinant immunoblot assay. The rate was 1.8% among the African-American persons and 0.1% among the white persons in the total sample (relative risk, 25.9 [95% CI, 8.4 to 80.0]). During the 45-year follow-up, liver disease occurred in 2 of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the 17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%) had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to 2.6]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years after the original phlebotomy, 5 (29%) died of non-liver-related disease a median of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes. One hundred nineteen HCV-negative persons (1.4%) died of liver disease. CONCLUSIONS: The rate of HCV infection from 1948 to 1954 among a sample of military recruits parallels that among present-day military recruits and volunteer blood donors. During 45 years of follow-up, HCV-positive persons had low liver-related morbidity and mortality rates. This suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought.

Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group.

BACKGROUND: Acute non-A, non-B hepatitis after blood transfusion often progresses to chronic hepatitis and sometimes culminates in cirrhosis or even hepatocellular carcinoma. However, the frequency of these sequelae and their effects on mortality are not known. METHODS: We traced patients with transfusion-related non-A, non-B hepatitis who had been identified in five major prospective studies conducted in the United States between 1967 and 1980. We matched each patient with two control subjects (identified as the first and second controls) who received transfusions but who did not have hepatitis. The mortality rates in the three groups were determined with use of data from the National Death Index and Social Security Death Tapes. Cause-specific mortality was determined by reviewing death certificates. RESULTS: Vital status was established for over 94 percent of the 568 patients who had had non-A, non-B hepatitis and the two control groups (526 first controls and 458 second controls). After an average follow-up of 18 years, the estimate by life-table analysis of mortality from all causes was 51 percent for those with transfusion-associated non-A, non-B hepatitis, as compared with 52 percent for the first controls and 50 percent for the second controls. The survival curves for the three groups were virtually the same. Mortality related to liver disease was 3.3, 1.1, and 2.0 percent, respectively, among the three groups (P = 0.033 for the comparison of the group with non-A, non-B hepatitis with the combined control group). Seventy-one percent of the deaths related to liver disease occurred among patients with chronic alcoholism. CONCLUSIONS: In this long-term follow-up study, there was no increase in mortality from all causes after transfusion-associated non-A, non-B hepatitis, although there was a small but statistically significant increase in the number of deaths related to liver disease.

Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. The VA Cooperative Study Group (No. 119)

Patients with overt alcoholic liver disease who had participated in a multicenter therapeutic trial and subgroups of controls (i.e., alcoholic patients without liver disease and patients with neither alcoholism nor liver disease) were tested for hepatitis B virus and hepatitis C virus antibodies to determine the prevalence of these antibodies to determine the prevalence of these antibodies and any clinical association in the progression and outcome of alcoholic liver disease. Antibodies to hepatitis B (anti-HBs and/or anti-HBc) were found in 29.2% of patients with alcoholic liver disease, in 26.1% of hospitalized alcoholic patients without liver disease and in 24.2% of hospitalized nonalcoholic patients without liver disease; frequencies were not significantly different from one another. HBsAg was not evaluated because HBsAg+ patients had been excluded from the original trial. The presence of these antibody markers correlated with ethnic origin of and immunoglobulin levels in the patients. In contrast, antibody to hepatitis C, as detected by enzyme immunoassay, was positive in 27.1%, 4.8% and 3.0% of the three groups, respectively, the first differing significantly from the other two. Antibody to hepatitis C virus positivity correlated significantly with clinical severity of the disease and with the presence of histological features that imply chronic viral infection (periportal inflammation, cirrhosis), despite the fact that the supplementary assay for antibody to hepatitis C virus, using recombinant immunoblot assay, reduced the positive rate by 79%.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody to human retroviruses among drug users in three east coast American cities, 1972-1976.

Between 1972 and 1976, 585 persons attending methadone maintenance clinics at East Coast veterans hospitals were enrolled in a survey of hepatitis antibody prevalence. Sera were tested for human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV) using both HTLV-I and HTLV-II immunoblots. Clinical and death records were also reviewed. None of the sera had HIV antibodies (upper 95% confidence limit, 0.5%); however, 103 (18%) had reactivity to HTLV. The profile of reactivity suggested that these subjects had been exposed to HTLV-II rather than to HTLV-I. Prevalence was as high in the early 1970s as today and correlated with duration of drug use rather than age. Neither cancers, specific neurologic diseases, nor excess deaths from any cause (overall 14%) could be ascribed to seropositivity. Therefore, HTLV (probably HTLV-II) has been a common infection of drug users for many years but adverse outcomes following infection were not demonstrated.

A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army.

An epidemic of icteric hepatitis in 1942 affected approximately 50,000 U.S. Army personnel. This outbreak was linked to specific lots of yellow-fever vaccine stabilized with human serum. To identify the responsible virus and the consequences of the epidemic, during 1985 we interviewed and serologically screened 597 veterans who had been in the army in 1942. These subjects were selected from three groups. Group I consisted of patients who had received the implicated vaccine and had jaundice; Group II had received the implicated vaccine but remained well; Group III had received a new, serum-free vaccine, with no subsequent jaundice. Ninety-seven percent of Group I, 76 percent of Group II, and 13 percent of Group III were positive for antibodies to hepatitis B virus. Only one subject had hepatitis B surface antigen, for a carrier rate of 0.26 percent among recipients of the implicated vaccine. The prevalence of hepatitis A antibody was similar in all three groups, and no subject had antibody to hepatitis delta virus. We conclude that hepatitis B caused the outbreak, that about 330,000 persons may have been infected, that the hepatitis B virus carrier state was a rare consequence, and that the outbreak induced hepatitis B antibodies that appear to persist for life.

Effect of thymosin immunostimulation with and without corticosteroid immunosuppression on chimpanzee hepatitis B carriers.

Carriers of hepatitis B surface antigen (HBsAg) are at a high personal risk of developing chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma, and they pose a potential health threat to others. Accordingly, erradication of the carrier state is an important therapeutic goal. Several categories of drugs have been evaluated for this purpose, with, at best, limited success. The immune stimulants constitute a drug group considered to have potential benefit, since altered cell-mediated immunity (CMI) appears to have a pathogenic role in the perpetuation of the carrier state. One such immune stimulant is the thymic hormone, thymosin, which is known to enhance suppressor T-cell activity. We therefore examined its possible therapeutic role by evaluating its effect on four chronic HBsAg- and hepatitis B e antigen (HBeAg)-positive chimpanzees. After baseline biochemical, serological, immunological, and histochemical studies were conducted, all four chimpanzees received parenteral thymosin for a period of 10-14 weeks; two of them were pretreated for 4 weeks with corticosteroids. All four were then reevaluated in the same manner at regular intervals during the 14-week period. Neither immunosuppression nor immunostimulation significantly affected biochemical, serological, or histological measures. Indices of CMI were altered, however: both T4 and T8 cells increased with thymosin treatment, although the T4/T8 ratio declined because of the relatively greater increase of the T8 than of the T4 cells. Thymosin did not affect the mitogen assays. Thus, while immunostimulation with thymosin did slightly alter CMI, it had no affect on the HBsAg carrier state or on measures of chronic hepatitis, even when preceded by corticosteroid immunosuppression.

Hepatitis B markers in United States drug addicts with special emphasis on the delta hepatitis virus.

Hepatitis B virus and hepatitis delta virus co-infection in drug addicts has been well described in Europe, the latter agent appearing to have been introduced there in the mid-1970's. Currently, similar data are scanty among United States addicts. We therefore reevaluated 99 drug addicts from three different geographic locations in the United States who had participated in a Veterans Administration Cooperative Study between 1972 and 1975. Almost all were asymptomatic, and all had been subjected to liver biopsy because of prolonged aminotransferase abnormalities. Stored sera were tested for antibody to hepatitis delta antigen (anti-HD) by radioimmunoassay and available liver biopsies examined for hepatitis delta antigen (HDAg) by immunofluorescence. Overall, 19.2% were HBsAg positive, 9.1% HBeAg positive, 90% anti-HBc positive and 10.1%, positive for anti-HD. Anti-HD was identified in 42.1% of addicts who were HBsAg positive and in 3.3% who were anti-HBs positive. No correlation was found between HBeAg and anti-HD, but anti-HD was present significantly more frequently in those with chronic active hepatitis than in those with chronic persistent hepatitis. We conclude that hepatitis delta virus infection is common in HBsAg-positive drug addicts in the United States dating back to at least 1972 and probably earlier.

Lack of transmission of type B hepatitis by fiberoptic upper endoscopy.

We prospectively investigated the possibility that type B hepatitis might be transmitted during fiberoptic endoscopy from hepatitis B surface antigen (HBsAg)-positive patients to others subsequently endoscoped. All 186 patients having upper gastrointestinal endoscopy during a 6-month period at the Washington, D.C., Veterans Administration Medical Center had a blood sample obtained at the time of the procedure. Three patients were found to be HBsAG-positive and 45 others to have either antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc). Follow-up evaluation for evidence of type B hepatitis and hepatitis B virus infection was possible in only 76% of patients. One patient developed type B hepatitis. This patient's endoscopy did not follow endoscopy of any known HBsAg-positive individual, but he had received five units of blood 5 months before hepatitis developed. No other patient showed clinical, biochemical, or serologic evidence of hepatitis during the follow-up period. These data suggest that transmission of type B hepatitis during fiberoptic endoscopy is rare, if it occurs at all, and support the current policy of not sterilizing the fiberoptic endoscope between procedures and of not routinely screening patients for HBsAg.