Infection with the hepatitis C virus may result in chronic liver disease for which no effective therapy is now available. We studied the effects of recombinant human interferon alfa in a prospective, randomized, double-blind, placebo-controlled trial in patients with well-documented chronic hepatitis C. Forty-one patients were enrolled in the trial, 37 of whom were later found to have antibody to hepatitis C virus. Twenty-one patients received interferon alfa (2 million units) subcutaneously three times weekly for six months, and 20 received placebo. The mean serum aminotransferase levels and the histologic features of the liver improved significantly in the patients treated with interferon but not in the patients given placebo. Ten patients treated with interferon (48 percent) had a complete response, defined as a decline in mean serum aminotransferase levels to the normal range during therapy; three others had a decrease in mean aminotransferase levels of more than 50 percent. After treatment e...

Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.

We treated 10 patients who had chronic non-A,non-B hepatitis with recombinant human alpha interferon in varying doses (0.5 to 5 million units) daily, every other day, or three times weekly for up to 12 months. In 8 of the 10 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. In two of these patients, the interferon therapy was stopped after four months, and in both cases, a prompt return of aminotransferase activities to pretreatment values occurred. Prolonged treatment was associated with a sustained improvement in aminotransferase levels; in three cases, biopsy specimens obtained after one year of therapy showed marked improvement in hepatic histology, even though low doses of alpha interferon had been used. These preliminary findings, although not adequately controlled, suggest that long-term, low-dose alpha interferon therapy may be effective in controlling the disease activity in some patients with chronic non-A,non-B hepatitis. A prospective controlled trial is now needed to assess the role of interferon therapy in this disease.

Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report.

Background In patients with chronic hepatitis B, treatment with interferon alfa and the consequent loss of hepatitis B e antigen (HBeAg) from the blood leads to a reduction in inflammatory activity, but the clinical benefits of this treatment have not been established. We evaluated whether HBeAg seroconversion induced by interferon alfa improves clinical outcome. Methods We studied prospectively a cohort of 103 patients treated with interferon alfa for chronic hepatitis B; the mean (±SD) follow-up was 50.0±19.8 months. Fifty-three untreated patients served as controls. Results After treatment with interferon alfa, 53 of 103 patients no longer had detectable HBeAg or hepatitis B virus DNA, although only 10 patients became seronegative for hepatitis B surface antigen (HBsAg) (Kaplan–Meier estimates of cumulative clearance rates at five years, 56.0 percent for HBeAg and 11.6 percent for HBsAg). Of the 53 untreated patients, only 7 spontaneously eliminated HBeAg (28.1 percent at five years), and all remained ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199605303342202

Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.

Some individuals infected with hepatitis C virus (HCV) experience multiple episodes of acute hepatitis. It is unclear whether these episodes are due to reinfection with HCV or to reactivation of the original virus infection. Markers of viral replication and host immunity were studied in five chimpanzees sequentially inoculated over a period of 3 years with different HCV strains of proven infectivity. Each rechallenge of a convalescent chimpanzee with the same or a different HCV strain resulted in the reappearance of viremia, which was due to infection with the subsequent challenge virus. The evidence indicates that HCV infection does not elicit protective immunity against reinfection with homologous or heterologous strains, which raises concerns for the development of effective vaccines against HCV.

https://science.sciencemag.org/content/sci/258/5079/135.full.pdf

Lack of protective immunity against reinfection with hepatitis C virus

Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients.

https://www.gastrojournal.org/article/0016-5085(80)90130-4/pdf

Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection

The long-term outcome of non-A, non-B post-transfusion hepatitis was evaluated in 21 patients who developed the illness after open-heart surgery and could be followed thereafter up to five years. Histological chronic sequelae were documented in 13 patients, and consisted of chronic persistent hepatitis in one case, chronic lobular hepatitis in two and chronic active hepatitis in 10, five of whom also developed superimposed cirrhosis. Progression to these chronic states was in most cases symptomless, independently of the severity of liver lesions; one patient, however, died of gastrointestinal bleeding due to cirrhosis of the liver. During follow-up the biochemical pattern of chronic non-A, non-B hepatitis was unique, while striking fluctuations of transaminase levels. Liver histology proved essential to identify the severity of chronic liver lesions, as clinical and biochemical features were uniform and not indicative of it. Our results suggest that cirrhosis may develop, often with an asymptomatic course, in a significant number of patients who do not recover after acute post-transfusion non-A, non-B hepatitis.

https://gut.bmj.com/content/gutjnl/23/4/270.full.pdf

Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis.

The cytotoxic effect of peripheral lymphocytes on chicken red blood cells (ChRBC) coated with purified hepatitis B surface antigen (HBsAg) has been studied as an in vitro parameter of cell-mediated immunity in acute and chronic infection with hepatitis B virus. Using this technique, the mean cytotoxic index of lymphocytes from patients with acute hepatitis B (29·13 ± 20·88) was significantly higher than that obtained with lymphocytes from control subjects (6·53 ± 3·75). Only 33·3% of the patients with HBsAg-positive chronic active hepatitis exhibited lymphocyte cytotoxicity to HBsAg-coated target cells and the mean cytotoxic index (11·66 ± 6·60) was in these cases significantly lower than that found in acute hepatitis B. Healthy chronic carriers of HBsAg failed to show lymphocyte cytotoxicity to target cells. The effector cells detected in acute hepatitis B by this in vitro assay have been demonstrated to be T-lymphocytes, as T-cell depleted subpopulations lacked cytotoxic activity. Target cell lysis could be blocked by addition of HBsAg-coated unlabelled ChRBC as well as of purified HBsAg in the culture tubes. It is suggested that damage to the liver cells in acute hepatitis B is related to the presence of cytotoxic T-lymphocytes reacting with HBsAg on the surface of infected hepatocytes. An inadequate lymphocyte response to the antigen may be responsible for the persistence of the infection in the liver with varied clinical manifestations and associated hepatic lesions.

https://gut.bmj.com/content/gutjnl/18/12/1004.full.pdf

T-lymphocyte cytotoxicity to HBsAg-coated target cells in hepatitis B virus infection

Immune-complexes and Australia antigen in cryoglobulinemic sera.

Liver cell membrane localization of hepatitis B surface antigen (HBsAg) was investigated in 31 asymptomatic chronic carriers by a direct immunofluorescence technique. A close relationship was found between absence of inflammatory liver disease, presence of large amounts of HBsAg in the liver and expression of the antigen at the hepatocyte surface. Capping of HBsAg after the addition of anti-HBs serum could be inhibited by factors (temperature, metabolic inhibition) that are known to influence viral antigenic mobility at the cell surface. In two patients with chronic active hepatitis as well as in some cases showing histological features of focal parenchymal necrosis, HBsAg could be detected in the cytoplasm of a few scattered hepatocytes but never at the surface of the cells. Both the cases with CAH and one with focal parenchymal necrosis had IgG bound to the liver cell membrane. These findings are in agreement with the hypothesis that the absence of liver damage in HBsAg healthy chronic carriers is related to immune tolerance to the antigen. In chronic active liver disease the presence of IgG on the membrane of hepatocytes suggests a possible role of blocking antibodies directed against viral antigens expressed at the hepatocyte surface.

A. M. Rigoli

Papers

Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection

Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis.

T-lymphocyte cytotoxicity to HBsAg-coated target cells in hepatitis B virus infection

Immune-complexes and Australia antigen in cryoglobulinemic sera.

Expression of HBsAg on the membrane of hepatocytes in chronic carriers of hepatitis B virus infection.