Jeanne G. Waggoner

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

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 ended, however, serum aminotransferases usually returned to pretreatment levels; 6 to 12 months after the discontinuation of interferon therapy, only two patients (10 percent) still had normal values. We conclude that interferon alfa therapy is beneficial in reducing disease activity in chronic hepatitis C; however, the beneficial responses are often transient.

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

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.

Seroconversion from Hepatitis B e Antigen to Antibody in Chronic Type B Hepatitis

Twenty-five patients with chronic type B hepatitis documented by liver biopsy were followed for 1 to 6 years with serial measurements of aminotransferase levels, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and antibody (anti-HBe), and hepatitis B virus DNA polymerase. Initially, all were positive for HBsAg and HBeAg and had elevations in serum aminotransferases. In follow-up, only one lost HBsAg reactivity. In 13, however, elevated aminotransferase levels spontaneously fell to normal and have remained normal. These 13 also had a seroconversion from HBeAg to anti-HBe, and all became negative for serum DNA polymerase. Most had a fall in HBsAg titer. This seroconversion occurred concurrently with or several months before the fall in aminotransferase levels. In contrast, the 12 persons who remained HBeAg positive continued to have elevated aminotransferase levels. All 10 of these patients who were initially positive for DNA polymerase remained positive. These data suggest that many patients with chronic type B hepatitis eventually have a spontaneous remission in clinical and biochemical evidence of active disease, usually heralded or accompanied by the disappearance of HBeAg and DNA polymerase.

Long-Term Remission of Chronic Hepatitis B after Alpha-Interferon Therapy

OBJECTIVE To evaluate whether remissions of chronic hepatitis B induced by alpha-interferon therapy are of long duration. DESIGN Cohort study. SETTING Clinical Center of the National Institutes of Health, a tertiary referral center. PATIENTS Sixty-four patients with chronic hepatitis B were treated with alpha-interferon between 1984 and 1986. MAIN OUTCOME MEASURES Patients were followed with frequent examinations and determinations of serum liver biochemical tests and hepatitis B virus (HBV) markers including hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA using blot hybridization and polymerase chain reaction. RESULTS Among 64 patients with chronic hepatitis B who were treated with alpha-interferon, 23 (36%) responded to treatment with loss of HBeAg and improvement in serum aminotransferases. All 23 have been followed for 3 to 7 years (mean, 4.3 years). During follow-up, 3 of 23 patients relapsed, with reappearance of HBeAg and abnormal serum aminotransferases, all within 1 year of therapy. The remaining 20 patients continued to have no detectable HBeAg or HBV DNA (using blot hybridization) in serum and to be asymptomatic for liver disease, although 3 had minimal elevations in serum aminotransferases. Thirteen patients (65%) became negative for HBsAg between 0.2 and 6 years (mean, 3 years) after loss of HBeAg. Although no patient had HBV DNA that was detectable by blot hybridization, the 7 patients who remained HBsAg positive all had HBV DNA in serum detected by polymerase chain reaction, but only 2 of 13 HBsAg-negative patients had viral genome using this method. Testing sequential samples indicated that HBV DNA detected by polymerase chain reaction usually disappeared at or around the time that test results for HBsAg became negative. CONCLUSIONS Remissions in chronic hepatitis B induced by alpha-interferon are of long duration and are followed, in most patients, by the loss of HBsAg and all evidence of residual virus replication.

Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B

BACKGROUND The prognosis of advanced cirrhosis due to chronic hepatitis B is poor, and results of therapies, including liver transplantation, have been unsatisfactory. Little is known about the effectiveness of interferon alfa in patients with cirrhosis. METHODS Between 1984 and 1991, 18 patients with clinically-apparent cirrhosis due to hepatitis B were treated with interferon alfa at the Clinical Center of the National Institutes of Health. RESULTS Six treated patients (33%) had a sustained loss of hepatitis B virus DNA and hepatitis B e antigen (if present initially) and decrease of amino-transferase levels into the normal or near normal range. In follow-up, these 6 patients resolved all symptoms of cirrhosis and are alive and fully active. In contrast, the 12 patients who did not have a sustained loss of hepatitis B virus have had evidence of progressive liver disease, 6 have died and 4 underwent hepatic transplantation. Side effects of interferon were common and included bacterial infections (n = 5) and exacerbations of disease (n = 9). CONCLUSIONS These findings indicate that interferon alfa is effective in selected patients with mildly decompensated cirrhosis due to hepatitis B.

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.

A Short Course of Prednisolone in Chronic Type B Hepatitis: Report of a Randomized, Double-Blind, Placebo-Controlled Trial

Fifteen patients with chronic type B hepatitis were treated with corticosteroids in a randomized, double-blind, placebo-controlled trial lasting 28 days. Ten patients received prednisolone, 60 mg/d for 2 weeks, then 30 mg/d for another 2 weeks; 5 patients received placebo. Serum aminotransferase levels decreased significantly during prednisolone therapy but 4 to 10 weeks after abrupt withdrawal of the drug, they rebounded to levels greater than those before treatment. This exacerbation of disease lasted for several months and was prolonged and symptomatic in 3 patients. Hepatitis B virus levels did not change substantially during treatment. Follow-up examinations showed no improvement in biochemical or serologic features of the disease in any of the 15 patients; follow-up liver biopsies showed a worsening in 4 of 7 treated patients but in 0 of 5 control patients. Thus, a 28-day course of prednisolone produced no beneficial effects in patients with mild-to-moderate chronic type B hepatitis; on the contrary, such treatment may be harmful.

Pilot study of recombinant human α-interferon for chronic type B hepatitis

Nine patients with chronic type B hepatitis were entered into a preliminary study of recombinant, human alpha-interferon therapy. Patients received one to four courses of interferon, each consisting of a fixed dose of 18, 36, 50, 68, or 100 million units given three times a week for 2 wk. Side effects including fever, chills, fatigue, myalgias, headache, and neutropenia were common and especially severe with higher doses. Serum hepatitis B virus DNA polymerase activity fell during therapy to 15%-30% of the pretreatment levels irrespective of interferon dose, but rose to the initial level by 10 days after the course ended. During follow-up, 2 patients had a sustained clinical remission in which hepatitis B virus DNA, DNA polymerase, and hepatitis B e antigen disappeared from serum and amino-transferase activities fell to normal. One patient became hepatitis B surface antigen negative. We conclude that higher doses (50 and 68 million units) of interferon have greater side effects than lower doses (18 and 36 million units), without having any greater antiviral efficacy. Further studies should be directed at therapy with lower doses given over longer periods.

Crigler-Najjar Syndrome: An Unusual Course with Development of Neurologic Damage at Age Eighteen

Extract: A patient with type I congenital nonhemolytic jaundice (type I Crigler-Najjar syndrome (CNJ)), who first developed overt neurologic signs at age 18, is reported. Studies with isotopic bilirubin, performed both when she was well and after the onset of brain damage, demonstrated normal hepatic bilirubin uptake and storage capacity, and normal bilirubin turnover (3.0 mg/kg/24hr). As a result of a virtual absence of conjugation, net bilirubin clearance was reduced to 0.0075 ml/min/kg, which is approximately 1% of normal (0.65 ± 0.18 ml/min/kg). Therapy with glutethimide, phenobarbital, blue light, and oral agar were all ineffective in reducing the concentration of unconjugated bilirubin in plasma or accelerating radiobilirubin disappearance.The acute onset of neurologic disease occurred at age 18, and may possibly have related to a transient increase in the molar bilirubin to albumin ratio to a value greater than 1.0. Exchange plasmapheresis, performed with a continuous flow centrifuge, rapidly reduced the bilirubin concentration in plasma from 41 to 6 mg/100 ml, and was associated with apparent clinical improvement. A total of 1,900 mg bilirubin was removed by this procedure.Although in vivo phototherapy was ineffective, in vitro illumination of the patients plasma with special blue lamps produced a rapid fall in the bilirubin concentration in plasma. Bilirubin was converted to polar, diazo-negative derivatives by a process in which several steps could be distinguished. The initial photodegradation products were colored, tightly albumin bound and nondialyzable, which explained their tendency to be excreted in the bile in preference to the urine. Continued illumination for up to 24 hr resulted in the production of colorless, nonalbumin-bound compounds which, when injected into rats, were excreted principally in the urine.Speculation: Pending the perfection of techniques for auxiliary hepatic transplantation in man, extracorporeal phototherapy or hemoperfusion over albumin-conjugated agarose columns may provide a means of prevention of the otherwise inevitable development of neurologic disease in patients with type I CNJ.

Glomerulonephritis Caused by Chronic Hepatitis B Virus Infection: Treatment with Recombinant Human Alpha-Interferon

STUDY OBJECTIVES To assess the efficacy of alpha-interferon therapy in patients with hepatitis B virus (HBV)-related glomerulonephritis. DESIGN Prospective, nonrandomized study. PATIENTS Five patients with persistence of hepatitis B surface antigen, hepatitis B e antigen (HBeAg) and HBV DNA in serum for at least 6 months and histologic changes of chronic hepatitis on liver biopsy as well as persistent proteinuria of greater than 2 g/d and histologic changes of glomerulonephritis on renal biopsy. INTERVENTIONS Patients received a 4-month course of recombinant human alpha-interferon (alfa-2b) beginning at a dose of 5 million units administered subcutaneously each day. RESULTS Serum levels of HBV DNA decreased in all patients and fell to undetectable levels during treatment in four of five patients. In the four responding patients, serum HBeAg disappeared, aminotransferases fell into the normal range, and a follow-up liver biopsy showed an improvement in the hepatocyte necrosis and inflammation. Urine protein excretion also decreased during treatment. In the four responding patients, urine protein excretion gradually fell to less than 1 g/d and serum albumin levels rose into the normal range. Resolution of the biochemical and serologic evidence of chronic hepatitis and glomerulonephritis was accompanied by disappearance of signs and symptoms of liver and kidney disease. CONCLUSIONS A high proportion of patients with HBV-related glomerulonephritis will respond to a 4-month course of alpha-interferon with a clinical, biochemical, and serologic remission.