Real-world effectiveness of peginterferon α-2b plus ribavirin in a Canadian cohort of treatment-naïve chronic hepatitis C patients with genotypes 2 or 3: results of the PoWer and RediPEN studies.

The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR) = 0.20; p = 0.007] and increased relapse (OR = 6.84; p = 0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR = 0.41; p = 0.009); F3 vs. F0/F1 (OR = 0.72; p = 0.338); F4 vs. F0/F1 (OR = 0.27; p = 0.001)]. Male gender (OR = 13.16; p = 0.020) and higher fibrosis score [F2 vs. F0/F1 (OR = 9.72; p = 0.016); F3/F4 vs. F0/F1 (OR = 4.23; p = 0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.

Peginterferon alfa-2a in patients with chronic hepatitis C.

BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

Hepatitis G and hepatitis C RNA viruses coexisting in cryoglobulinemia.

OBJECTIVE: Hepatitis G virus (HGV) has been identified as a new member of the Flaviridae family, which includes the hepatitis C virus (HCV). There is a well established association between HCV and cryoglobulinemia; however, to date HGV has not been linked with various types of cryoglobulinemia. We investigated the association of HGV with cryoglobulinemia. METHODS: We studied 10 patients with cryoglobulinemia. The cryoglobulins were purified and identified by immunofixation electrophoresis. HGV and HCV RNA were studied in the serum and in purified cryoglobulins by reverse transcriptase polymerase chain reaction. RESULTS: Nine of 10 patients were women, aged 37-74 years. These patients had combinations of hepatitis C (6), vasculitis (7), lymphoproliferative (3), and autoimmune and connective tissue diseases (3). Of the 10 patients, 3 were positive for both HGV RNA and HCV RNA. Two of three patients with dual infection of HGV and HCV had malignancies (Waldenstrom's macroglobulinemia, B cell lymphoma). In one of these 3 patients HGV RNA was positive in the cryoglobulin fraction, but not in serum. Three other patients were positive for HCV RNA alone. CONCLUSION: HGV may be associated with cryoglobulins. Our three patients were co-infected with HCV. Since our series is small, the pathogenetic role of hepatitis G and its relationship to malignancy remain to be elucidated.

Re-treatment of chronic hepatitis C with consensus interferon .

A multicenter, open-label, phase 3 study was conducted in 337 patients with chronic hepatitis C virus (HCV) infection who had either not responded to previous interferon therapy or had relapsed after discontinuation of therapy with either consensus interferon (9 microg) or interferon alpha-2b (3 million U) three times a week for 24 weeks. Patients were randomized to receive a higher dose of consensus interferon (15 microg) administered subcutaneously three times a week for 24 or 48 weeks and then were observed for an additional 24 weeks. Patients who had relapsed after prior interferon therapy were more likely to have a sustained alanine aminotransferase response and HCV RNA response (as measured by reverse transcription-polymerase chain reaction with a sensitivity of < 100 copies/mL) than were patients who had not responded to prior interferon therapy. For relapsers, the sustained HCV RNA response rate was 58% (48 weeks) and 28% (24 weeks). The sustained alanine aminotransferase response for relapsers was 52% (48 weeks) and 39% (24 weeks). The sustained HCV RNA response rate among prior nonresponders was 13% (48 weeks) and 5% (24 weeks), and the sustained alanine aminotransferase response rate for nonresponders was 17% (48 weeks) and 12% (24 weeks). The administration of 15 microg of consensus interferon was well tolerated and was not associated with an increase in the incidence of side effects. These data demonstrate that re-treatment with 15 microg of consensus interferon is safe and effective therapy for patients with chronic hepatitis C who have either not responded to previous interferon therapy or relapsed after discontinuation of interferon therapy.

A 5' splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease.

Cholesteryl ester storage disease (CESD) results from inherited deficiencies of the lysosomal hydrolase, acid lipase (LAL; E.C. 3.1.1.13). To establish the molecular defects in LAL deficiency, two unrelated probands with severely reduced LAL activity were examined. DNA amplification by reverse-transcription polymerase chain reaction and subsequent sequence analysis of LAL cDNA identified two mutant alleles. Patient 1, presenting with hepatosplenomegaly, mildly elevated liver function tests, and hyperlipidemia, was homozygous for a deletion of nucleotides 823 to 894 of the LAL cDNA. This 72-bp deletion maintained the reading frame and resulted in a loss of 24 amino acids from the LAL protein. Analysis of genomic DNA revealed that the 72 bp corresponded to an exon of the LAL gene. A single G to A point mutation at the last exon position was observed in the genomic DNA of patient 1, indicating a splicing defect with consecutive exon skipping underlying the 72-bp deletion. Patient 2 was a compound heterozygote for the 72-bp deletion and a dinucleotide deletion at positions 967 and 968. This deletion resulted in a shifted reading frame carboxyterminal of codon 296, and 43 random amino acids followed the frame shift. A premature stop at codon 339 truncated the mutant LAL protein by 34 amino acids. Allele-specific hybridization confirmed that patient 1 was homozygous for the 72-bp deletion mutation, and that patient 2 was a compound heterozygote for the 72-bp deletion and the 2-bp deletion.

Post-transfusion hepatitis: impact of non-A, non-B hepatitis surrogate tests. Canadian Post-Transfusion Hepatitis Prevention Study Group.

Canada has not introduced the non-A, non-B (NANB) surrogate marker tests (antibodies to hepatitis B core antigen and alanine aminotransferase) to screen donated blood. We evaluated the effect of NANB surrogate markers in reducing post-transfusion hepatitis in a prospective randomised intervention study. From 1988 to 1992, 4588 subjects were enrolled into two study groups that received allogeneic blood from which units positive for NANB surrogate markers were either withheld (n = 2311) or not withheld (n = 2277). We also assessed a simultaneous non-randomised cohort (n = 650) of subjects who received only syngeneic blood. All subjects were followed up for 6 months and assessed for the presence of post-transfusion hepatitis due to hepatitis A, B, C, non ABC, Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Withholding of blood containing NANB surrogate positive units reduced the overall post-transfusion hepatitis rate by 40% (p = 0.065) and the hepatitis C rate by 70% (p = 0.05). Most of the benefit of NANB surrogate testing was due to reduced frequency of hepatitis C virus after transfusion before all donor blood was screened for anti-HCV. During this time the overall post-transfusion hepatitis rate per 1000 transfusion recipients was 20.2 in the no-withhold group compared with 5.0 in the withhold group (p = 0.05), and the HCV hepatitis rate was 12.6 and 0 respectively (p = 0.06). After the introduction of HCV screening, the overall post-transfusion hepatitis rates were 8.6 and 6.8 per 1000 (p = 0.55) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of interferon-alpha therapy on serum and liver HBV DNA in patients with chronic hepatitis B.

The aim of this study was to evaluate the effect of interferon-alpha therapy on serum and liver HBV DNA in 20 patients with chronic hepatitis B and to correlate the presence or absence of HBV DNA with the clinical response. There were 11 responders and all lost HBV DNA from the serum. Ten of the 11 were followed for 36 months following IFN treatment and remained well with absence of HBeAg and HBV DNA from the serum and with normal ALT. Five also lost HBsAg. HBV DNA became undetectable in the liver of nine of 10 of these patients in whom liver tissue was available for study. HBV DNA persisted in the liver of seven of nine nonresponders and was not detected in two in spite of the presence of HBV DNA and HBeAg in the serum of these two patients. We conclude that IFN may induce long remissions in patients with chronic hepatitis B with loss of HBV DNA from the serum and that occasionally HBV DNA may persist in the liver of such patients.

Prevalence of bloodborne infective agents among people admitted to a Canadian hospital.

OBJECTIVE: To determine the prevalence rates of hepatitis B surface antigen (HBsAg) and antibodies to the human immunodeficiency virus (anti-HIV) and the hepatitis C virus (anti-HCV) among people admitted to an urban Canadian hospital. DESIGN: Anonymous unlinked serosurvey. SETTING: A 420-bed teaching hospital in Toronto. PARTICIPANTS: All 3000 patients admitted to the hospital on weekdays from January to June 1990. An attempt was made to exclude those who were readmitted during the study period. INTERVENTIONS: Serum samples from all the patients were tested for HBsAg and anti-HIV, and 1306 samples were also tested for anti-HCV by means of enzyme immunosorbent assays; reactions were confirmed by means of specific antibody neutralization or immunoblot assay. MAIN RESULTS: The prevalence rates of HBsAg, anti-HIV and anti-HCV were 2.1% (95% confidence interval [CI] 1.6% to 2.6%), 0.6% (95% CI 0.3% to 0.9%) and 0.5% (95% CI 0.1% to 0.9%) respectively. CONCLUSIONS: This is the first report defining rates of infection with these bloodborne agents among patients admitted to a Canadian hospital. The observed rates likely reflect the patient population served by our hospital and do not necessarily apply to other Canadian centres. The results support the use of universal precautions in health care settings.

Anti-HCV in post-transfusion hepatitis: deductions from a prospective study.

Stored sera from 52 patients who developed post-transfusion hepatitis (PTH) during a prospective study of PTH in Toronto in 1984/85, sera from 111 donors whose blood was transfused into these patients and sera from 50 patients with chronic active hepatitis with a remote history of blood transfusion were tested for anti-HCV. In patients with PTH seroconversion occurred relatively early. Ten converted in less than 14 weeks after transfusion. Only three of the 34 patients (9%) whose hepatitis resolved developed anti-HCV compared to 11 of 18 (61%) whose hepatitis became chronic. Patients who seroconverted had higher alanine aminotransferase (ALT) values during the phase of acute hepatitis than those who did not seroconvert. Most of the patients who developed PTH received blood that was negative for anti-HCV. Four donors whose blood was positive for anti-HCV transmitted hepatitis. Three of the patients developed anti-HCV and chronic hepatitis. One of the recipients did not seroconvert and the hepatitis resolved. Forty-two of the 50 patients (84%) with chronic hepatitis and a remote history of blood transfusion were positive for anti-HCV. We conclude that anti-HCV-positive donors may transmit hepatitis C; that if anti-HCV is diagnostic of hepatitis C, most cases of acute PTH are either not due to hepatitis C or may represent cases of hepatitis C in which the anti-HCV test was undetectable. On the other hand, most cases of PTH which progress to chronic hepatitis are caused by HCV.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum HBV-DNA (hepatitis B virus DNA) in acute and chronic hepatitis B infection.

HBV DNA was measured in the sera of 69 patients with hepatitis B virus infections. Sixteen patients had acute hepatitis B, 24 had chronic active hepatitis (CAH), 6 had chronic persistent hepatitis (CPH), 5 had cirrhosis without CAH and 18 were asymptomatic HBsAg carriers. In patients with acute hepatitis B who recovered, HBV DNA was present in the serum transiently early in the illness. HBV DNA persisted in the serum in the two patients who developed chronic hepatitis. Sera of 23 of 24 patients with CAH were persistently positive for HBV DNA. There was no relationship between the quantity of HBV DNA in the serum and the histological intensity of activity. Thirteen of the 24 patients with CAH had histological evidence of cirrhosis in addition to CAH and HBV DNA was detected in the sera of all 13. The sera of 2 of 6 patients with CPH were positive for HBV DNA. In one it was positive only where there was clinical evidence of reactivation of HBV infection. The other patient subsequently developed CAH. Sera of 5 patients with established HBsAg positive cirrhosis but without evidence of CAH were negative for HBV DNA. Two of these patients had hepatocellular carcinoma. Sera of 18 asymptomatic anti-HBe positive carriers with normal ALT were negative for HBV DNA. HBeAg and HBV DNA were not always found in the serum together. In acute hepatitis 5 patients with HBV DNA in the serum were HBeAg positive, but in 6 patients the sera were HBeAg positive inthe absenceof HBV DNA.

Posttransfusion hepatitis in Toronto, Canada.

Five hundred seventy-six consecutive patients from the surgical, obstetrical, and medical services who had received transfusions of volunteer blood were followed-up at regular intervals for 6 mo. Fifty-three (9.2%) developed acute posttransfusion non A, non B hepatitis. Forty-seven (89%) had an incubation period between 2 and 8 wk. The frequency was not related to the age or sex of the patient, the indications for transfusion, the type of surgery, anesthesia, the presence of perioperative hypotension, or the number of units of blood transfused. There were no cases of fulminant hepatitis. Nineteen of the 53 patients (36%) with acute posttransfusion hepatitis progressed to chronic hepatitis. Development of chronic hepatitis was not related to the age or sex of the patient, the incubation period of the preceding acute hepatitis, the presence of shock or malignancy, or the number of units of blood transfused. Patients with higher levels of alanine aminotransferase during the acute hepatitis were more prone to develop chronic hepatitis. The finding of 9.2% of transfusion-related hepatitis in recipients of hepatitis B surface antigen-screened blood from volunteer donors underscores the potential sequelae of blood transfusion, especially as a source of contribution to the pool of chronic liver disease.

Hepatitis B virus DNA in asymptomatic HBsAg carriers: comparison with HBeAg/anti-HBe status.

Sera of 17 HBeAg positive and 104 anti-HBe positive asymptomatic HBsAg carriers from two cohorts were tested for HBV DNA. HBV DNA was found in 13 of 17 HBeAg positive carriers (76.5%) and in only 7 of 104 of anti-HBe positive carriers (6.7%). Eleven of the 17 HBeAg positive carriers were retested for HBV DNA over a period of 7 to 36 months after the initial test. HBV DNA disappeared from the serum in 2 patients in spite of persistence of the HBe antigen. Of the 104 anti-HBe carriers, 89 were retested for HBV DNA over a period of 6 to 52 months after the initial test. HBV DNA disappeared from the serum in 5 of the 7 who were previously positive for HBV DNA, and persisted in 2. These findings indicate that there is an inconstant relationship between the time of seroconversion of HBeAg to anti-HBe and the disappearance of HBV DNA. In one HBeAg positive patient, HBV DNA, which was absent in the serum on first testing, was present on retesting. This suggests that the presence of HBV DNA in the serum of some patients may be intermittent. The presence of HBV DNA in the serum of some anti-HBe positive carriers accounts for the finding that they may be infective. All but one of the HBV DNA positive anti-HBe carriers were born outside North America, most in Asia. HBV DNA were found more frequently in the serum of anti-HBe positive carriers who had biochemical and histological evidence of liver disease than in carriers without such evidence.

Hepatitis B markers and risk factors for hepatitis B in liver biopsy patients.

As part of a study of all patients undergoing liver biopsy in 6 Toronto teaching hospitals from February 1, 1981 to January 31, 1982, participants had hepatitis B marker (HBV) studies and were interviewed concerning, among other things, potential hepatitis B exposure risk factors. All analyses were conducted by sex. Of 376 males, and 342 females participating in the study, complete data were available on 243 (65%) males and 230 (67%) females. Information was obtained on country of birth, race, previous exposure to hepatitis, previous blood transfusions, sexual preference, use of intravenous drugs, occupation, tattooing, and ear piercing. Thirty-five percent of males and 17 percent of females had at least one HBV marker present. Males with at least one HBV marker, compared to males with no HBV markers were more frequently oriental (p less than 0.001), homosexual (p less than 0.05), or born in a country with a higher level of HBV endemicity than in Canada (p less than 0.001). Females with at least one HBV marker, compared to females with no HBV markers were more frequently oriental (p less than 0.001), employed in a health occupation (p less than 0.05), or born in a country with a higher level of HBV endemicity than in Canada (p less than 0.0001). For each sex, multiple logistic regression analysis was conducted to adjust for potential confounding by significant variables detected in univariate analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of fatty infiltration or cirrhosis of the liver in relation to ethanol consumption: a case-control study.

A case-control study was conducted to investigate the risk of either fatty infiltration of the liver or cirrhosis, in males and females, in relation to varying levels of ethanol consumption. Male and female cases of fatty infiltration of the liver (47 males and 43 females) and male and female cases of cirrhosis (85 males and 66 females) were identified during 1981-1982 as part of a liver biopsy study in 6 teaching hospitals in Toronto. All cases were confirmed by biopsy. Male and female controls (394 males and 225 females) were obtained from 7 different local industries during the same period as part of a study for the early detection of liver disease. Cases and controls were interviewed by a nurse practitioner using a standard questionnaire designed to elicit data on daily and cumulative alcohol consumption. In both males and females, a dose-response effect between increasing levels of both daily and cumulative alcohol consumption and increasing risk of either fatty liver or cirrhosis was demonstrated and was independent of effects of age and duration of consumption. In males, risk for fatty liver was 1.37 (95% CL = 0.47, 4.0) for those consuming 40-59 g absolute alcohol/day compared to males consuming less than 40 g/day, rising to 50 (95% CL = 15.0, 170.7) for males consuming 80 or more g/day. In females, risk for fatty liver appeared at lower levels and was 2.82 (95% CL = 1.02, 7.82) for females consuming 20-59 g/day compared to females consuming less than 20 g/day, rising to 8.53 (95% CL = 2.12, 34.31) for females consuming 60 or more g/day.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA: DNA hybridization method for the diagnosis of hepatitis B infection.

Hepatitis B viral (HBV) DNA was detected in a hepatoma cell line which produces hepatitis B surface antigen (HBsAg) and in patients with acute hepatitis B. The serum of one patient with acute hepatitis B was found to be infectious when injected i.v. into a chimpanzee up to a dilution of 10(-8). Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were detectable in the same serum sample by radioimmunoassay up to a dilution of 10(-5) and of 10(-3), respectively. Using DNA: DNA hybridization on nitrocellulose membranes, HBV DNA sequences were detectable up to 10(-8) dilution corresponding to the infectivity level. Based on this finding, it appears that DNA: DNA hybridization is the most sensitive method for detecting hepatitis B virus (HBV) infection. In situations with low virus levels it may be the only indicator of the presence of infectious hepatitis B virus. The use of a tritium-labelled probe makes the method economical and adaptable to hospital laboratories.