G. Norkrans

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon

BACKGROUND/AIMSnThis study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA.nnnMETHODSnWe performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994.nnnRESULTSnAt biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients.nnnCONCLUSIONnIn this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection

SUMMARY.u2002 Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon‐alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non‐3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non‐3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non‐3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.

Long‐term clearance of hepatitis C virus following interferon α‐2b or peginterferon α‐2b, alone or in combination with ribavirin

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG‐IFN) α‐2b or IFN α‐2b. We conducted two phase 3b long‐term follow‐up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α‐2b and/or PEG‐IFN α‐2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow‐up studies. In total, 636 patients with SVR following treatment with IFN α‐2b and 366 with SVR following treatment with PEG‐IFN α‐2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α‐2b and three patients treated with PEG‐IFN α‐2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1–99.7%] for IFN α‐2b and 99.4% (95% CI, 97.7–99.9%) for PEG‐IFN α‐2b. Successful treatment of hepatitis C with PEG‐IFN α‐2b or IFN α‐2b leads to clinical cure of hepatitis C in the vast majority of cases.

Therapy of chronic post-transfusion non-A, non-B hepatitis with interferon alfa-2b: Swedish experience

Thirty-three Swedish patients with chronic post-transfusion non-A, non-B hepatitis entered a randomized trial of interferon alfa-2b treatment (INTRON A, Schering-Plough Corporation) (3 million units, three times weekly, subcutaneously for 36 weeks). Twenty-two patients (67%) were reactive for antibodies against hepatitis C virus. Nineteen patients completed the course of therapy; 11 (58%) had a complete response with normalization of serum alanine aminotransferase levels, compared to none of the 12 controls (p less than 0.001). Four treated patients with chronic active hepatitis were non-responders. Non-responders had a significantly higher mean body weight than responders (p less than 0.05) and tended to have a longer duration of prior disease. During the 10-month follow-up period post treatment, 4/11 (36%) complete responders had a sustained response and three (75%) of these four were reactive for antibodies against hepatitis C virus, whereas 7/11 (64%) relapsed, of whom four (57%) were reactive for antibodies against hepatitis C virus. All patients who were treated again responded but relapsed once more after retreatment was stopped. We conclude that the majority of patients with chronic post-transfusion non-A, non-B hepatitis will respond to 9 months interferon alfa-2b treatment, but that only one of three responders will have a sustained response 10 months post treatment. Reactivity for antibodies against hepatitis C virus is not predictive of the outcome of therapy.

Comparison of 3 Quantitative HCV RNA Assays - Accuracy of Baseline Viral Load to Predict Treatment Outcome in Chronic Hepatitis C

The correlation between 3 assays for hepatitis C virus (HCV) RNA quantification and their respective accuracy in predicting the response to interferon and interferon/ribavirin therapy was evaluated by analysing pre-treatment sera from 100 patients. A total of 97%, 100%, and 98% of the patients tested positive by the branched DNA 2.0 assay (Quantiplex), a multi-cycle reversed transcriptase polymerase chain reaction quantitative assay (Superquant) and the Roche Amplicor Monitor assay, respectively. The correlations between the assays, in all patients and in the major genotypes 1, 2, and 3, were significant, although the levels detected by the Amplicor Monitor assay were more than 1 log lower than by the other assays. Sustained virological responders to interferon therapy, but not to combination therapy, had lower baseline viral levels than long-term non-responders (p = 0.002 by Quantiplex 2.0; p = 0.008 by Superquant; p = 0.06 by Roche Amplicor Monitor). Pre-treatment viral load greater than 3 x 10(6) Eq or copies/ml by the Quantiplex 2.0 and Superquant assays and greater than 100,000 copies/ml by the Amplicor Monitor assay predicted long-term non-response in 94%, 93% and 91% of the interferon treated patients, respectively. In conclusion, acceptable correlations between available commercial quantitative assays were found. High baseline viral load predicted long-term non-response to interferon monotherapy, whereas it did not to interferon/ribavirin combination therapy.

Perinatal transmission of hepatitis G virus (GB virus type C) and hepatitis C virus infections--a comparison.

Hepatitis G virus (HGV) infection is more common than hepatitis C virus (HCV) infection and is frequently found in healthy individuals. Although parenteral spread of HGV is well recognized, other routes of transmission probably occur as well. In a prospective study of mother-to-infant transmission of hepatitis viruses, 69 pregnant women with antibodies to HCV and their 81 newborn children were included. Serum levels of HCV RNA and HGV RNA were detected by polymerase chain reaction (PCR) assays, and antibodies to HCV and HGV envelope protein E2 were detected by enzyme-linked immunosorbent assay. Fifty-nine of the mothers had HCV viremia, whereas 16 had HGV viremia. HCV transmission from viremic mothers occurred in 2.8%-4.2% of the cases, whereas HGV transmission from viremic mothers occurred in 75.0%-80.0% of the cases (P < .001). Sequencing of the PCR products of HGV from the mother-infant serum pairs showed minor differences in most cases but sequence homology in each pair. Although the rate of perinatal HGV transmission highly exceeded that of perinatal HCV transmission, HGV did not seem to induce hepatitis in the children.

Hepatitis C virus RNA kinetics during the initial 12 weeks treatment with pegylated interferon-alpha 2a and ribavirin according to virological response

Summary.u2002 To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non‐1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non‐1, 19 and 34, respectively) during treatment with pegylated interferon α‐2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, Pu2003=u20030.0003 and 2.89 vs 1.72 at week 4, Pu2003=u20030.0159), whereas no difference was noted after day 1. For patients with a 2‐log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2‐log10 drop. For patients with genotype non‐1 and a 2‐log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non‐1 were 43, 40 and 100% respectively. During treatment with pegylated interferon α‐2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2‐log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.

Chronic Hepatitis C in Sweden: Genotype Distribution Over Time in Different Epidemiological Settings

Hepatitis C virus (HCV) strains are divided into 6 genotypes and several subtypes. Recent studies reported a change in the relative frequency of genotypes within certain regions. We studied the HCV genotype in 312 Swedish patients with chronic hepatitis C, using a core region primer-specific PCR, and grouped the patients according to parenteral risk factors. The date of infection could be estimated in 127 cases. Genotypes 1a (35%) and 3 (31%) were the most common genotypes, followed by genotype 2 (17%), while only 6% had genotype 1b. Genotype 3 was relatively more frequent among subjects infected sexually or by intravenous drug use. The genotype distribution was different from that in studies from other parts of the world, with a lower frequency of genotype 1 (especially 1b) and a higher frequency of genotype 3. The frequency of genotype 1b has decreased and genotype 3 increased over time. The reasons for a different distribution of genotypes in Sweden, compared with other countries, might be a relatively recent introduction of HCV into the population, or a different pattern of transmission.

HCV genotypes in Swedish blood donors as correlated to epidemiology, liver disease and hepatitis C virus antibody profile

SummarySixty-two anti-HCV and HCV-RNA positive Swedish blood donors (44 men, 18 women; median age 34 years) were studied. HCV genotypes were correlated to parenteral risk factors, liver morphology, serum alanine aminotransferase (ALAT) levels and HCV antibody profile. Forty percent of the donors were infected with HCV genotype 1a, 10% with 1b, 21% with 2b, and 29% with 3a. Intravenous drug use (IVDU) was more common in donors with genotype 3a than in those with genotype 1a (p=0.024), and prior blood transfusion more common in genotype 2b than in 3a (p=0.012). Chronic active hepatitis with and without cirrhosis was found in 38% of donors infected with genotype 2b as compared to 8% of donors infected with 1a (p=0.034). Forty percent of donors with genotype 1a had normal ALAT at the time of liver biopsy versus 11% with genotype 3a (p=0.046). Antibodies to C33c and C22-3 were present in nearly all donors whereas reactivity to C100-3 and 5-1-1 was detected more often in donors with genotypes 1a and 1b as compared to donors with genotypes 2b and 3a. In conclusion, genotype 3a was correlated to IVDU or tattooing as parenteral risk factors for the acquisition of HCV infection, and genotype 2b to prior blood transfusion. Donors with genotypes 1a seemed to have less severe liver disease than those infected with genotypes 2b and 3a.Zusammenfassung62 anti-HCV und HCV-RNA-positive schwedische Blutspender (44 Männer, 18 Frauen, Alter im Median 34 Jahre) wurden untersucht. Die HCV-Genotypen wurden in Korrelation gesetzt zu parenteralen Risikofaktoren, Lebermorphologie, Serum-Alanin-Aminotransferase (ALAT)-Spiegeln und HCV-Antikörperprofil. 40% der Spender waren mit dem HCV-Genotyp 1a infiziert, 10% mit 1b, 21% mit 2b und 29% mit 3a. Bei Spendern mit Genotyp 3a bestand häufiger eine Vorgeschichte von intravenösem Drogenabusus als bei den mit Genotyp 1a Infizierten (p=0,024). Bluttransfusionen waren bei Genotyp 2b häufiger vorausgegangen als bei Typ 3a (p=0,012). Bei 38% der mit Genotyp 2b aber nur bei 8% der mit Genotyp 1a infizierten Spender fand sich eine chronisch aktive Hepatitis mit oder ohne Zirrhose (p=0,034). 40% der Spender, die Genotyp 1a aufwiesen, hatten zur Zeit der Leberbiopsie normale ALAT-Werte, bei Genotyp 3a waren es nur 11% (p=0,046). Bei fast allen Spendern waren Antikörper gegen C33c und C22-3 nachzuweisen. Reaktivität gegen C100-3 und 5-1-1 fand sich häufiger bei Spendern mit Genotyp 1a oder 1b als bei Spendern mit Genotyp 2b oder 3a. Zusammenfassend ist festzustellen, daß Genotyp 3a mit intravenösem Drogenabusus oder Tätowierung als Risikofaktoren für eine intravenöse Akquisition der Infektion assoziiert war, Genotyp 2b dagegen mit Bluttransfusionen. Spender mit Genotyp 1a hatten offensichtlich eine weniger schwere Lebererkrankung als Spender, die mit den Genotypen 2b oder 3a infiziert waren.

Second-generation hepatitis C Elisa antibody tests confirmed by the four-antigen recombinant immunoblot assay correlate well with hepatitis C viremia and chronic liver disease in Swedish blood donors

Seventy‐three Swedish blood donors (52 men, 21 women; median age 36 years) repeatedly reactive for hepatitis C antibodies (anti‐HCV C‐100‐3) were tested with a second‐generation (2nd‐gen) anti‐HCV Elisa and a 4‐band recombinant immunoblot assay (RIBA 2). These results were correlated to serum alanine aminotransferase (S‐ALAT), liver morphology and viremia as detected by ‘nested’ polymerase chain reaction (PCR) based on primers from a 5′‐noncoding sequence of the HCV genome. Thirty‐five of 46 (76%) donors with positive 2nd‐gen Elisa tests confirmed by RIBA 2 were PCR positive whereof 27 had histological findings compatible with chronic persistent hepatitis (CPH) and 7 had chronic active hepatitis (CAH). Ten of 56 (18%) 2nd‐gen Elisa‐positive donors were RIBA 2 negative (or indeterminate) and none of these had chronic hepatitis nor were PCR positive. Seventeen of 73 (23%) donors were 1st‐gen Elisa positive but 2nd‐gen Elisa negative. All of these were PCR negative and only 1 (6%) had chronic hepatitis (CPH). An elevated S‐ALAT level (reference <0.7 μkat/1) was found in 26 2nd‐gen Elisa and RIBA 2‐positive donors of which 18 had CPH and 7 had CAH and all 25 were PCR positive. A normal S‐ALAT level was found in 9 of 34 (26%) donors with chronic hepatitis (all had CPH) and positive PCR. We have found that blood donors with positive 2nd‐gen anti‐HCV Elisa tests confirmed by RIBA‐2 and especially with a concomitant elevated S‐ALAT are highly likely to be viremic as demonstrated by PCR and to have chronic hepatitis.