Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.

Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b (n = 4) and pegylated interferon-alfa-2a (n = 2) for 24-48 weeks according to genotype with a dose of 50 or 135 mug/week respectively. All patients were given reduced ribavirin doses, initially 200-400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10-15 micromol/L. Interferon related side-effects were common, in one patient peg-alfa-2b was permanently reduced to 50 mug every 9-10 days with improvement in tolerance. Average ribavirin dose was 170-300 mg/day. Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood-transfusions were not needed. All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.

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

SUMMARY: 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 alpha-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, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), 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 alpha-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.

Viral kinetics and treatment response in patients with hepatitis C during induction and standard interferon therapy in combination with ribavirin.

BACKGROUND: The early decline of hepatitis C virus (HCV) RNA levels during therapy may predict the outcome and can be utilized to improve treatment regimens. We studied the HCV RNA levels during induction and standard interferon (IFN) and ribavirin treatment. METHODS: Patients received IFN 3 MU daily for 14 days followed by 3 MU three times a week (induction group; n = 10), or IFN 3 MU three times a week from start (standard group; n = 21), in combination with ribavirin 1000-1200 mg/day. HCV RNA was quantified day 0, 1, 2, 3, 7, 14, 28, 56 and 84 during treatment, and tested qualitatively at the end of treatment and at follow-up. RESULTS: The initial viral load decline was more pronounced in the induction group, and in patients infected with genotype non-1. The sustained response rate was not significantly different between the study groups. At day 1, the mean viral load decline from baseline was significantly greater in patients who became sustained responders than in those who became non-responders; 1.4 log (96%) versus 0.3 log (55%) (P < 0.05). All sustained responders had a viral load decline of at least 0.7 log (79%) after the first IFN dose. CONCLUSIONS: Our short-term induction treatment did not improve the long-term treatment outcome significantly, although a trend was seen. An absent or low initial viral load decline can be used to predict non-response in the individual patient.

Cost-effectiveness of interferon alfa-2b with and without ribavirin as therapy for chronic hepatitis C in Sweden.

BACKGROUND: Recent trials have shown that treatment with a combination of interferon alfa-2b and ribavirin results in sustained loss of detectable hepatitis C-virus (HCV) RNA in a higher proportion of patients than treatment with interferon alone. Combination therapy, however, is two to three times as expensive as monotherapy. METHODS: Based on data from recent randomized clinical trials and a previously published decision model, we developed a Markov model to estimate the cost-effectiveness of initial combination therapy with interferon and ribavirin versus interferon alone for previously untreated patients with chronic HCV infection in Sweden. Clinical praxis and quality adjustments were based on expert estimates and costs were gathered from different health care providers in Sweden. RESULTS: Combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 0.5 to 1.1 years at marginal cost-effectiveness ratios of US$ 1,400 to US$ 6,000 per DQALY (discounted quality-adjusted life-year) for patients with genotype 1. In genotype 1, 48 weeks compared to 24 weeks of combination therapy prolonged quality adjusted life expectancy by 0.6 years at a marginal cost-effectiveness ratio of $US 9,800 per DQALY. For patients with genotype non-1, combination therapy for 24 or 48 weeks, compared to interferon alone, prolonged quality adjusted life expectancy by 2.3 years, with combination therapy for 24 weeks being money-saving. The results were robust in sensitivity analyses. CONCLUSION: Combination therapy with interferon and ribavirin increased quality-adjusted life expectancy and was cost-effective for patients with chronic hepatitis C.

Hepatitis C virus kinetics during induction and standard 3 times a week interferon-alpha therapy.

We studied HCV kinetics during the first 84 d of interferon-alpha (IFN) treatment. IFN was administered either at a dose of 3 million units daily for the first 14 d and thereafter 3 times per week (t.i.w.) (induction treatment), or at a dose of 3 million units t.i.w. throughout (standard treatment). No patient had received HCV treatment previously, and all had a pretreatment viral load of < 1.2 x 10(6) IU/ml at screening. Ten patients were given induction treatment and 21 received the standard t.i.w. regimen. Twenty patients were infected with genotype 1. At Day 2, the median HCV RNA level in the induction group was significantly lower compared to that of the standard treatment group. This significant difference persisted during the study period for patients infected with genotype 1, but was not maintained from Day 14 onwards for patients with genotype non-1. At Day 84, 80% (8/10) of patients in the induction group, compared to 16% (3/19) in the standard treatment group, had undetectable (< 600 IU/ml) HCV RNA levels (p < 0.05). We conclude that induction treatment resulted in a significantly greater decline in HCV RNA levels than standard treatment.

HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin.

Interferon (IFN) alpha in combination with ribavirin (RIB) is standard therapy for patients with chronic hepatitis C virus (HCV) infection. However, many patients do not respond with sustained HCV clearance to this therapy. At present, no accepted treatment strategy exists for these patients. Recent preliminary data have suggested that amantadine (AMA) is effective against HCV infection. In a pilot study, we treated 13 nonresponders and 10 response/ relapsers to previous IFN/RIB therapy with AMA 200 mg per day in combination with IFN 3 MU thrice weekly, and RIB 1000 mg per day for 24 weeks, with a 24-week follow-up period after end-of-treatment. At the end-of-treatment, 1 previous nonresponder and 5 previous response/relapsers were HCV RNA negative. At the end of follow-up, only 1 previous response/relapser remained HCV RNA negative and had a sustained response. During therapy, serum HCV RNA became undetectable in 4 previous nonresponders, of whom 3 had a breakthrough at week 24. Twenty-one patients continued therapy without dose reductions. One patient discontinued therapy prematurely due to sleeping disturbances, and another patient was withdrawn from therapy due to heavy alcohol intake. We conclude that the addition of AMA to IFN and RIB was well tolerated but had little, if any, impact on HCV RNA eradication in nonresponders or response/relapsers to previous IFN/RIB combination therapy.

Histological and virological long-term outcome in patients treated with interferon-alpha2b and ribavirin for chronic hepatitis C.

Long-term virological and histological outcome following interferon-alpha2b (IFN-alpha2b) and ribavirin treatment for 24 weeks was studied in 20 patients with chronic hepatitis C who were without a lasting response to IFN as monotherapy. Following combination therapy, sustained virological response (SR) was achieved in 12 patients (i.e. hepatitis C virus (HCV) RNA negative in serum 6 months post-treatment). Eleven of these patients remained HCV RNA negative in serum 2 years post-treatment. A virological long-term response (LTR) was more frequent in patients with a previous end-of-treatment response to IFN monotherapy than in non-responders. Liver histology at follow-up, >/=24 months post-treatment, showed substantial improvement in patients with a virological LTR to the combination treatment. In all nine patients biopsied at the 2-year follow-up, liver inflammation had disappeared totally (grade=0), and the stage (fibrosis) had improved. In contrast, no significant changes in grade or stage were noted in patients with a virological non-LTR to combination treatment. A significant improvement in inflammation was noted, in patients with a virological LTR, from 3.6 to 0.2 (P<0.01) and in fibrosis from 2.0 to 1.4 (P<0.05) whereas the corresponding scores for patients with a virological non-LTR did not change significantly, from 3.1 to 1.5 for inflammation and for fibrosis from 1.3 to 1.3. We conclude that patients with chronic hepatitis C who achieve a virological sustained response 6 months post-treatment with IFN-alpha2b and ribavirin will remain virological responders for a follow-up period of least 24 months, concomitant with a disappearance of inflammatory activity and a marked improvement of fibrosis in the liver.

Influence of pre-treatment factors on outcome of interferon-alpha treatment of patients with chronic hepatitis C.

A total of 172 Swedish patients treated with interferon-alpha for at least 24 weeks and followed-up > or =24 weeks after treatment was stopped were analysed for pre-treatment factors of importance for achieving a virological sustained response (SR). Furthermore, the predictive value for a virological SR of a positive or negative HCV RNA test at week 12 of treatment was evaluated. A low baseline viral load and genotype non-1b were pre-treatment factors indicating a favourable response. Thus, 44% (38/86) of patients with a low baseline viral load vs. only 16% (14/86) of those with a high viral load had a virological SR (p<0.0001). Of patients with a negative qualitative HCV RNA test after 12 weeks of interferon treatment, 46% (44/95) had virological SR, whereas only 5.9% (4/68) of those with a positive test had (p<0.0001). Prolonged ( > 6 months) treatment with interferon-alpha tended to increase the chance of virological SR (p<0.052).

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

BACKGROUND/AIMS: This 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. METHODS: We 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. RESULTS: At 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. CONCLUSION: In 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.

Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.

BACKGROUND: Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon alpha-2b and ribavirin than with interferon alpha-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon alpha-2b and ribavirin compared with interferon alpha-2b alone. METHODS: In this double-blind trial 100 patients were randomly assigned to treatment with interferon alpha-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. FINDINGS: 18 (36%) of the 50 patients in the interferon alpha-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon alpha-2b and placebo group (p = 0.047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon alpha-2b and ribavirin group than the interferon alpha-2b and placebo group (42 vs 20%, p = 0.03), respectively. More patients with baseline HCV-RNA concentrations greater than 3 x 10(6) genome equivalents (Eq) per mL had a sustained response with interferon alpha-2b and ribavirin than with interferon alpha-2b and placebo (12/29 vs 1/26, p = 0.009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3 x 10(6) Eq per mL (6/21 vs 8/24, p = 0.67), respectively. INTERPRETATION: More patients with chronic hepatitis C have a sustained virological response with interferon alpha-2b and ribavirin than with only interferon alpha-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon alpha-2b and ribavirin.

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.

Therapy of hepatitis C: alpha interferon and ribavirin.

Ribavirin is a nucleoside analogue that has been evaluated as a therapy of chronic hepatitis C alone and in combination with alpha interferon. Ribavirin is well absorbed orally and is typically given in doses of 1,000 to 1,200 mg/d. Three randomized, placebo-controlled studies comprising more than 150 patients have shown that therapy with ribavirin alone for 24 to 48 weeks resulted in a significant reduction in serum alanine aminotransferase (ALT) levels during therapy. However, ribavirin therapy did not lead to a substantial reduction in hepatitis C virus (HCV) RNA levels; almost all patients remained viremic, and serum aminotransferase levels increased to pretreatment values when therapy was stopped. The most common adverse event was a moderate and reversible hemolysis during treatment that caused a decrease in hemoglobin by 10% to 20% of baseline levels. Combination therapy of ribavirin with alpha interferon has demonstrated promise both in pilot studies and a recently completed randomized controlled trial. Ribavirin in standard doses combined with alpha interferon in doses of 3 million units (MU) three times weekly for 6 months was found to significantly improve the sustained biochemical and virological response rates compared with interferon alone. Combination therapy offers a promise to become standard therapy for patients with nonsustained response to alpha interferon alone, because the majority of such patients achieve a durable response after treatment with combination therapy. However, nonresponders to alpha interferon alone rarely achieve a sustained beneficial response to combination treatment. For interferon-naive patients, combination therapy is superior to therapy with alpha interferon alone in achieving sustained biochemical and virological responses, but the combination demonstrates clear-cut superiority only in patients with unfavorable profiles for a response to interferon, in particular patients with high levels of HCV RNA. The optimal use and regimen of combination therapy awaits further investigation. New antiviral agents are still needed for the proportion of patients who do not respond to alpha interferon, even in combination with ribavirin.

Interferon-alpha 2b treatment in hepatitis B carriers. Effect on hepatitis B virus DNA levels in children infected with different genotypes.

Eleven hepatitis B virus (HBV) carrier children, infected with genotypes A-D, were treated with interferon-alpha. Two children had a sustained loss of hepatitis B e-antigen and HBV DNA. They were infected with the non-Asian genotypes A and D, and had low HBV DNA and high ALT levels in serum before treatment. However, HBV DNA titres decreased during treatment also in children infected with the East-Asian genotypes B and C.

Short-term versus sustained response to interferon therapy: effect on histology.

In order to evaluate the histological treatment response in patients with chronic hepatitis C virus (HCV) infection, different histological scoring systems have been developed. The scoring systems provide means of statistically comparing histopathological parameters in serial liver biopsies and have thus become important requirements of therapeutic trials. Patients with biochemical and virological responses to interferon (IFN) also improve histologically during treatment. However, after treatment cessation, many patients will have a biochemical/virological relapse. These short-term responders also relapse histologically, thus limiting the long-term benefit of a single treatment course, although, repeated courses of IFN in short-term responders may retard histological deterioration. In contrast, sustained biochemical/virological responders seem to have a durable histological response with a continuous and gradual improvement of all necroinflammatory parameters and fibrosis posttreatment.

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study.

BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS: A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS: Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS: These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

Factors influencing the response to interferon therapy in chronic hepatitis C. Studies on viral genotype and induction of 2',5'-oligoadenylate synthetase in the liver and peripheral blood cells.

BACKGROUND: The mechanism behind the antiviral action of interferon (IFN) therapy in chronic hepatitis C virus (HCV) infection is not well understood, and, furthermore, few factors have been shown to be good predictors of a favourable response to IFN treatment in chronic HCV infection. METHODS: Freshly explanted liver cells and peripheral blood mononuclear cells (PBMC) from 80 patients with chronic HCV infection were used to study the capacity of IFN to induce the enzyme 2',5'-oligoadenylate synthetase (2'5'-AS) in vitro. The HCV genotype was determined in 53 patients. The induction of 2'5'-AS was correlated to the results of IFN-alpha treatment in 36 patients. RESULTS: Normalization of transaminases during IFN treatment was significantly associated with 2'5'-AS levels in liver cells cultured in the absence of IFN. A similar tendency, although not statistically significant, was found for IFN-induced levels of 2'5'-AS in liver cells. No such associations were found when PBMC were analysed. Six patients showed a sustained biochemical response. These six did not deviate significantly from the remaining patients with regard to base-line or IFN-induced levels of 2'5'-AS in liver cells or PBMC. Eradication of HCV RNA during IFN treatment did not correlate with 2'5'-AS levels in liver cells. Comparison of HCV genotype and clinical response showed that patients with genotype 3a had the most favourable outcome. No association was found between liver histology and treatment outcome. CONCLUSION: These data imply that direct effects of IFN on liver cells are of importance for the response to IFN treatment.

Two-year biochemical, virological, and histological follow-up in patients with chronic hepatitis C responding in a sustained fashion to interferon alfa-2b treatment.

Fourteen patients with chronic hepatitis C who had a sustained response to a 60-week interferon alfa-2b treatment course were followed, biochemically and virologically, 2 years after treatment cessation. Biopsies were repeated in 12 of 14 for histological and virological evaluation at 2-year follow-up. All 14 patients had normal serum alanine transaminase (s-ALT) levels and were negative for hepatitis C virus (HCV) RNA in serum during treatment and at short-term follow-up 6 months post-treatment. At 2-year follow-up, 13 patients still had normal ALT levels (< 0.6 mukat/L for women; < 0.8 mukat/L for men), 1 a near normal level (0.76 mukat/L); all were HCV RNA negative in serum, and 11 of 12 also in the liver. Liver histology improved during treatment and remained stable during the 2-year follow-up. The authors conclude that most sustained responders, who have normal ALT levels and are nonviremic at short-term follow-up 6 months after interferon treatment, will continue to have a durable long-term response without relapse of the viremia.