Tony Carlsson

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

Summary.  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 μg/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 μmol/L. Interferon related side‐effects were common, in one patient peg‐alfa‐2b was permanently reduced to 50 μg 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.

A Risk for Hepatocellular Carcinoma Persists Long-term After Sustained Virologic Response in Patients With Hepatitis C-Associated Liver Cirrhosis

BACKGROUND The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. METHODS These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. RESULTS Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. CONCLUSIONS The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

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 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, 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 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.

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.

Pegylated interferon and ribavirin combination therapy for chronic hepatitis C virus infection in patients with Child-Pugh Class A liver cirrhosis

Objective. Pegylated interferon (peg-IFN) and ribavirin (RBV) treatment is less effective in patients with hepatitis C virus (HCV) and liver cirrhosis than in non-cirrhotic patients. Many patients with advanced liver disease have been excluded from the pivotal randomized controlled studies. The aim of this study was to investigate the efficacy and tolerability of combination therapy in unselected patients with Child-Pugh Class A liver cirrhosis at a Swedish university clinic. Material and methods. The virologic response and adverse events were retrospectively analyzed in 104 patients with HCV-associated Child-Pugh Class A liver cirrhosis who had been treated with peg-IFN and RBV. Results. Overall sustained virologic response (SVR) was achieved in 13% genotype 1-, 60% genotype 2-, and 31% genotype 3-infected patients. In treatment-naïve patients, the corresponding rates were 13%, 82%, and 38%, respectively. In 46% of patients, treatment was discontinued prematurely owing to lack of virologic response in the majority. Conclusions. SVR rates found in our study, in particular for genotype 1 patients (13%), were lower than those generally found in randomized controlled studies. For cirrhotic patients, new treatment alternatives are urgently needed to improve treatment outcome.

The anti-HBs response after 2 different accelerated intradermal and intramuscular schemes for hepatitis B vaccination

To study early seroconversion rates after hepatitis B vaccination intramuscular (i.m.) and low-dose intradermal (i.d.) vaccination was compared when given either according to the registered 0, 4, 8 weeks scheme (scheme A), or to an accelerated 0, 2, 6 weeks scheme (scheme B). Medical staff received either 2 microg i.d. or 20 microg i.m. of a recombinant hepatitis B vaccine, in a non-randomized open trial. Two weeks after the third dose i.m. vaccinees overall had significantly higher rates of protective anti-HBs levels (anti-HBs > or = 10 IU/I), (23/30, 77%) compared with i.d. vaccinees (75/166, 45%) (p < 0.001). We conclude that when rapid protection against hepatitis B virus (HBV) infection is desirable, such as for post-exposure prophylaxis, an accelerated low-dose i.d. vaccination schedule cannot be used.

Rapid viral response and treatment outcome in genotype 2 and 3 chronic hepatitis C: comparison between two HCV RNA quantitation methods

Fifty consecutive patients with genotype 2 or 3 chronic hepatitis C were treated with peg‐IFN alfa‐2a 135 µg weekly and ribavirin (11 mg/kg body weight) daily during 24 weeks. Rapid viral response treatment week 4, end‐of‐treatment response, and sustained viral response were analyzed by two different HCV RNA quantitation methods, the Cobas Amplicor Monitor test and the TaqMan test with a sensitivity of 600 and 15 IU/ml, respectively. The TaqMan test differentiated patients with rapid viral response finally achieving sustained viral response better. Hence, patients with and without rapid viral response as tested by the TaqMan test finally achieved sustained viral response in 97% (32/33) versus in 75% (12/16), P < 0.017. The corresponding figures for the Cobas Amplicor test was 91% (41/45) versus (80%) 4/5 a non‐significant difference. In conclusion, the more sensitive TaqMan test yielded a lower number of patients with rapid viral response than the less sensitive Amplicor Monitor test, but predicted sustained viral response in a higher percentage of patients with rapid viral response than the Amplicor Monitor test. A rapid viral response meaning HCV RNA levels <15 IU/ml predicted a sustained viral response in 97% of patients with genotype 2 or 3. J. Med. Virol. 80:803–807, 2008.

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.

High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1-Infected Patients.

Background: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration-monitored ribavirin. Methods: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of >15 &mgr;mol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. Results: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P < 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. Conclusions: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given.

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 × 106 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.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.