Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C.

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

Impact of international consensus guidelines on antiviral therapy of chronic hepatitis C patients in Switzerland.

AIM OF THE STUDY: To assess the impact of international consensus conference guidelines on the attitude of Swiss specialists when facing the decision to treat chronic hepatitis C patients. METHODS: Questionnaires focusing on the personal situation and treatment decisions were mailed to 165 patients who were newly diagnosed with hepatitis C virus (HCV) infection and enrolled into the Swiss Hepatitis C Cohort Study during the years 2002-2004. RESULTS: Survey respondents (n = 86, 52.1%) were comparable to non-respondents with respect to severity of liver disease, history of substance abuse and psychiatric co-morbidities. Seventy percent of survey respondents reported having been offered antiviral treatment. Patients deferred from treatment had less advanced liver fibrosis, were more frequently infected with HCV genotypes 1 or 4 and presented more often with a history of depression. There were no differences regarding age, socio-economic background, alcohol abuse, intravenous drug abuse or methadone treatment when compared with patients to whom treatment was proposed. Ninety percent of eligible patients agreed to undergo treatment. Overall, 54.6% of respondents and 78.3% of those considered eligible had actually received antiviral therapy by 2007. Ninety-five percent of patients reported high satisfaction with their own hepatitis C management. CONCLUSIONS: Consistent with latest international consensus guidelines, patients enrolled in the Swiss Hepatitis C Cohort with a history of substance abuse were not withheld antiviral treatment. A multidisciplinary approach is warranted to provide antiviral treatment to patients suffering from depression.

Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. PATIENTS AND METHODS: In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). RESULTS: 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. CONCLUSIONS: Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.

Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients.

SUMMARY: Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Comparison of two PEG-interferon alpha-2b doses (1.0 or 1.5 microg/kg) combined with ribavirin in interferon-naïve patients with chronic hepatitis C and up to moderate fibrosis.

Health regulatory approval of the 1.5 microg/kg body weight dose of pegylated interferon (PEG-I) alpha-2b in combination with ribavirin for the treatment of chronic hepatitis C was based on a study using PEG-I alpha-2b at doses of only 0.5 and 1.5 microg/kg body weight (BW), in spite of the previously shown flat dose-response curve at doses of > or =1.0 microg/kg. Our aim was to compare PEG-I alpha-2b 1.0 microg/kg with 1.5 microg/kg, both in combination with ribavirin. Open-label, randomized study in 227 patients with biopsy-proven chronic hepatitis C (Metavir < or =F2), receiving oral ribavirin (400 mg, twice daily) in combination with subcutaneous PEG-I alpha-2b (1.0 or 1.5 microg/kg, once weekly) for 24 weeks (genotype 2 or 3), or 48 weeks (other genotypes), followed by a 24-week drug-free period. Virologic response rates did not differ between the two doses of PEG-I alpha-2b: in patients infected with hepatitis C virus (HCV) genotype 1 or 4 treated with PEG-I 1.0 microg/kg BW, 38% (22/58) had a sustained virologic response compared with 39% (27/70) in the PEG-I 1.5 microg/kg BW dose group (P = ns). The corresponding values in patients infected with HCV genotype 2 or 3 were 71% (39/55) and 81% (29/36) respectively (P = ns). Adverse events led to transient or permanent dose reductions in fewer patients in the 1.0 microg/kg BW dose group (48/113 patients; 42%) than in the 1.5 microg/kg BW dose group (63/106 patients; 59%, P = 0.015). Furthermore, 89% of patients treated for 24 weeks but only 58% of patients treated for 48 weeks (P < 0.001) tolerated the treatment without relevant dose reduction or premature termination. In combination with ribavirin, PEG-I alpha-2b 1.0 microg/kg was as effective as 1.5 microg/kg but was better tolerated in patients with chronic hepatitis C and up to moderate fibrosis.

[Cost comparison of two combination therapies with peginterferon alfa and ribavarin for the treatment of hepatitis C]. / Kostenvergleich zwischen zwei Kombinationstherapien gegen Hepatitis C mit pegylierten Interferonen und Ribavirin.

The two approved combination therapies for the treatment of hepatitis C in Switzerland (Pegasys/Copegus, PAC; PegIntron/Rebetol, PIR) are very similar in terms of efficacy and safety. This study aims at comparing the cost of the two therapies and determining the cost-efficient treatment algorithm. Average cost amounts to CHF 21700.-(PAC) and CHF 19700.- (PIR) for patients with genotype 1 and to CHF 15600.- (PAC) and CHF 15000.- (PIR) for patients with genotype 2/3, respectively. The consistent use of PIR is 9 to 12% cheaper than PAC. Further cost savings of 3% are possible if patients with a bodyweight below 85 kg (genotype 1) or below 75 kg (genotype 2/3) are treated with PIR while patients with a bodyweight over 85 kg (genotype 1) or over 75 kg (genotype 2/3) are treated with PAC.

Hepatocellular defence against acidosis is preserved after cold storage.

BACKGROUND: Primary non-function of liver allografts is related to preservation time, during which hypoxia leads to intracellular accumulation of acid. Preservation-induced failure of hepatocellular pH regulation may play a role in the pathogenesis of primary graft non-function. METHODS: Using cultured/suspended rat hepatocytes and fluorimetric determination of intracellular pH, we determined whether preservation in University of Wisconsin solution (4 degrees C) impairs hepatocellular defence mechanisms against acidosis. RESULTS: In non-preserved, 24-h-preserved and 48-h-preserved hepatocytes acidified to pH 6.7-6.8, initial Na+/H+ antiport-mediated H+ fluxes averaged 12 +/- 5, 9 +/- 5 and 12 +/- 5 nmol microL-1 min-1 and initial Na+/HCO3- symport-mediated HCO3- fluxes 7 +/- 2, 7 +/- 3 and 6 +/- 2 nmol microL-1 min respectively (P = NS). Preservation did not affect the inverse relationship between Na+/H+ antiport activity and intracellular pH. Thus, hepatocellular defence against intracellular acidosis is maintained during up to 48 h in University of Wisconsin solution. CONCLUSION: Altered pHi homeostasis is unlikely to play a role in the pathogenesis of primary non-function of liver allografts.

Decreased release of glutathione into the systemic circulation of patients with HIV infection.

Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. In order to gain more insight into the mechanisms responsible for the deranged sulphydryl homeostasis in HIV infection, the release of GSH into the circulation, an estimate of the systemic production of GSH, was determined using a pharmacokinetic approach. The basal plasma concentrations of free GSH (3.3 +/- 1.3 vs. 5.3 +/- 1.9 mumol L(-1)) and cysteine (7.7 +/- 2.6 vs. 13.4 +/- 4.9 mumol L(-1)) were significantly lower in eight HIV-infected patients than in eight controls. Upon infusion of GSH at a constant rate of 1 mumol min-1 kg-1, GSH in plasma reached a new plateau. The increment in plasma GSH was significantly larger in the HIV-infected patients than in the controls. The input of GSH into the circulation (12.9 +/- 5.7 vs. 30.1 +/- 11.7 mumol min-1; P < 0.01) and the clearance of GSH (25 +/- 7 vs. 35 +/- 7 mL min-1 kg-1) were significantly lower in patients with HIV-infection. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.

[Reactivation of hepatitis B following withdrawal of chloroquine]. / Reaktivierung einer Hepatitis B nach Absetzen von Chloroquin.

A severe flare-up of chronic hepatitis B infection with liver cell insufficiency has been observed in two patients after discontinuation of chloroquine administered either as malaria prophylaxis or as treatment of presumed rheumatoid arthritis. Chloroquine is known to inhibit the association of the major histocompatibility complex type II with hepatitis B virus antigens, thereby inhibiting T-cell mediated lysis of infected cells. Furthermore, it inhibits uptake of duck hepatitis B virus by duck liver cells. These in vitro studies and our clinical observations suggest that chloroquine inhibits the lysis of hepatitis B virus infected hepatocytes. Withdrawal of chloroquine in patients with chronic hepatitis B virus infection can lead to a rebound immune response manifesting as a reactivation of hepatitis B, similar to that observed after steroid withdrawal.