G. Lunghi

Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine†

Progression of hepatitis B in patients with lamivudine‐resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg‐negative patients at the time of phenotypic resistance (group A, >6 log10 copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3‐6 log10 copies/mL of HBV‐DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO‐LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2‐year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV‐related side effects. In conclusion, to optimize antiviral treatment in HBeAg‐negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected. (HEPATOLOGY 2005.)

The impact of hepatitis C virus infection on survival in dialysis patients: meta‐analysis of observational studies

Summary.  The impact of hepatitis C virus (HCV) infection on mortality of patients receiving regular dialysis remains unclear. The assessment of the natural history of HCV in dialysis population is difficult because of the low progression of HCV‐related liver disease over time and the reduced life expectancy in patients with end‐stage renal disease. The aim of the study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on the survival of patients undergoing maintenance dialysis. The relative risk of mortality was regarded as the most reliable outcome end‐point. Study‐specific relative risks were weighted by the inverse of their variance to obtain fixed‐ and random‐effects pooled estimates for mortality with HCV across the published studies. We identified seven studies involving 11 589 unique patients on maintenance dialysis; two (29%) were case–control studies. Pooling of study results demonstrated that presence of anti‐HCV antibody was an independent and significant risk factor for death in patients on maintenance dialysis. The summary estimate for adjusted relative risk (aRR) (all‐cause mortality) was 1.34 with a 95% confidence interval (CI) of 1.13–1.59. Heterogeneity statistics, Ri = 0.48 (P‐value by Q‐test = 0.13). In a sensitivity analysis including only (n = 5) cohort studies, the pooled aRR was 1.38 (95% CI, 1.20–1.59); heterogeneity statistics Ri = 0.46. As a cause of death, hepatocellular carcinoma and liver cirrhosis were significantly more frequent among anti‐HCV‐positive than ‐negative dialysis patients. Our meta‐analysis indicates that anti‐HCV‐positive patients on dialysis have an increased risk of mortality compared with HCV‐negative patients. The excess risk of death in HCV‐positive patients may be at least partially attributed to chronic liver disease with its attendant complications.

Meta-analysis: anti-viral therapy of hepatitis C virus-related liver disease in renal transplant patients

The efficacy and safety of interferon‐based therapy in renal transplant recipients with hepatitis C remains unclear, although a number of small clinical trials have been published addressing this issue.

Natural history of hepatitis B and C in renal allograft recipients.

Background. In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. Methods. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. Results. At enrollment in 1989 (5.5±4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. Conclusions. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Occult hepatitis B virus infection in dialysis patients: a multicentre survey

Background : The epidemiology and clinical significance of occult hepatitis B virus infection (serum hepatitis B surface antigen‐negative patients with detectable hepatitis B virus viraemia in serum) remains controversial with only limited information about its prevalence in patients on long‐term dialysis.

Changes in viremia and circulating interferon-α during hemodialysis in hepatitis C virus-positive patients: only coincidental phenomena?

BACKGROUND It has been hypothesized that hemodialysis (HD) treatment per se can preserve patients from an aggressive course of hepatitis C virus (HCV) infection by reduction of viral load. The aim of the present study in HCV-positive (HCV+) HD patients is to determine whether HD induces the production of interferon-alpha (IFN-alpha) and if such production can contribute to viremia reduction. METHODS To address this issue, HCV RNA and IFN-alpha levels were determined in 11 HCV+ patients immediately before and at the end of a 4-hour dialysis session using cellulosic membranes and 24 and 48 hours later, ie, immediately before the subsequent dialysis session using the same membrane and at the end of the dialysis session. The same protocol was repeated 1 week later using a high-biocompatibility synthetic membrane. RESULTS HCV titer decreased in all patients after dialysis (range, 3% to 95%; P = 0.001) and thereafter progressively increased and returned to basal levels within 48 hours, with a new reduction during the next dialysis treatment. There was no significant difference in the magnitude of changes in HCV titers in tests performed using cellulosic or synthetic membranes. Plasma IFN-alpha levels increased markedly after dialysis using both cellulosic (in 9 of 11 cases) and synthetic membranes (in 10 of 11 cases; P < 0.01) and returned to basal levels within 48 hours; thereafter, IFN-alpha levels increased again during the next dialysis session. In some patients, plasma IFN-alpha levels after HD were approximately 50% of the level observed after therapeutic administration of 6 million units of IFN-alpha to 4 HD patients with chronic hepatitis. CONCLUSION Although without a proven direct cause-effect relationship between HCV level reduction and induction of IFN-alpha after dialysis, our observation suggests an additional new mechanism for the unusually mild course of HCV infection in HD patients.

Antiviral therapy of hepatitis C in chronic kidney diseases: meta-analysis of controlled clinical trials

Summary.  Hepatitis C virus (HCV) infection remains frequent in patients with chronic kidney disease and the detrimental role of HCV on survival is well‐established in this population. Several authors have reported on efficacy and safety of antiviral therapy for hepatitis C in this polulation but there is no clear consensus on management. To evaluate efficacy and safety of antiviral therapy for hepatitis C in patients with chronic kidney disease, we performed a systematic review of the published medical literature and completed a meta‐analysis of controlled clinical trials. The primary outcome was sustained virological response (as a measure of efficacy); the secondary outcome was drop‐out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. We identified 13 studies including 539 unique patients; 10 (76.9%) concerned patients on maintenance dialysis. Only prospective, controlled clinical trials were included. Pooling of study results showed a significant increase of viral response in study (patients treated with antiviral therapy) than control patients (patients who did not receive therapy), the pooled odds ratio (OR) of failure to obtain a sustained viral response was 0.081 [95% confidence intervals (CI), 0.029–0.230], P = 0.0001. The pooled OR of drop‐out rate was significantly increased in study vs control patients, OR = 0.389 (95% CI, 0.155–0.957), P = 0.04. The studies were heterogeneous with regard to viral response and drop‐out rate. In the subset of clinical trials (n = 6) involving only dialysis patients receiving interferon (IFN) monotherapy for chronic HCV, there was a significant difference in the risk of failure to obtain a sustained viral response (study vs control patients), OR = 0.054 (95% CI, 0.019; 0.150), P = 0.0001 (random‐effects model). No significant (NS) heterogeneity was found (Q = 14.604, P = 1.0). No difference in the drop‐out rate between study and control patients was shown, OR = 0.920 (95% CI, 0.367; 2.311), NS. This result being homogeneous (Q = 3.639, P = 0.388). Our meta‐analysis showed that the viral response was greater in patients with chronic kidney disease who received antiviral therapy than controls. No difference in the drop‐out rate between study and control patients occurred in the subgroup of dialysis patients on IFN monotherapy. These results support IFN‐based therapy for hepatitis C in patients on maintenance dialysis.

Novel Assay Using Total Hepatitis C Virus (HCV) Core Antigen quantification for Diagnosis of HCV Infection in Dialysis Patients

ABSTRACT Dialysis patients remain a high-risk group for hepatitis C virus (HCV) infection. The current diagnosis of HCV infection among dialysis patients includes serological assays and nucleic acid amplification technology (NAT) for assessing serum anti-HCV antibody and HCV viremia, respectively. However, current NAT techniques are expensive and labor-intensive and often lack standardization. An assay prototype designed to detect and quantify total HCV core antigen (total HCV core Ag) protein in serum and plasma in the presence or absence of anti-HCV antibodies has been recently developed. A comparison between a total anti-HCV core Ag enzyme-linked immunosorbent assay (ELISA) and a quantitative HCV RNA assay based on reverse transcription-PCR (RT-PCR) (Amplicor HCV Monitor test) was performed using a large (n = 305) cohort of ELISA HCV 3.0 HCV-negative and -positive patients on maintenance dialysis. The concentrations of HCV core Ag and HCV RNA levels (measured by RT-PCR) were significantly correlated (r = 0.471, P = 0.0001) over a wide range of HCV RNA levels and were maintained among different HCV genotypes (HCV genotype 1, r = 0.862, P = 0.0001; HCV genotype 2, r = 0.691, P = 0.0001). We estimated that 1 pg of total HCV core Ag per ml is equivalent to approximately 19.952 IU of HCV RNA per ml, even if the wide range in the ratio of core Ag to HCV RNA (95% confidence intervals, 2.8 × 103 to 1.6 × 105 IU/ml) precluded definitive conclusions. In summary, total HCV core Ag proved to be useful for performing HCV RNA measurement among dialysis patients in routine laboratories without the need for special equipment or training. The present study supports the use of the total anti-HCV core Ag ELISA for assessing viral load among dialysis patients with HCV infection.

Reviews: Hepatitis C Virus Infection and the Dialysis Patient

Hepatitis C virus (HCV) remains common in patients undergoing regular dialysis and is an important cause of liver disease in this population both during dialysis and after renal transplantation (RT). Anti‐HCV screening of blood products has almost eliminated posttransfusion HCV infection but acquisition of HCV continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis population is not completely understood though recent data show that HCV infection has a detrimental role on survival of chronic dialysis patients. Several clinical trials have suggested that the response rate to conventional interferon (IFN) is higher in dialysis patients than those with normal kidney function but tolerance is lower. There are only limited data about pegylated IFN alone or in association with ribavirin for hepatitis C in dialysis population. IFN remains contraindicated post‐RT because of concern about precipitating graft dysfunction; however, preliminary evidence shows the durability of sustained response to antiviral therapy pre‐RT after renal transplant. Successful pretransplant therapy is associated with several benefits after RT including reduced incidence of posttransplant diabetes mellitus and de novo glomerulonephritis in HCV‐infected recipients.

Clinical significance of residual viremia detected by two real-time PCR assays for response-guided therapy of HCV genotype 1 infection

BACKGROUND & AIMS The duration of current standard dual and protease inhibitor-based triple therapies for chronic hepatitis C is determined by assessment of early viral kinetics. Little is known about differences between HCV RNA assays for the use in response guided therapy. METHODS HCV RNA was assessed by two widely used real-time PCR-based assays, Cobas Ampliprep/Cobas TaqMan (CAP), and Real-Time HCV (ART) in 903 samples of hepatitis C genotype 1 patients treated with dual (n=169) or telaprevir-based triple therapy (n=164) in three European countries. RESULTS Overall, CAP and ART were in excellent agreement for the determination of HCV-RNA concentrations (mean difference 0.21 log10 IU/ml). For treatment-naïve patients treated with peginterferon-alfa and ribavirin a lower rate of undetectable HCV-RNA at week 4 (RVR) was observed for ART (9%) vs. CAP (16%). Although 11/27 (41%) of patients with shortened treatment (24weeks) had detectable HCV-RNA <12IU/ml by ART at week 4 none of these patients experienced virologic relapse after treatment cessation. In patients who received triple therapy, 67% and 37% had undetectable HCV-RNA at week 4 by CAP and ART, respectively. However, 18/31 (58%) eligible patients for shortened treatment based on CAP had detectable HCV-RNA by ART at week 4. Again, relapse was not observed in these patients. CONCLUSIONS Lower rates of undetectable HCV-RNA at week 4 were observed with ART compared to CAP in patients treated with dual and triple therapies. For ART, detectable <12IU/ml HCV-RNA levels at week 4 may be sufficient as part of the criteria used for selecting patients who receive a shortened treatment regimen.