Treating hepatitis C infection in liver transplant recipients.

Chronic infection with hepatitis C virus (HCV) is a growing problem worldwide, with up to 300 million individuals infected, and those with chronic infection are at risk for cirrhosis and hepatocellular carcinoma. HCV infection is the most common indication for liver transplantation in the United States and Europe. Unfortunately, although transplantation is effective for treating decompensated cirrhosis and limited hepatocellular carcinoma associated with hepatitis C, HCV reinfection is virtually the rule among transplant recipients. Reinfection of the graft is associated with more rapidly progressive disease, with a median time to cirrhosis of 8 to 10 yr. Unfortunately, treatment of chronic HCV in liver transplant recipients is suboptimal. Combination therapy with interferon (pegylated and nonpegylated forms) plus ribavirin appears to provide maximum benefits. Drug therapy is usually administered for recurrent disease. No prophylactic therapy is available. Preemptive regimens offer no distinctive advantages over treatments begun for recurrent disease. Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially from cytopenias, and drug discontinuations in up to 50% of patients. Optimizing drug doses is important in maximizing sustained virological response rates. Future therapies may include ribavirin alternatives with lower rates of anemia, alternative interferons with lower rates of cytopenias, and new antiviral drugs that can be used alone or in combination with either interferon or ribavirin to enhance sustained virological response rates and improve tolerability. Liver Transpl 12:1192-1204, 2006. (c) 2006 AASLD.     

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection.

Fibrosing cholestatic hepatitis (FCH) has been described as a specific manifestation of hepatitis B virus (HBV) infection in liver allograft recipients characterized by a rapid progression to liver failure. Only sporadic cases have been reported in other immunocompromised groups infected with HBV and in a few transplant recipients with hepatitis C virus (HCV) infection. We present the occurrence of FCH in 4 HCV-infected renal transplant recipients within a series of 73 renal transplant recipients with HCV infection followed up closely serologically and with consecutive liver biopsies. All 4 patients received the triple-immunosuppressive regimen (azathioprine, cyclosporine A, methylprednisolone). The interval from transplantation to the appearance of liver dysfunction was 1 to 4 months and to histological diagnosis, 3 to 11 months. The biochemical profile was analogous to a progressive cholestatic syndrome in 3 patients, whereas the fourth patient had only slightly increased alanine aminotransferase and gamma-glutamyl transferase (gammaGT) levels. Liver histological examination showed the characteristic pattern of FCH in 2 patients, whereas the other 2 patients had changes compatible with an early stage. All patients were anti-HCV negative at the time of transplantation, whereas 2 patients, 1 with incomplete and 1with complete histological FCH features, seroconverted after 3 and 31 months, respectively. The patients were HCV RNA positive at the time of the first liver biopsy and showed high serum HCV RNA levels (14 to 58 x 10(6) Eq/mL, branched DNA). HCV genotype was 1b in 3 patients and 3a in 1 patient. After histological diagnosis, immunosuppression was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months posttransplantation, whereas the seroconverted patients showed marked improvement of their liver disease, which was histologically verified in 1 patient. In conclusion, FCH can occur in HCV-infected renal transplant recipients. It seems to develop as a complication of a recent HCV infection during the period of maximal immunosuppression and is associated with high HCV viremia levels. There are indications that drastic reduction of immunosuppression may have a beneficial effect on the outcome of the disease.     

The impact of hepatitis C virus infection on liver disease in renal transplant recipients

Abstract To assess the prevalence of hepatitis C virus (HCV) infection in renal transplant recipients and its impact on posttransplant liver disease, the sera from 176 recipients who had been followed for 1–20 years (mean 8.3 years) were tested for HCV-pecific antibody using enzyme immunoassay. HCV-pecific antibody was detected in 53 patients (30.1%) including 2 patients also positive for hepatitis B surface antigen (HBsAg). Among 167 HBsAg-negative patients, the presence of HCV-pecific antibody was associated with an increased incidence of chemically significant hepatitis (70.6% vs. 9.5% in anti-HCV-negative patients, P<0.01). Hepatitis was more likely to be chronic in anti-HCV-positive patients than in anti-HCV-negative patients (P<0.05) Serious liver disease developed in 4 of 51 anti-HCV-positive, HBsAg-negative patients: liver failure causing death in 3 and hepatoma in 1. Liver biopsy specimens from anti-HCV-positive patients showed more aggressive histological lesions compared with those from anti-HCV-negative patients. We conclude that HCV infection is quite prevalent in our renal transplant recipients and plays a major role in posttransplant chronic liver disease.     

The long-term effects of immune suppression on liver transplant recipients with recurrent hepatitis C viral infection

INTRODUCTION: Adequate immune suppression following liver transplantation in recipients with recurrence of hepatitis C virus (HCV) is not standardized. The aim of this study was to evaluate the association between immune suppression protocol and the clinical/histological parameters in HCV transplant recipients with an HCV recurrence. METHODS: A retrospective analysis was performed on recipients of liver transplants from June 1998 to October 2003 who experienced HCV recurrence. Only patients with liver biopsies at 3 to 5 years following liver transplantation were included in the analysis. The data set included: patient demographics, immune suppression, antiviral therapies, as well as histology to evaluate ductopenia and chronic rejection. Patients divided into groups of high, medium, and low immune suppression were subdivided by treatment with versus without interferon. A control group with similar demographics suffering from cryptogenic cirrhosis was used for comparison. RESULTS: During this period 45 patients had liver biopsies at 3 to 5 years posttransplantation. Their mean age was 56.5 years and mean time from transplant to biopsy was 1543 days. Their average posttransplant survival was 1964 days. There was no difference among the three groups with respect to HCV RNA levels (log(10) IU/mL), age, gender, time from transplant, donor age, and UNOS status. Median HCV RNA levels within the three groups were comparable at various time periods pre- and posttransplant. CONCLUSION: The development of chronic allograft damage following transplantation in recipients with recurrent HCV tended to be worse among patients with low levels of immune suppression, suggesting the importance of therapy to maintain allograft function.     

Pegylated interferon for recurrent hepatitis C in liver transplant recipients with renal failure: a prospective cohort study

BACKGROUND: Hepatitis C (HCV) universally recurs following orthotopic liver transplantation (OLT), representing an important cause for retransplantation. Although it is often treated with interferon and ribavirin, ribavirin is contraindicated in the presence of renal failure. In this setting of renal failure, pegylated-interferon monotherapy may be useful for recurrent HCV in liver transplant patients. METHODS: Between June 2001 and November 2002, patients with recurrent HCV were screened to determine if they were eligible for treatment. Renal failure was defined as serum creatinine greater than 1.8 mg/dL. HCVRNA and liver biopsies were performed prior to treatment, end of treatment (EOT) and 6 months after EOT for those who were HCV-RNA negative at EOT. Patients were followed prospectively after starting weekly pegylated-interferon alpha 2b 1.0 microg/kg (Schering-Plough, Kenilworth, NJ, USA). RESULTS: Among the 45 patients with recurrent HCV screened, 9 were eligible, including 8 men and 1 woman of average age 55 years. Eight patients were intolerant to the treatment requiring discontinuation within the first 3 months. Two patients developed a sustained response to HCV eradication. One patient who completed treatment has normal liver tests but is still viremic. CONCLUSIONS: Pegylated-interferon alpha 2b is poorly tolerated in liver transplant recipients with recurrent HCV and chronic renal failure. Larger, prospective studies are required to determine the optimum duration of treatment and the impact of treatment on histology and quality of life.     

Clinical course of hepatitis C virus infection in renal transplant recipients

Patients with end-stage renal disease are at high risk for exposure to hepatitis C virus (HCV) infection. Although both viral replication and liver disease progression are accelerated after renal transplantation, the long-term impact of chronic HCV infection is unclear. Our aim was to analyze the course of HCV infection in renal transplant recipients and the effects of HCV reactivation on patient and graft survival. METHODS: We retrospectively examined the 21-year (1985-2006) data of 1274 renal transplant recipients, 43 of whom were anti-HCV positive at the time of transplantation. RESULTS: The mean posttransplant follow-up of 43 patients was 62.0 +/- 7.3 months. At the time of transplantation, HCV RNA was positive in 11 (25.6%) patients and negative in 32 (74.4%) patients. HCV reactivation was seen in 19 (45.2%) patients at a mean time of 20.8 +/- 5.7 months. In 31 (72%) patients, acute rejection occurred, whereas graft loss occurred in 10 (23%) patients. Three (7%) patients died. Among 43 patients, 22 (51.2%) were treated with interferon before transplantation. There was a statistically significant association between pretransplant interferon therapy and pretransplant HCVRNA level (P=.024), but no significant association of HCV reactivation and graft rejection, mortality, or kidney survival. CONCLUSION: HCV reactivation occurred in nearly half of the renal transplant recipients, mostly in the second year. Patient survival and graft survival were not affected by HCV reactivation. Anti-HCV positivity should not preclude chronic renal failure patients from renal transplantation.     

Living donor liver transplantation for end-stage hepatitis C

Living donor liver transplantation is important for patients with end-stage viral hepatitis because of the shortage of organs from deceased donors. However, preliminary results indicate that living liver donation might be disadvantageous for hepatitis C virus-positive patients. Twenty-seven patients who underwent living donor liver transplantation for hepatitis C virus cirrhosis preemptively received antiviral therapy using interferon-alpha2b and ribavirin, which was started an average of 32 days after the operation and continued for at least 6 months thereafter. The serum hepatitis C virus RNA became negative in the 8 of 16 patients with more than 1 year follow-up. The cumulative 3-year patient survival was 85%, which was comparable to that of hepatitis C virus negative patients (n = 93; 90%). Preemptive antiviral therapy after transplantation may be necessary for satisfactory results after living donor liver transplantation.     

Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience

Jain A, Sharma R, Ryan C, Safadjou S, Kashyap R, Mantry P, Maliakkal B, Orloff M. Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience.
Clin Transplant 2010: 24: 104–111. © 2009 John Wiley & Sons A/S.   Abstract: 
Introduction:  Recurrence of hepatitis C virus (HCV) in hepatic allograft is a major concern after successful liver transplant (LTx).
Aim:  To examine the response rate to pegylated interferon (PEG–IFN) and ribavirin in post-LTx patients with HCV recurrence.
Patients and methods:  Between January 2003 and September 2006, 60 patients with biopsy proven HCV recurrence (46 males and 14 females) received PEG–IFN 2a (n = 40) or IFN 2b (n = 20) with ribavirin. All patients were followed until July 2007.
Results:  Fourteen patients (23.3%) tolerated antiviral therapy for less than six months and 10 (16.7%) discontinued therapy between six and 11 months. PEG–IFN dose was reduced in 21 (35%) patients and ribavirin dose was reduced in 16 (26.7%) patients. Overall, 55% patients achieved end of treatment response (EOT) and 35% sustained virological response (SVR). Mean Hepatitis Activity Index and Fibrosis Score pre-therapy was 5.8 ± 1.9 and 1.7 ± 1.3 and post-therapy, it was 4.4 ± 2.1 and 2.4 ± 1.6, respectively. Overall, three yr patient and graft survival was 73.9% and 69.2%, respectively. The patients with SVR had significantly lower viral load compared with other groups (p = 0.028).
Conclusion:  PEG–IFN and ribavirin therapy achieved 55% EOT and 35% SVR; 60% patients tolerated therapy. Biochemical response was observed in all groups of patients irrespective of virological response.     

Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus

INTRODUCTION: Liver transplant recipients with allograft failure due to recurrent hepatitis C virus (HCV) infection often develop marked muscle wasting and ascites prior to death and are denied repeat liver transplantation. We sought to determine whether topical testosterone therapy is associated with improved muscle mass and survival in patients with chronic allograft failure post-liver transplant. METHODS: We performed a retrospective review of liver transplant recipients with chronic allograft failure. Group 1 patients were treated for >6 months with testosterone gel 1%; group 2 patients were untreated. RESULTS: Fourteen patients were identified with stage 3 or 4 fibrosis, muscle wasting, and allograft failure due to recurrent HCV. Group 1 (n=9) patients had statistically significant improvement in albumin, testosterone, muscle strength, well-being, and MELD/CTP scores, while there was no improvement seen for any of these parameters in group 2 (n=5). There were no deaths in group 1, while four of five patients in group 2 died on average 84 days posttransplant. Adverse effects of testosterone treatment included lower extremity edema (which resolved upon dose adjustment), hypertension, and pruritus. CONCLUSIONS: Topical testosterone gel appears to increase muscle strength, stimulate albumin synthesis, and improve survival in patients with allograft failure post-liver transplant.     

Prevalence of Helicobacter pylori in patients with end-stage renal failure and renal transplant recipients.

The prevalence of Helicobacter pylori was determined using an ELISA technique for IgG antibodies to H. pylori in 76 patients with end-stage renal failure who were receiving regular haemodialysis and 202 patients with functioning renal transplants. Twenty-seven (34%) of the haemodialysis group and 58 (29%) of the transplant group were positive for H. pylori IgG antibodies, and the prevalence did not differ significantly from that in 247 age-matched healthy controls. In the haemodialysis group, patients positive for H. pylori were older, median age 60 years (range 22-73), compared to those patients without H. pylori antibodies, median age 52 years (range 22-75), p less than 0.05, more suffered from dyspeptic symptoms, 35 vs. 10% (p less than 0.01), yet fewer had been prescribed aluminium-containing antacids, 38 vs. 78% (p less than 0.01). In the transplanted group, those positive for H. pylori were more symptomatic for dyspepsia, 30 vs. 11% (p less than 0.01), and had lower serum creatinine values, 136 +/- 10 mumol/l (mean +/- SEM) vs. 172 +/- 12 mumol/l (p less than 0.05), compared to those without H. pylori antibodies. Almost all the transplant patients with H. pylori antibodies were taking steroids (98%) compared to 84% of those without antibodies (p less than 0.05). The prevalence of antibodies to H. pylori in this study was increased in symptomatic dyspeptic subjects and reduced in those patients prescribed aluminium-containing phosphate binders.     

Practical management of liver transplant recipients for hepatitis C

Hepatitis C is one of the leading indications for liver transplantation. Recipients can expect at least a short-term survival equivalent to other indications for liver transplantation. However, the rates of cirrhosis and decompensation development is substantially faster than those rates seen in non-transplant setting. Advances in antiviral therapy are now associated with a sustained virological response of 20% with combination antiviral with interferon and ribavirin. Higher response rates are expected with utilizing pegylated interferon.     

Gamma-glutamyltransferase activity in chronic dialysis patients and renal transplant recipients with hepatitis C virus infection

The prevalences of chronic infection by hepatitis C virus (HCV) and its genotypes vary among countries and ethnic groups. Among patients with end-stage renal disease (ESRD) and transplant recipients, the evolution of hepatic disease seems atypical and has not been established. In this study we compared the prevalence and HCV genotypic distribution among Brazilian patients with ESRD on dialysis or with transplantations. Moreover, we sought to compare the behavior of biochemical markers of hepatic activity of HCV infection in both groups. We prospectively evaluated 87 ESRD patients on dialysis and 105 transplant patients. Blood samples were obtained to perform qualitative HCV-RNA, genotyping, and, periodically, serum levels of aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT), alpha-fetoprotein (AFT), and albumin. The prevalence of HCV in ESRD patients was similar to recipients (19.5% vs 25.7%; P = NS) and the most frequent genotype was 1a. There was no difference in the mean values of ALT, GGT, AFT, and serum albumin between both groups with HCV infection. The mean values of aminotransferases were slightly elevated and a high frequency of patients evolved with persistently normal parameters. In contrast, the mean values of the GGT were 3 or 4 times above the reference limit and a greater frequency of patients evolved with values persistently elevated in the 2 groups. In conclusion, in the 2 groups the prevalence of HCV infection was elevated; the most frequent genotype was 1a. Among the biochemical parameters, GGT seemed to be useful as an indirect marker of liver disease.     

Chronic hepatitis B virus infection in renal transplant recipients

Although in Western Europe and North America the prevalence of chronic hepatitis B virus (HBV) infection has declined in patients awaiting renal transplantation, it remains a relevant clinical problem, mainly in patients with a long history of renal replacement therapy (RRT) who may have been infected many years ago. At the same time, a significant proportion of renal transplant recipients (RTR) is at risk for HBV infection in areas with endemic HBV. HBV infection may increase morbidity and mortality in RTR. The majority of long-term studies reported reduced patient survival compared with hepatitis B surface antigen (HBsAg)-negative RTR. The risk for morbidity and mortality of HBsAg-positive RTR transplantation is probably related to the extent of pretransplant liver disease. A thorough evaluation, including liver biopsy in many patients, is required to assess the individual HBsAg-positive patient's risk-benefit ratio. The influence of immunosuppressive therapy on HBV replication and HBV-associated complications is not well established and for clinical practice individually tailored immunosuppression is recommended in HBsAg-positive RTR. Careful screening for HBV reactivation in HBsAg-positive RTR and a regular clinical follow-up after renal transplantation (RTX) including liver sonography is required for early detection of HBV-associated complications. With the availability of new antiviral drugs, new options for pre- and posttransplant therapy might improve the prognosis of RTR with chronic HBV infection.     

Minimal model analysis in nondiabetic renal transplant recipients with hepatitis C

INTRODUCTION: Epidemiological data suggest that hepatitis C virus (HCV) infection may contribute to the development of posttransplantation diabetes mellitus (PTDM). METHODS: We investigated the glucose metabolism in 19 renal transplant recipients with antiHCV antibodies and without DM according to World Health Organization criteria before or after transplantation. We measured insulin sensitivity (SI), glucose effectiveness (SG), and pancreatic insulin response using the frequently sampled intravenous glucose tolerance test (FSIGTT). SI and SG were estimated using the Bergman minimal model method and pancreatic insulin response was expressed as the area under insulin curve (AUIC) between 0 and 19 minutes. RESULTS: Impaired glucose tolerance was shown in 42% of patients, some (31.5%) in the range of glucose intolerance (KG: 1-1.5) and others (10.5%) in the diabetes range (KG < 1). SI and SG were decreased in 39% and 63% of patients, respectively. Pancreatic insulin response revealed high variation among patients although showing a tendency to be enhanced. CONCLUSIONS: A high number of HCV-positive renal transplant recipients without clinically manifest PTDM have impaired glucose tolerance, which suggests the future development of diabetes in these patients.     

Lamivudine monoprophylaxis for liver transplant recipients with non-replicating hepatitis B virus infection

Background: The aim of this study was to evaluate the efficacy of lamivudine (LAM) monoprophylaxis for patients with non-replicating hepatitis B virus (HBV) infection at orthotopic liver transplantation (OLT). METHODS: Among 128 liver recipients with HBV infection between 1994 and 2004 transplanted at our institution, 60 had non-replicating HBV infection at the time of OLT. Of those, 26 patients received LAM prophylaxis (monoprophylaxis group) and 34 patients received LAM and hepatitis B immunoglobulin (HBIG) prophylaxis (combination group) after OLT. RESULTS: Median follow-up after OLT was 67 and 54 months, for monoprophylaxis and combination groups respectively. One and five yr patient/graft survival were 96/85% and 96/80% in monoprophylaxis group, and 85/79% and 67/55% in combination group. HBV DNA was re-detected or increased >10(5) IU/mL in four patients (15%) at 20-29 month in monoprophylaxis group and six (18%) at 4-35 months in combination group. Recurrent hepatitis was seen in two patients (8%) at 27 and 45 months and monoprophylaxis group and three (9%) at 21-35 months in combination group. The rate of recurrence was not statistically different between two groups. CONCLUSION: LAM monoprophylaxis seemed to be effective for OLT recipients with HBV infection who had non-replicating HBV at transplantation. HBIG administration may play a less valuable role in preventing HBV recurrence in this group of patients.