Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti-core antibodies may develop overt " de novo " HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O-HBV). In the native liver, 8/30 patients had detectable O-HBV; during the follow-up, O-HBV infection was demonstrated in 14 graft specimens. Graft O-HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O-HBV and no O-HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post-transplant O-HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O-HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.     

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.     

Long‐term,maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case–control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well‐matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.     

Rapidity of fibrosis progression in liver transplant recipients with recurrent hepatitis C is influenced by toll‐like receptor 3 polymorphism

Liver transplantation activates the innate immune system through toll‐like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single‐nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two‐center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real‐time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (−1237T/C and −1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02‐3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49–5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01–4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT.     

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.     

Anemia in liver transplant recipients undergoing antiviral treatment for recurrent hepatitis C.

Adherence to antiviral therapy is essential to achieve sustained virological responses in patients treated for hepatitis C. An important limitation to use of appropriate doses of ribavirin is development of anemia. The aim of this study is to identify risk factors associated with anemia in liver transplant recipients undergoing treatment for recurrent hepatitis C virus (HCV). Retrospective analysis was performed on 115 adult liver transplantation (LT) recipients who received antiviral treatment. Anemia was defined as hemoglobin of <10 gm/dL or the use of erythropoietin replacement therapy. Variables found to be significant in univariate analysis were further studied in multivariate analysis. The mean (+/- standard deviation [SD]) age of our cohort was 52.1 (+/- 8.8) yr. Anemia developed in 44 patients (38.3%). Mean (+/- SD) onset of anemia was 8.9 (+/- 6.8) weeks after initiation of antiviral therapy. A total of 30 patients (26%) required erythropoietin replacement, at a mean (+/- SD) of 7.9 (+/- 6.0) weeks after start of antiviral treatment. A total of 27 patients (24%) required ribavirin dose reduction, at a mean (+/- SD) time to dose reduction of 8.1 (+/- 6.3) weeks. In univariate analysis, body mass index (BMI) (P < 0.01), mycophenolate mofetil use (P = 0.05), trimethoprim-sulfamethoxazole (P = 0.02), and age (P = 0.02) were statistically significant. In conclusion, in multivariate analysis, BMI (P < 0.01) and age (P = 0.02) were found to be independent predictors of anemia. Anemia is common in liver transplant recipients treated for recurrent HCV. Special vigilance is required for older patients and patients with a low BMI.     

Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C

Background

Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.

Aim

The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).

Methods

We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.

Results

On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.

Conclusions

Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.     

Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression

Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.     

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.     

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.     

A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation.

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal. A subset of these patients develop advanced fibrosis and cirrhosis and it is believed that this leads to increased posttransplantation mortality. The specific aims of this study were to determine the incidence of advanced fibrosis and those factors associated with this process, and to evaluate causes for mortality in patients with recurrent HCV. A total of 227 patients who underwent LT with chronic HCV were monitored prospectively. The mean age of this group at LT was 49.5 yr; 76% were male and 85% were Caucasian. Fibrosis progression was monitored by protocol liver biopsy, initially performed 6 months after LT and then at 6- to 24-month intervals. Advanced fibrosis, defined as the bridging fibrosis or cirrhosis, developed in 1%, 11%, 25%, and 41% of patients after 1, 3, 5, and 6-10 yr, respectively. Acute cellular rejection hepatic steatosis, a persistent elevation in serum alanine aminotransferase and donor-race were associated with the development of advanced fibrosis. In contrast, the development of advanced fibrosis was not affected by the use of interferon prior to undergoing LT, cytomegalovirus disease, or donor age. A total of 60 patients (26%) died over 15 yr of follow-up. Although graft failure accounted for 45% of deaths in patients with advanced fibrosis, this represented only 8% of all deaths in patients with recurrent HCV. Sepsis was the most common cause of death and this was observed with similar frequency in patients who developed advanced fibrosis (45%) and in those with less advanced fibrosis (47%). In conclusion, approximately 41% of patients with recurrent HCV developed advanced fibrosis 6-10 yr after LT. However, complications associated with sepsis, not recurrent cirrhosis, was the most common cause of death in patients with recurrent HCV and this was similar in patients with or without advanced fibrosis.     

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.     

Kidney transplantation for end-stage renal failure in liver transplant recipients with hepatitis C viral infection

BACKGROUND: End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft. METHOD: The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx. RESULTS: During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance. CONCLUSION: In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.     

Late onset cytomegalovirus disease in liver transplant recipients: de novo reactivation in recurrent hepatitis C virus hepatitis

Late onset cytomegalovirus (CMV) disease (occurring more than 1 year post-transplant] was documented in two liver transplant recipients with recurrent hepatitis C virus hepatitis in the absence of factors known to precipitate CMV disease, i. e., primary acquisition of CMV, allograft rejection, augmented immunosuppression, concomitant infections, or blood transfusions. Both patients had CMV enteritis (with CMV adrenalitis in one case]; however, other symptoms and signs of overt CMV infection, i. e., fever, leukopenia, or atypical lymphocytes, were lacking. Hepatitis C virus is an immunomodulatory virus; impaired CMV-specific T-cell responses may have accounted for the predisposition of our patients to unprovoked, late onset CMV disease. Given the high incidence of hepatitis C virus recurrence after liver transplantation, awareness of the occurrence and recognition of the unusual presentation of CMV disease in this setting is both clinically relevant and significant, particularly since CMV is treatable if recognized promptly. Received: 25 September 1997 Received after revision: 27 January 1998 Accepted: 2 March 1998     

Combination of interferon alfa-2b and ribavirin in liver transplant recipients with histological recurrent hepatitis C

Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and cirrhosis after liver transplantation (LT), with histological recurrence developing in at least 50% of patients within the first year. The aim of this study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin in treating histological recurrent HCV after LT. Since 1998, patients with HCV with significant histological recurrence (fibrosis ≥ 3 and/or histological activity index ≥ 5) or progressive cholestatic disease after LT were treated with interferon alfa-2b (3 million units subcutaneously three times weekly) plus ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of treatment, and 6 months after therapy. The primary end point was loss of HCV RNA 6 months after therapy, whereas the secondary end point was histological response. Fifty-four patients met criteria for treatment and have completed follow-up. Patients were mainly men (71% men; mean age, 51 ± 5 years) with genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 ± 9 mEq/mL). Dose modification was required in 72% of patients because of cytopenia or side effects. Intent-to-treat analysis showed that serum HCV RNA was undetectable in 19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at the 6-month follow-up. Paired liver biopsy results (before and within 6 months after treatment) were available for 35 patients. Patients who achieved viral eradication had no significant progression of fibrosis after 1 year of therapy. In summary, combination therapy is a reasonable antiviral option for recurrent HCV infection for established post-LT hepatitis and appears to prevent histological progression of disease if viral eradication is successful. (Liver Transpl 2002;8:1000-1006.)     

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.