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.     

Virological response for recurrent hepatitis C improves long‐term survival in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally and is regarded as a major cause of mortality after liver transplantation (LT) for HCV‐related end‐stage liver disease. We conducted this large, single‐center, retrospective study to ascertain the long‐term impact of virological response to treatment of recurrent hepatitis C on survival of LT recipients. From August 1987 to October 2011, 285 patients have received interferon‐based antiviral therapy for recurrent hepatitis C. Of these 285, 245 patients were enrolled in this study. One hundred and twenty‐six patients (51.4%) achieved sustained virological response (SVR). Relapsers (undetectable HCV‐RNA at end of treatment, becoming positive afterward) comprised 9.0% (22/245), and nonresponse (NR; never achieving undetectable HCV‐RNA) 39.6% (97/245). The median follow‐up after completion of antiviral treatment was 2081 days. Using Kaplan–Meier method, patients who achieved SVR were shown to have significantly better 5‐year patient survival (95.2%) than the NR group (49.9%) (P < 0.001), and a trend toward better 5‐year survival than relapsers (87.5%) (P = 0.14); relapsers had a significantly longer survival than NR group (P = 0.005). When compared with NR, SVR and relapse appeared to be significant predictors of better survival, independent of underlying characteristics. In conclusion, virological response, especially SVR, translates into markedly improved long‐term patient outcomes in patients transplanted for hepatitis C.     

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.     

Outcome after liver re-transplantation in patients with recurrent chronic hepatitis C

Long-term outcome after liver retransplantation for recurrent hepatitis C has been reported to be inferior to other indications. The identification of factors associated which improved long-term results may help identify hepatitis C positive patients who benefit from liver retransplantation. Outcome after liver retransplantation for recurrent hepatitis C was analyzed in 18 patients (group 1) and compared with hepatitis C positive patients undergoing liver retransplantation for initial nonfunction (group 2, n=11) and patients with liver retransplantation for other indications (group 3, n=169). Five-year patient survival following retransplantation for groups 1, 2 and 3 was 59% 84% and 60%. Increased alanine aminotransferase (ALT) and serum bilirubin, as well as white cell count and MELD score at day of retransplantation were associated with impaired patient outcome. Five-year survival after retransplantation in patients with recurrent hepatitis C is similar to that in patients undergoing liver retransplantation for other indications. Our analysis showed MELD score, bilirubin, ALT levels and white cell counts preorthotopic liver transplantation are important predictive factors for outcome. This observational study may help select patients and identify the optimal time-point of liver retransplantation in 'Hepatitis C' virus positive patients in the future.     

Impaired kidney transplant survival in patients with antibodies to hepatitis C virus.

BACKGROUND: With a few exceptions, most published studies do not show an influence of antibodies to the hepatitis C virus (HCV) on the success of a kidney transplant. METHODS: We studied all our renal transplant recipients who had received kidneys from cadaver donors (n = 335) and had been treated with quadruple immunosuppression (steroids, azathioprine, and antilymphocyte antibodies, followed by cyclosporin). We had information on the status of the hepatitis C antibodies before and/or after the transplant in 320 cases (95.5%; in 300, pre-transplant). Patients with HCV antibodies before and/or after the transplant were considered to be HCV positive (HCV+). RESULTS: The HCV+ patients had more time in dialysis and a greater number of transfusions, hyperimmunized cases, and re-transplants. The evolution in the first post-transplant year was similar in both groups, but afterwards, the HCV+ patients had proteinuria more often as well as worse kidney function. The survival rate of the graft was significantly less in the HCV+ cases: 90.6, 68.3 and 51.0% at respectively 1, 5 and 10 years, compared with 91.5, 84.7 and 66.5% in HCV-patients (P<0.01). The patient survival rate was: 96.4, 87.0, and 71.9% in the HCV+ patients at 1, 5, and 10 years, compared with 98.2, 96.0 and 90.0% in the HCV- cases respectively (P<0.01). The differences remained the same in stratified studies according to time spent in dialysis or pre/post-transplant evolution of HCV antibodies, even when immunologically high-risk patients were excluded. In multivariant analysis, the presence of HCV antibodies acted as a independent prognostic factor for the survival of the kidney and the patient: 3.0 (1.8-5.0) and 3.1 (1.2-7.8) odds-ratio (95% of the confidence interval), respectively. The main cause of death among HCV+ patients was cardiovascular; there was no apparent increase in mortality rate due to infections or chronic liver disease. The loss of organs was mainly due to chronic nephropathy or death with a functioning kidney. CONCLUSION: The presence of hepatitis C antibodies, before or after transplantation, is associated with a worse long-term survival rate for both the patient and the transplanted kidney in our patients treated with quadruple therapy.     

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.     

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C.

The pathogenic mechanisms of accelerated graft fibrosis in hepatitis C recurrence after liver transplantation (LT) are not well established. The aim of the study was to assess whether a greater activation of hepatic stellate cells (HSC), the major collagen-producing cells in the liver, can occur in these patients as compared to non-LT patients with chronic hepatitis C. We determined the amount of activated HSC by computer-based morphometric analysis of alpha-smooth muscle actin (alphaSMA)-positive cells and the hepatic TGFbeta(1) expression by immunohistochemistry in 46 LT patients with hepatitis C recurrence, 35 non-LT patients with chronic hepatitis C, and 16 controls. Hepatic alphaSMA and TGFbeta(1) expression was higher in LT patients with hepatitis C recurrence than in controls and was correlated with fibrosis stage and progression rate. No significant difference in alphaSMA and TGFbeta(1) expression was observed between LT and non-LT patients with hepatitis C, with the exception of a higher transforming growth factor beta-1 (TGFbeta(1)) expression in non-LT patients in the early stages of fibrosis. LT patients receiving cyclosporine (CsA) or tacrolimus (FK) had a similar fibrosis progression rate and alphaSMA and TGFbeta(1) expression. In conclusion, the accelerated fibrosis observed in LT patients with hepatitis C recurrence does not seem to be related to a greater amount of activated HSC and TGFbeta(1) expression in the grafts of these patients as compared to non-LT patients with chronic hepatitis C. In LT patients, the amount of activated HSC and TGFbeta(1) expression correlated with fibrosis stage and progression, without any apparent influence of the type of calcineurin inhibitor administered.     

Successful rescue of severe recurrent hepatitis C with interferon and ribavirin in a liver transplant patient

BACKGROUND: Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority. METHOD: We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings. RESULTS: Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy. CONCLUSION: This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.     

Scarce influence of corticosteroid boluses on long-term viral load and liver histology in transplanted patients with recurrent hepatitis C

Corticosteroid boluses, which are the treatment for acute rejection episodes, have been shown to produce transient increases in viremia. However, their effect on long-term viral load, histological activity index (HAI), and fibrosis has not been well established. The aim of our study was to compare late viral load, HAI, and fibrosis in patients with versus without steroid boluses in the immediate posttransplant period. We analyzed patients transplanted due to hepatitis C virus. Inclusion criteria were: no change in immunosuppression (cyclosporine or tacrolimus with/without mycophenolate); no steroids in the previous 4 months; no antiviral treatment; liver biopsy and viral load determination >12 months after transplantation. Exclusion criteria were HIV, hepatitis B, and active cytomegalovirus infection. Nonparametric tests were used to compare viral load, HAI, and fibrosis (Ishak-score) among patients who received steroid boluses for an acute rejection episode (group 1) versus those who did not (group 2). Among the 48 selected patients were 38 men with the overall mean age of the entire group of 55.6 +/- 10.9 years. The mean period from liver transplantation was 53.25 +/- 33.4 months. Thirty-four (70.1%) were treated with tacrolimus and the rest, cyclosporine. Eleven (22.9%) had and 37 (77.1%) had not received corticosteroid boluses. The viral load was similar in groups 1 and 2 (5.74 +/- 0.54 vs 5.98 +/- 0.53 Log(10) IU per mL, P = .32). Fibrosis was also similar (2.5 +/- 1.6 vs 2.2 +/- 1.7, P = .56). However, HAI was higher in group 1 (7.5 +/- 1.7 vs 6.0 +/- 1.7, P = .026). In conclusion, although long-term viral load was similar in patients who had versus had not received one cycle of steroid boluses, the HAI was significantly higher in the former cohort, but had not resulted in greater fibrosis during the study follow-up.     

One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection.

Determinants of progression to cirrhosis in hepatitis C virus (HCV) infection have been well described in the immunocompetent population but remain poorly defined in liver transplant (LT) recipients. This cohort study determines the factors contributing to the development of fibrosis and its rate of progression in the allograft. Predictive factors analyzed include: demographics, host and donor factors, surgery-related variables (cold and warm ischemia time), rejection episodes, cytomegalovirus infection (CMV), and immunosuppression. Over 12 years, 842 adult LTs were performed at our institution; 358 for the indication of HCV. A total of 264 patients underwent protocol liver biopsies at month 4 and yearly after LT. Using the modified Knodell system of Ishak for staging fibrosis, the median fibrosis progression rate was .8 units/year (P < .001). Rapid fibrosis progression (> .8 units/year) was best identified by liver histology performed at 1 year. Donor age > 55 years was associated with rapid fibrosis progression and development of cirrhosis (P < .001). In contrast, donor age < 35 years was associated with slower progression of fibrosis (P = .003). Risk factors for graft loss due to recurrent HCV included recipient age > 35 years (P = .01), donor age > 55 years (P = .005), and use of female donor allografts (P = .03). In conclusion, fibrosis progression in HCV-infected LT recipients occurs at a rate of .8 units/year. Increased donor age has a major impact on disease progression, graft failure, and patient survival. A liver biopsy performed at 1 year posttransplant can help identify those patients more likely to develop progressive disease and may allow better targeting of antiviral therapy.     

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.     

Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) in the United States. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV. METHODS: We analyzed the United Network for Organ Sharing Liver Transplant Registry database from April 1987 to March 2003 to examine predictors of death or retransplantation in patients with HCV. Univariate models for each predictor were evaluated. Factors significant in the univariate model were used to develop a multivariable model. RESULTS: Of 6,956 patients meeting the inclusion/exclusion criteria, 1,527 (22.0%) died or received retransplants during the first year after transplant. Recipients with graft failure were older, had greater serum creatinine levels, and were more likely to require mechanical ventilation and hemodialysis before transplant. Donors of patients with graft failure were older and more likely to have diabetes mellitus. In the multivariable regression model, predictors of graft failure at 1 year were donor age, recipient age, recipient creatinine greater than 2 mg/dL, and the requirement for mechanical ventilation for the recipient. CONCLUSIONS: Both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV.     

Longer survival of liver transplant recipients with hepatitis virus coinfections

Hepatitis virus coinfections [HBV plus HCV coinfection (HBV/HCV) or HBV plus HDV coinfection (HBV/HDV)] may progress more rapidly to cirrhosis than hepatitis B or C monoinfections in immunocompetent patients. Only limited information is available on the outcome of coinfected patients after liver transplantation. We studied survival rates of 204 patients with viral hepatitis transplanted at our center between 1972 and 1997. HBV/HDV and HBV/HCV coinfections were present in 23 and nine individuals, respectively, while 97 patients had monoinfection by HCV and 75 had HBV monoinfection. Survival of coinfected patients was significantly longer than that of monoinfected patients (14.4 +/- 0.9 vs. 8.5 +/- 0.6 yr; p = 0.0003). The same was true for graft survival (p = 0.0002). In Cox's regression, viral coinfection (p = 0.0001), absence of hepatocellular carcinoma (HCC) (p = 0.00001) and no retransplantation (p = 0.02) were independently associated with patient survival. After exclusion of patients with HCC (n = 62), survival of coinfected patients was still significantly longer than that of monoinfected individuals (p = 0.002). The improved outcome was similar for both HBV/HDV and HBV/HCV coinfections. In contrast to immunocompetent patients, individuals with multiple hepatitis virus infections had an improved outcome after liver transplantation. Thus, viral coinfections may be associated with ameliorated courses of diseases under certain conditions.     

Loss of serum HBsAg after interferon-A therapy in liver transplant patients with recurrent hepatitis-B infection

Reinfection with hepatitis B virus after orthotopic liver transplantation is nearly universal in patients who have not received posttransplant immunoprophylaxis. Recurrence almost invariably leads to chronic liver disease. Interferon has been used both prophylactically and therapeutically but has not been effective. We treated 2 liver transplant patients with recurrent hepatitis B virus (HBV) infection (serum hepatitis B surface antigen [HBsAg] and HBV DNA positive on polymerase chain reaction, and positive liver biopsy result) with interferon, 3 to 6 MU three times weekly for 6 to 22 months. A full response to therapy was manifested in both patients by normalized serum alanine aminotransferase levels and the loss of serum HBsAg and HBV DNA. The effectiveness of interferon in our patients may have been related to coinfection with hepatitis D virus in the first case and the high interferon dose (6 MU, three times weekly) and long treatment period (22 months) in the second. No episodes of rejection were noted during therapy. We conclude that interferon can induce a complete response in liver transplant patients with recurrent HBV infection. Future studies should investigate the use of interferon therapy at higher doses and/or for longer periods. (Liver Transpl Surg 1997 Jul;3(4):394-7)