Treatment of hepatitis C in liver transplant patient

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 50–54

© 2012, Indraprastha Medical Corporation Ltd

Treatment of hepatitis C in liver transplant patient

Sanjay Sikka**Senior Consultant, Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.

ABSTRACT

A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop cirrhosis and complications of end-stage liver disease over two to three decades and require liver transplantation. However, reinfection is com-mon and leads to further adverse events under immunosuppression. Pretransplant antiviral or pre-emptive therapy is limited to mildly decompensated patients due to poor tolerance. The main stay of management represents directed antiviral therapy after evidence of recurrence of HCV in the transplanted patient.

Keywords: Chronic hepatitis C (HCV), interferon, liver transplant

Correspondence: Dr. Sanjay Sikka, E-mail: sikkageind55@gmail.comdoi: 10.1016/S0976-0016(12)60121-5

INTRODUCTION

According to the World Health Organization, 130–170 million people are chronically infected with hepatitis C virus (HCV) worldwide.1 The expected median time for develop-ment of cirrhosis in patients with HCV is 20–25 years. The HCV is the major cause of chronic liver disease, cirrhosis, and liver cancer in most developed countries,2 including Japan.3 It is the most common indication for liver transplan-tation (LT) in developed nations.4,5 Liver transplantation is an effective treatment to reduce morbidity and mortality in this population. Regretfully, recurrence of HCV infection is almost universal after LT and is a critical complication with major effects on graft and patients survival. Indeed, the real challenge of controlling HCV begins after LT under lifelong immunosuppression.

CLINICAL COURSE AFTER LIVER

TRANSPLANTATION

Spontaneous clearance of HCV after transplantation is rare,6–10 and reinfection of the allograft is common.11,12 Large studies have demonstrated that recipients with HCV have about 10% <5-year graft and patient survival rates

than non-HCV controls.13,14 Hepatitis C virus reinfection occurs during transplantation in the reperfusion phase of the graft, and acute hepatitis can be detected 1–3 months after transplantation.15 The clinical course following reinfection varies. In general, 8–30% of the recipients will present with severe progression within 5 years.16–18 The median time to cirrhosis in the non-transplant patient was 30 years19 and in the transplanted patients with HCV disease is expected to be 10 years. The risk of decompensation is 50% within 1 year after diagnosis in the absence of therapeutic interven-tion.16,19 A small percentage of recipients can develop an early cholestatic hepatitis within the first year after transplan-tation with a risk (2–8%) of progressive liver dysfunction and rapid development of cirrhosis.11,20 Retransplantation in these patients is associated with poor outcomes and is controversial.21 One of the most important issues in the man-agement of HCV after LT is a correct follow-up of these patients. It is now clear the fibrosis progression is signifi-cantly faster in immunosuppressed than in normal individu-als and that a close monitoring of liver damage is essential. Assessment of the severity of HCV recurrence after LT is performed by frequent liver biopsies is sampling variability, which might become a relevant issue in individuals with rapid disease progression. The presence of the portal hypertension (hepatic venous pressure gradient, HVPG >6 mmHg) is even more accurate than liver biopsy at identifying with severe

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HCV recurrence who are at risk of clinical decompensation.22 This is relevant to adopt therapeutic decisions due to the limited efficacy and high incidence of adverse events of current antiviral therapy in HCV-infected LT patients.

Therefore, liver biopsy and/or HVPG measurement on a protocol basis are highly recommended to monitor liver damage in HCV-infected LT recipients.

Recently measurement of liver stiffness has shown a good correlation with the fibrosis stage in LT recipients. Carrion et al23 showed that using transient elastography most HCV-infected LT patients with significant liver fibrosis and/or portal hypertension were correctly identified. Apart from liver stiffness, it is possible that in the near future the use of serum fibrosis marker as may become an additional tool to identify patients at risk of disease progression and in whom antiviral therapy is indicated.24

RISK FACTORS FOR SEVERE RECURRENT

HEPATITIS C VIRUS

There are many variables which predict the recurrence of severe HCV after LT. The most common variable factor to have a negative impact of HCV infection on graft survival is donor age and strong immunosuppressive regimens.25 Avoid the utilization of anti-lymphocyte antibodies or corti-costeroid boluses as they may enhance viral replication and induce a more severe liver disease. Other factors with a sig-nificant negative impact on HCV infection on graft survival is a preoperative model for end-stage liver disease (MELD) score,26 fibrosis stage of 2 or greater at 12 month biopsy, history of hepatocellular carcinoma (HCC) and early acute rejection. Diabetes mellitus (DM), cytomegalovirus (CMV) infection, early lobular hepatitis and chronic cholestasis due to biliary complication.27,28

VIRAL KINETICS

Powers et al29 confirmed that viral loads begin to rise 15 hours after the anhepatic phase. In total, 19% heptocytes are infected in an average of 37 days after transplantation. Schiano et al30 demonstrated accelerated HCV kinetics in living donor liver transplantation (LDLT) recipients (n = 11) compared to deceased donor liver transplantation (DDLT) recipients (n = 15). Another study27 focusing on the histologic aspects of HCV recurrence with protocol biopsy reported more severe progression of liver disease in LDLT compared to DDLT.

TREATMENT OF HEPATITIS C VIRUS

RECURRENCE AFTER LIVER

TRANSPLANTATION

Once HCV recurs after transplantation, treatment can be ini-tiated at different stages: immediately following transplan-tation, during the acute phase of infection (acute hepatitis) and once chronic hepatitis has been histologically proven.

Treatment of HCV infection in the early phase after LT would prevent liver damage, but the potential risk of rejec-tion, the poor tolerance of antiviral therapy immediately after LT and early viral kinectics following LT are some of the limitations of this strategy. Data from randomized con-trolled studies analyzing the efficacy of interferon/pegylated interferon (PEG-INF) monotherapy initiated as early as 2–3 weeks after LT did not show any efficacy in terms of viral clearance.31,32

The safety and efficacy of antiviral therapy during the acute phase of infection has been evaluated in one study. Twenty-four patients with histologically proven HCV were treated with PEG-INF alfa-2b and ribavirin for 48 weeks.33 Median time from transplantation to antiviral therapy was 4 months. Sustained virological response (SVR) was achieved in 35% of the cases. The results of this are promising, but they need to be validated in larger cohorts. Currently, treat-ment in the acute phase of the disease would be reserved for individuals with evidence of an early severe recurrence: cholestatic hepatitis, high aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels (>200), or severe necroinflammation in the liver biopsy.

The most common strategy to treat HCV infection in patients undergoing LT is to initate therapy several months (or even years) after LT, once the presence of histological (particularly liver fibrosis) has been documented. The pres-ence of significant fibrosis (extending beyond the portal tract) or portal hypertension (HVP > 6) 1 year after transplan-tation identifies individuals at risk of severe recurrence.22 Most studies indicate that the efficacy of antiviral therapy in LT recipients is low; adverse events make it often neces-sary to modify and/or discontinue therapy.31 Overall, using PEG-INF the efficacy of combination therapy is around 30–35%.34–41 A systematic review of studies evaluating anti-viral therapy with PEG-INF and ribavirin in >600 LT recipi-ents showed a mean rate of SVR of 35%; the lack of an early virologic response (3 months) was the strongest predictor of non-response.42 As expected, dose reduction and discontin-uation of treatment were common (73% and 28%, respec-tively). Rejection induced by interferon is a rare event, but changes in the liver enzyme profile (particularly in virologi-cal responders) should prompt rapid liver biopsy to exclude this possibility. It is important to notice that ductopenic

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rejection induced by interferon therapy may be severe and cause graft loss.

One of the most important issues regarding antiviral therapy is its potential long-term benefit in individuals who achieve viral eradication. In the study by Carrion et al,36 it became clear that in individuals who achieved an SVR, liver fibrosis improved or stabilized and, more importantly, portal pressure normalized. These data, which were obtained in a small prospective series, are strongly supported by recent study by Berenguer et al.42 In this study, progression to cirrhosis and clinical decompensation was assessed retro-spectively in 89 HCV-infected patients who underwent anti-viral therapy and 75 untreated disease-matched controls. Patients survival was higher in treated compared to controls. Regarding treated patients the 5-year risk of graft decom-pensation is greater in non-responders compared to patients who achieved SVRs (33% vs 16%; P = 0.04), whereas the 5-year survival was higher in SVR as compared with non-responders (93% vs 69%; P = 0.032). Thus, antiviral therapy appears to be associated with improved long-term outcome in recurrent HCV.

NEW DRUGS AND LIVER

TRANSPLANTATION

With the introduction of HCV protease inhibitors (PIs), telaprevir and boceprevir, which are DAA (direct-acting anti-virals), the future of genotype-I HCV post transplant patient is bright.

The PIs added to standard of care (SOC) therapy have increased the rate of SVR-infected genotype-I naive chronic HCV patients up to 70%. The expectations regarding the efficacy of therapeutical regimens adding PI to the current SOC in LT recipients are not as high as in immunocompetent individuals.

In the post transplant setting, the type of problems in patients undergoing triple therapy (PEG-INF, ribavarin, and PI) will be quite different. The most relevant issue will be the drug-drug interaction and high rate of adverse events. Since most PIs are substrates and inhibitors of P-glycoprotein and the cytochrome system (particularly CYP3A4) drug-drug interaction with immunosuppressant are expected. P-glycoprotein (both in gut and the liver) decreases absorption and increases excretion of cyclosporin A (CsA) and tacrolimus (TAC) and the two drugs are meta-bolized by CYP3A4. After PI initiation or interruption blood levels of CsA or TAC might dramatically increase or decrease due to the narrow therapeutic ranges of these drugs. Some adverse events due to rapid increase in CsA or TAC

levels when starting PI may be life-threatening (acute renal failure, seizures, hypertension, and diabetes). Similarly, a sudden decrease in CsA or TAC levels when interrupting the administration of PI may lead to graft injection. An addi-tional problem in LT recipient undergoing triple therapy will be anemia.

It is well known that first cause of treatment adjustments and discontinuations in LT recipients undergoing PEG-INF and ribavirin therapy is anemia. Among the causes of high rate of anemia are renal failure (which increases ribavirin toxicity) and bone marrow suppression by several drugs. Taking into account drug-drug interaction and additional toxicity of PI, dose adjustments and/or discontinuation will be frequent. In order to avoid PI dose adjustment, which would facilitate the appearance of HCV-resistant state. It will be relevant to use erythropoietin and/or reduce rebavirin dose when required.

Despite all the abovementioned limitation, it is obvious that the addition of PI to current SOC will increase the rate of viral clearance in HCV-infected LT patients.

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