management of chronic hepatitis c before and after liver transplant

Management of chronic hepatitis C before and after liver transplant

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 24–31

© 2012, Indraprastha Medical Corporation Ltd

Management of chronic hepatitis C before and after liver transplant

Manav Wadhawan*, Sunil Taneja*, Rajeev Shandil*, Neerav Goyal**, Subash Gupta**, Ajay Kumar**Consultant, Department of Gastroenterology and Hepatology and Liver Transplantation, **Consultant, Department of Surgical Gastroenterology and Liver Transplantation, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.

ABSTRACT

Hepatitis C infection is the most common cause of cirrhosis worldwide. Management of chronic hepatitis C in peri-transplant period is challenging. Patients with compensated/Child’s A cirrhosis due to hepatitis C virus (HCV) infec-tion are treated like noncirrhotics, with peginterferon (PEG-IFN) and ribavirin, albeit with a higher incidence of complications. Treatment is not recommended for decompensated cirrhotics due to higher complication rate includ-ing the risk of death. After liver transplant, immunosuppression should be adjusted to prevent/delay recurrent HCV disease. Incidence and severity of recurrent HCV disease as well as patient and graft survival is similar between living donor and deceased donor liver transplants. It is currently recommended to treat established recurrent hepati-tis C, that is raised alanine aminotransferase (ALT) with HAI >4 and/or F >1. Pre-emptive/prophylactic antiviral ther-apy is poorly tolerated and has low efficacy. Standard dose regimen (PEG-IFN 1.5 μg/Kg or 180 μg weekly + ribavirin 800–1200 mg/day) for 48 weeks irrespective of the genotype is the recommended treatment protocol. Therapy poses significant problems in the form of anemia, neutropenia, higher risk of rejection, and so on.

Keywords: Decompensated cirrhosis, hepatitis C, interferon treatment, liver transplant

Correspondence: Dr. Manav Wadhawan, E-mail: [email protected]: 10.1016/S0976-0016(12)60116-1

Hepatitis C accounts for almost one-third of cases of chronic liver disease (CLD) and is a major cause of liver disease deaths, and cases of hepatocellular carcinoma. It represents the most common indication for liver transplan-tation in India and abroad. Treatment of chronic hepatitis C has well-documented and published guidelines. However, peritransplant management of hepatitis C is a difficult problem and ridden with controversies. In this article, we have tried to summarize the Indian data on demography of HCV infection, discuss the problems and results of treat-ment of HCV infection in compensated and decompensated cirrhosis and also reviewed the current management of HCV recurrence post-liver transplant.

CHRONIC HEPATITIS C IN INDIA

The community prevalence of hepatitis C in India is 0.4–1.5%.1–3 Chronic hepatitis C is responsible for 15–35% of all CLD in India.4–6 The most common genotype in India is

3 (50–80%). Studies from some parts of southern India have a higher prevalence of genotype 1 infection, whereas in northern India genotype 3 is most common.7–9 Virological response (VR) of hepatitis C in India varies according to the type of interferon (IFN) used (peginterferon [PEG-IFN] vs standard [Std] IFN), schedule of Std IFN (daily vs 3 times a week [TIW]), genotype (1/4 vs 2/3), extent of liver disease (chronic hepatitis vs cirrhosis), and severity of cir-rhosis (compensated vs decompensated cirrhosis). The syn-opsis of the available published Indian data is as follows:1. Sustained virological response (SVR) rates are better

with PEG-IFN (50–95%) compared with Std IFN (33–90%).10,11

2. Sustained virological response is better with daily IFN (60–90%) compared with TIW IFN (33–75%).12,13

3. Genotype 2/3 (50–100%) have a better SVR rates than genotype 1/4 (33–78%).10–13

4. Noncirrhotics (50–95%) have a higher SVR than cir-rhotics (25–90%).14–16

5. Higher SVR for compensated cirrhosis (53%) compared with decompensated cirrhosis (32–46%).14–16

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Management of chronic hepatitis C before and after liver transplant Review Article 25


6. Studies from north India have shown a higher response rate for both genotype 1/4 and genotype 2/3 in contrast to studies published from southern India.

7. There are no published data on results of the treatment of hepatitis C post-liver transplant from India.

CURRENT STATUS OF HEPATITIS C

TREATMENT IN CIRRHOSIS

In cirrhosis, the rationale for treatment is based on four principles. Treatment may halt the progression of disease in a proportion of cases, may prevent the development of hepatocellular carcinoma (HCC) in HCV cirrhotics, may decrease/delay the need for transplant in those who respond to treatment, and finally it may prevent the recurrence of HCV infection/disease post transplant. Treatment of HCV in compensated (Child’s A and early Child’s B cirrhotics) is based on the first three principles, whereas in decompen-sated cirrhosis, the prevention of disease recurrence is clearly the main target.

Treatment of hepatitis C in compensated cirrhosis/Child’s A cirrhosis should be identical to that in non-cirrhotic patients with chronic hepatitis C (PEG-IFN + ribavirin). There is good evidence that lower dose of PEG-IFN alfa-2b (1 μg/Kg) may be as effective as the standard dose (1.5 μg/Kg).10,11,14,17 The incidence of complications during treatment is higher in the cirrhotic patients com-pared with noncirrhotic population, requiring higher rate dose adjustments and discontinuation. Also, there is a risk of decompensation while on treatment which has to be explained to the patient before starting treatment. Dose adjust-ments have also been quantified according to the level of cytopenias (Table 1).18

The treatment in decompensated cirrhosis carries a lot of risks. In addition to lower SVRs, treatment causes cyto-penias (neutropenia and thrombocytopenia), hemolysis, and increase in life-threatening infections especially when treat-ing Child’s C cirrhotics. Some subjects may suffer from severe depression and suicidal tendencies; others may have worsening of Child-Turcotte-Pugh (CTP) score. Frequent

dose adjustments (60–100%) are required when treating these patients; a significant proportion is not able to complete treatment due to these problems. Currently International Liver Transplanta tion Society (ILTS) recommends treatment of hepatitis C in cirrhosis (Table 2).19

ROLE OF VIRAL LOAD REDUCTION

PRETRANSPLANT

Very few trials have studied the efficacy of treatment of HCV with interferon-based regimens in patients awaiting liver transplant.20–22,23,24 Five trials published as full papers are summarized in Table 3. Of these studies, four have used interferon with or without ribavirin, only one trial is on PEG-IFN with ribavirin. The median duration of treatment in these trials vary from 2 months to 14 months. The SVR rate at 6 months after transplant in these trials varies between 20% and 26%. The factors associated with good response to therapy were non-1 genotype, low pretreatment viral load and >2 log reduction in viral load at 4 weeks.20,24 A short, calibrated treatment course for patients awaiting transplant may be specially relevant in a living donor liver transplant (LDLT) program where the timing of transplant can be opti-mally timed.

Thus, from these data, it can be inferred that treatment of hepatitis C in patients listed for transplant may decrease the recurrence of HCV post transplant in those who respond to treatment. In nonresponders, treatment may actually worsen the disease severity.22,24,25 Considering the poor tolerability and low success rate of HCV treatment post transplant, treat-ment for hepatitis C may be carefully considered before trans-plant in a subset of patients listed for transplant.

If it is decided to treat patients with decompensated cirrhosis, patient should be listed for transplant before starting treatment. The treatment should be started as per low accelerating dose regimen (LADR).20 Dose should be

Table 1 Dose adjustments of peginterferon and ribavirin in relation to cytopenias.

Peginterferon dose 2/3 normal Ribavirin

ANC <1200/platelet <60 Hb <10,800 mgANC <750/platelet <35½ normal Hb <8600 mgANC <500/platelet <20 stop Hb <6 stop

ANC: absolute neutrophil count; Hb: hemoglobin.

Table 2 Treatment of hepatitis C virus in cirrhosis—International Liver Transplanta tion Society recommendations.

Consider CTP MELD treatment score score

Strongly consider ≤7 <18 In select cases 8–11 18–25 Treat carefully with transplant (Tx) plannedTreatment not >11 >25 Consider Tx and advised treat post-Tx

CTP: Child-Turcotte-Pugh; MELD: model for end-stage liver disease.

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26 Apollo Medicine 2012 March; Vol. 9, No. 1 Wadhawan et al


slowly increased to maximum tolerated to achieve best response.

IMMUNOSUPPRESSION PROTOCOLS IN

HEPATITIS C VIRUS-RELATED TRANSPLANTS

Hepatitis C virus recurrence is accelerated in transplant recipients due to immunosuppression. Serological recur-rence is seen in all patients who are HCV-viremic at the time of liver transplant. The type and intensity of immuno-suppression is a predictor of severity of recurrence of hepa-titis C post transplant. Immunosuppression protocols should be different for HCV recipients as compared with nonHCV-transplant recipients.

Corticosteroids and Liver Transplant

Corticosteroids enhance HCV replication and may be asso-ciated with more severe recurrence of hepatitis C. Steroid boluses cause a marked but transient increase in HCV viremia.26 However, the role of pulse steroids for rejection in increasing HCV recurrence is controversial (trials before 2000 showing higher incidence, most trials after 2000 show-ing similar recurrence rates).

Steroid Taper, Withdrawal, and Avoidance

The role of steroids in HCV replication has prompted multi-ple trials on steroid withdrawal. Many groups advocate early steroid withdrawal.27,28 But a number of trials have shown that early taper of steroids (before 6–12 months) should be avoided as it increases the severity of HCV recurrence.29,30

The jury is still out on the role of complete steroid avoid-ance in HCV-related liver transplants. First published trial is an interim analysis of a study in 39 patients recruited out of a planned total of 50 patients.31 All patients received

tacrolimus (TAC) and mycophenolate mofetil (MMF) and were randomized to receive either daclizumab or cortico-steroids. There was a trend toward less cellular rejection with daclizumab. However, there was no difference in HCV recur-rence other than that the small number of cases with advanced fibrosis all occurred in the corticosteroid arm of the trial. Another prospective trial published recently enrolled 28 patients, used steroid-free immunosuppression (calcineurin inhibitor [CNI], MMF, and anti-CD25 antibody in 18 patients vs steroid-based immunosuppression in 10 patients).32 Steroid-free immunosuppression was associated with lower incidence of cytomegalovirus (CMV) infection (P = 0.049). Acute cellular rejection rates were similar in both groups. Steroid-free group showed a rapid increase in HCV-RNA (ribonucleic acid) (P < 0.05), and a higher HCV recurrence (46% vs 18.1% at 1 year, P = 0.009).

Currently, most centers limit the use of steroids by using initial small doses and withdrawing completely by 6–12 months post transplant.

Tacrolimus versus Cyclosporine

Cyclosporine has in vitro inhibitory activity on the replica-tion of HCV. But in vivo effect has been questioned as most studies show no difference in the severity of HCV recur-rence with CysA or TAC.33–35 However, what is documented is that if a patient needs treatment for HCV recurrence with interferon, SVR is higher in those on cyclosporine as pri-mary immunosuppressant compared with TAC.36 An on-going multicenter trial is evaluating the use of CysA versus TAC in HCV-positive transplant recipients.

Other Issues

OKT3 induction or its use for treatment of rejection is associated with increased severity of HCV recurrence.30 Most centers all over the world have replaced azathioprine with MMF in triple immunosuppression. However, in

Table 3 Trials evaluating treatment of hepatitis C virus cirrhosis patients awaiting liver transplant.

N Treatment Duration (mo) ETR SVR Transplanted SVR after LT

Crippin (2002)23 15 IFN ± Riba 2 5 (33%) – 2 –Thomas (2003)22 20 IFN 14 12 (60%) – 20 4 (20%)Everson (2005)20 124 IFN + Riba 6–12 57 (46%) 30 (24%) 47 12 (26%)Forns (2003)21 30 IFN + Riba 3 9 (30%) – 30 6 (20%)Carrion (2009)24 51 PEG-IFN + Riba 4 15 (29%) – 43 10 (20%)

ETR: end of treatment response; IFN: interferon; LT: liver transplantation; PEG-IFN: peginterferon; SVR: sustained virological response.

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liver transplant, the superiority of MMF over AZA is not clearly demonstrated. A very recently published paper has reviewed all trials regarding the use of azathioprine vis-à-vis MMF in liver transplant patients.37 These authors report no difference in graft or patient survival between liver transplant recipients treated with MMF or azathioprine. Another recently published trial comparing TAC monotherapy with triple therapy with TAC, azathioprine, and steroids showed a slower onset of histologically proven severe fibrosis and portal hypertension in triple therapy compared with TAC alone.38 Use of azathioprine has been associated with decreased severity of recurrence of HCV post transplant in other trials also39,37 and it may be considered along with CNIs as a part of immunosuppression regimen. Rate and severity of HCV recurrence is similar in interleukin (IL)-2 receptor antagonist immunosuppressive regimens compared with conventional regimen.39 There is no available literature on the use of sirolimus in liver transplant for HCV-related disease.

NATURAL HISTORY OF CHRONIC

HEPATITIS C POST-LIVER TRANSPLANT

Cirrhosis due to HCV is a major indication for orthotopic liver transplantation (OLT) in India and in the West account-ing for almost 30% of total patients. Graft HCV re-infection is early and universal in patients who are viremic at the time of transplant. Five-year survival after HCV recurrence in deceased donor liver transplant (DDLT) is lower than nonHCV-related liver transplants. Histologic recurrence is seen in 50% of these patients at 1 year post transplant. Cumulative probability of graft cirrhosis is 30% at 5 years post transplant, as compared with 5% in chronic HCV infection in nontransplanted population. Actuarial risk of decompensation once these transplant recipients develop cirrhosis is 42% at 1 year, 62% at 5 years; whereas in nontransplant HCV, it is 5% and 10% at 1 year and 3 years, respectively. Three-year survival after decompensa-tion is <10% for recurrent HCV after liver transplantation. Of the total number of patients transplanted for HCV-related liver disease, 10–25% will need re-transplantation within 5 years. All these data are from cadaveric liver transplants.40–42

Initial comparative data of the severity of HCV recur-rence following LDLT versus DDLT showed greater sever-ity of recurrence and poorer 1 year graft survival.43,44 Subsequently, many trials have been published which show no difference in the mean inflammation score or mean fibrosis score, with similar occurrence of cirrhosis and

similar graft and patient survival at 4 years, in patients with recurrent HCV in LDLT versus DDLT.42,45–47,48

DO ALL PATIENTS WITH HEPATITIS C VIRUS

NEED TREATMENT POST-LIVER

TRANSPLANT?

Treatment protocols for HCV post-liver transplant can be broadly divided in two main categories. Treatment for all irrespective of alanine aminotransferase (ALT) and liver biopsy findings (pre-emptive therapy) and treatment of recurrent disease (ALT raised, liver biopsy HAI >4 and/or Fibrosis >1). Multiple trials of pre-emptive therapy have shown a pooled end of treatment response (ETR) of 13.6% and a SVR of 9.1% (0–18%).49 The incidence of complica-tions has been 60–90% (dose reduction—85%, discontinu-ation—37%, and serious adverse events—27%). Only 15% of total patients were able to receive complete and full-dose treatment. However, one recent trial published from Japan has shown a 45% ETR and 39% SVR after pre-emptive treatment which continued for 1 year after first negative HCV-RNA report.50 This study also showed similar survival between patients transplanted for HCV and nonHCV cirrhosis.50

The minimum criteria for established disease needing treatment are raised ALT levels, HAI >4 and/or fibrosis >1 on liver biopsy score according to modified Ishak’s system.19 The pooled SVR rate on IFN + ribavirin combination (27 published trials) has been reported to be 24% (13–53%). Pooled discontinuation rate in these studies was 24%. On the combination of PEG-IFN and ribavirin (21 studies), pooled SVR rate was slightly higher (27% [26–50%]), and so was the pooled discontinuation rate (26%).51 Acute cel-lular rejection was reported in 2% (0–4%) receiving IFN and 5% (2–25%) of those receiving PEG-IFN.

CURRENT TREATMENT PROTOCOL OF

TREATMENT OF HEPATITIS C VIRUS

POST-LIVER TRANSPLANT

Treatment is recommended for established HCV recurrence post transplant only (HAI >4, F ≥1).19 Two treatment proto-cols are followed: escalating dose regimen—PEG-IFN (0.5–1.5 μg/Kg or 90/135/180 μg weekly) + ribavirin (400–1200 mg/day) or standard dose regimen (PEG-IFN 1.5 μg/Kg or 180 μg weekly + ribavirin 800–1200 mg/day). Most centers prefer the standard dose over escalating regimen. Treat-ment should be started at fibrosis score 1–2 as response

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rates decrease with higher fibrosis scores at the start of treatment (48% vs 19%).52 The duration of treatment is rec-ommended to be 48 weeks irrespective of the genotype.

PROBLEMS IN HEPATITIS C VIRUS

TREATMENT POST-LIVER TRANSPLANT

Treatment of HCV recurrence post-liver transplant is diffi-cult. Problems can be related to drug discontinuation/dose reduction of PEG-IFN and/or ribavirin, the risk of graft rejection, or other miscellaneous issues like post transplant diabetes mellitus (PTDM), CMV, and occult hepatitis B virus (HBV).

Anemia is seen in 36–81% LT recipients treated for chronic hepatitis C.53 The mechanisms can be multiple: ribavirin induces hemolysis by the accumulation of phos-phorylated ribavirin in RBCs causing oxidative injury,54 Interferon induces myelosuppression contributing to ane-mia,55 HCV interference in erythropoietin production (EPO) by direct inhibition as well as ribavirin-induced renal insuf-ficiency.56 Treatment is by using weight-based dosing of ribavirin, the use of EPO which is started pre-emptively when hemoglobin (Hb) ≤10 g% or when there is ≥2 g% reduction in Hb. More vigilance is required in elderly and in those on concurrent MMF.

Neutropenia and thrombocytopenia are reported in up to 50% of patients on treatment with PEG-IFN + Riba. Treatment discontinuation is reported in 0–40% of patients in various studies.57–61 Usual management is by reducing the dose/frequency of PEG-IFN and restarting normal dos-age once it comes back to normal. Gm-CSF is also used concurrently to increase counts while on treatment.

One of the most important risks of treatment for HCV is graft rejection. It has been variously reported between 0% and 25% in various published studies.57–61 The proposed mecha-nisms of rejection is that interferon enhances the expression of HLA-DR antigens on donor bile duct epithelial cells and hepatocytes. Further, antiviral therapy improves hepatocyte microsomal function leading to decreased immunosuppres-sion levels.53 Median time to rejection has been reported to be 3.5 months (range 0.3–15.7 months) after HCV-RNA becomes undetectable.62 The incidence of rejection is shown to be higher in responders vs nonresponders.62 Another study has reported a higher incidence of fibrosing cholestatic hepa-titis (FCH) in nonresponders after stopping IFN therapy.63 Risk of chronic rejection is miniscule and overstated.

The PTDM is seen in 7.2% of liver transplant recipients at 6 months post transplant. Incidence is higher with TAC than with cyclosporine, and 4–8-fold higher prevalence is

seen in HCV-related liver transplants than in nonHCV transplants. Exact mechanism is not known but both HCV direct effect and immune-mediated effects have been pro-posed. It is recommended that insulin be used in thin patients and oral hypoglycemics in overweight patients.64 Sulfonylureas and thiazolidinediones have been found to be safe.64–66 Metformin is not to be used post-liver transplant for the concern of lactic acidosis.

Cytomegalovirus infection does not increase the risk of HCV recurrence post transplant. There is no difference in HCV viral load, degree of liver injury, and fibrosis in CMV PCR positive vs negative patients with HCV-related liver transplant.67 On the other hand, CMV viral load is similar between HCV-related and nonHCV liver transplants.67

CONCLUSION

Hepatitis C infection accounts for maximum end-stage liver disease patients. Management of chronic hepatitis C in per-itransplant period requires specialized care by dedicated hepatologists. Patients with compensated/Child’s A cirrho-sis due to HCV infection should be treated like chronic hepatits C patients without cirrhosis. The risk of treatment associated complications is much higher in this group. Decompensated cirrhotics have a very high-risk of compli-cations including the risk of further worsening of liver dis-ease and death. After liver transplant, immunosuppression should be adjusted to prevent/delay recurrent HCV disease. There is no difference in the incidence and severity of recurrent HCV disease as well as patient and graft survival between LDLT and DDLT. It is currently recommended to treat established recurrent hepatitis C post-liver transplant. The minimum criteria for treatment are raised ALT with HAI >4 and/or F >1 on liver biopsy. Pre-emptive/Prophylactic antiviral therapy is poorly tolerated and has low efficacy. Standard dose regimen (PEG-IFN 1.5 μg/Kg or 180 μg weekly + ribavirin 800–1200 mg/day) for 48 weeks irrespective of the genotype is the recommended treatment protocol. Therapy is associated with a high complication rate in the form of anemia, neutropenias, higher risk of rejection, and fibrosing cholestatic hepatitis.

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management of chronic hepatitis c before and after liver transplant

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