Peritransplant management of chronic hepatitis C

Hepatitis C accounts for almost one third of cases of chronic liver disease and is a major cause of liver disease related deaths and causes hepatocellular carcinoma. It represents the most common indication for liver transplantation in India and abroad. Treatment of chronic hepatitis C has been well documented with 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, the problems and results of treatment of HCV infection in compensated and decompensated cirrhosis and also reviewed the current management of HCV recurrence following liver transplantation.

Chronic hepatitis C in India

The community prevalence of hepatitis C in India is 0.4 to 1.5%.[1,2,3] Chronic Hepatitis C is responsible for 15-35% of all chronic liver diseases in India.[4,5,6] 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.[7,8,9] Virological response of hepatitis C in India varies according to type of IFN used (PEG Interferon {IFN} vs. Standard {Std} IFN), schedule of standard IFN (daily vs. thrice a week {TIW}), genotype (1/4 vs. 2/3), extent of liver disease (chronic hepatitis vs. cirrhosis), severity of cirrhosis (compensated vs. decompensated cirrhosis). The synopsis of available published Indian data is as follows:

1. Sustained virological response (SVR) rates are better with Peg IFN (50%-95%) compared to Std IFN (33%-90%).[10,11]

2. SVR is better with daily IFN (60-90%) compared to TIW IFN (33-75%).[12,13]

3. Genotype 2/3 (50-100%) have a better SVR rates than Genotype 1/4 (33-78%).[10,11,12,13]

4. Non-cirrhotics (50-95%) have a higher SVR than cirrhotics (25-90%).[14,15,16]

5. Higher SVR for compensated cirrhosis (53%) compared to decompensated cirrhosis (32%-46%).[14,15,16]

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

7. There is no published data on results of 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 progression of disease in a proportion of cases, may prevent the development of HCC in HCV cirrhotics, may decrease the need for transplant in those who respond to treatment and finally it may prevent recurrence of HCV infection post transplant. Treatment of HCV in compensated (Child class A and early Child class B) cirhotics is based on the first three principles. Whereas in decompensated cirrhosis, prevention of disease recurrence after liver transplantation is clearly the main target.

Treatment of hepatitis C in compensated cirrhosis should be identical to that in non-cirrhotic patients (PEG IFN + Ribavirin). There is good evidence that lower dose of PEG IFN _2b (1 mcg/Kg) may be as effective as the standard dose (1.5 mcg/kg).[10,11,14] The incidence of complications during treatment is higher in the cirrhotic patients compared to noncirrhotic population, requiring higher rates 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 adjustments have been also quantified according to the level of cytopenias (Table 1).[17]

The treatment in decompensated cirrhosis carries a lot of risks. In addition to lower SVRs, treatment causes cytopenias (neutropenia and thrombocytopenia), hemolysis and increase in life-threatening infections specially when treating Child class C cirrhotics. Some subjects may suffer from severe depression and suicidal tendencies, others may have worsening of Child-Pugh score. Frequent dose adjustments (60-100%) are required when treating these patients, a significant proportion are not able to complete treatment due to these problems. Currently International Liver Transplantation Society (ILTS) recommends treatment of hepatitis C in cirrhosis as follows (Table 2).[18]

Role of viral load reduction: Pre transplant setting

Very few trials have studied the efficacy of treatment of HCV with interferon based regimens in patients awaiting liver transplant.[19,20,21,58,59] 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 – 14 months. The sustained viral response rate at 6 months after transplant in these trials varies between 20-26%. The factors associated with good response to therapy were non-1 genotype, low pretreatment viral load and more than 2 log reduction in viral load at 4 weeks.[19,59] A short, calibrated treatment course for patients awaiting transplant may be specially relevant in a living donor liver transplant program where timing of transplant can be optimally timed.

So, from this data it can be inferred that treatment of hepatitis C in patients listed for transplant may decrease recurrence of HCV post transplant in those who respond to treatment. In non-responders, treatment may actually worsen the disease severity.[21,22,59] Considering the poor tolerability and low success rate of HCV treatment post transplant, treatment for hepatitis C may be carefully considered before transplant 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).[19] Dose should be slowly increased to maximum tolerated to achieve best response.

Keypoints

1. All patients with compensated cirrhosis should receive full dose treatment for HCV.

2. Treatment may be considered for cirrhotics with Child score 8-11, with prior listing for transplant

3. Treatment with Child score 8-11 is worthwhile only if SVR expected, (Geno 2/3, low pretransplant viral load, 2 log reduction at week 4)

4. Tolerability is poor with increased incidence of severe adverse events

5. Treatment slows disease progression and improves survival in responders

6. Child score worsens in non responders

7. Treatment is not advised in Child score > 11.

Immunosuppression protocols in HCV related transplants

HCV recurrence is accelerated in transplant recipients due to immunosuppression. Serological recurrence is seen in all patients who are HCV viremic at the time of liver transplant. The type and intensity of immunosuppression is a predictor of severity of recurrence of hepatitis C post transplant. Immunosuppression protocols should be different for HCV recipients as compared to non HCV transplant recipients.

Corticosteroids and Liver Transplant

Corticosteroids enhance HCV replication and may be associated with more severe recurrence of hepatitis C. Steroid boluses cause a marked but transient increase in HCV viremia.[25] However, role of pulse steroids for rejection in increasing HCV recurrence is controversial (Trials before 2000 showing higher incidence, most trials after 2000 showing similar recurrence rates).

Steroid Taper, Withdrawal and Avoidance

Based on role of steroids in HCV replication has prompted multiple trials on steroid withdrawal. Many groups advocate early steroid withdrawal.[60,61] But a number of trials have shown that early taper of steroids (before 6-12 months) should be avoided as it increases severity of HCV recurrence.[23,24]

The jury is still out on the role of complete steroid avoidance 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.[62] All patients received tacrolimus and mycomenofolate mofetil (MMF) and were randomized to receive either daclizumab or corticosteroids. There was a trend towards less cellular rejection with daclizumab. However, there was no difference in HCV recurrence 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 versus steroid-based immunosuppression in 10 patients.[63] 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 (p < 0.05), and a higher HCV recurrence (46% vs 18.1% at 1 yr, p = 0.009). Currently most centers limit the use of steroids by using initial small doses and withdrawing completely by 6-12 months posttransplant.

Tacrolimus vs Cyclosporin

Cyclosporine has in vitro inhibitory activity on replication of HCV. But in vivo effect has been questioned as most studies show no difference in severity of HCV recurrence with cyclosporin A or tacrolimus.[26,27,28] However, what is documented is that if a patient needs treatment for HCV recurrence with interferon, SVR is higher in those on cyclosporine as primary immunosuppressant compared to tacrolimus.[29] An ongoing multicenter trial is evaluating use of cyclosporine A vs tacrolimus in HCV positive transplant recipients.

Other issues

OKT3 induction or its use for treatment of rejection is associated with increased severity of HCV recurrence.[24] Most centers all over the world have replaced azathioprine (AZA) with MMF in triple immunosuppression. However, in 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 a vis MMF in liver transplant patients.[64] These authors report no difference in graft or patient survival between liver transplant recipients treated with MMF or azathioprine. Another recently published trial comparing tacrolimus monotherapy with triple therapy with tacrolimus, azathioprine, and steroids showed a slower onset of histologically proven severe fibrosis and portal hypertension in triple therapy compared to tacrolimus alone.[66] Use of azathioprine has been associated with decreased severity of recurrence of HCV post transplant in other trial also[30,64] and it may be considered along with CNI’s as a part of immunosuppression imen. Rate and severity of HCV recurrence is similar in IL-2 receptor antagonist immunosuppressive regimens compared to conventional regimen.[30] There is no available literature on use of sirolimus in liver transplant for HCV related disease.

Natural history of chronic hepatitis C following liver transplantation

Cirrhosis due to HCV is major indication for OLT in India and in the West accounting for almost 30% of total patients. Graft HCV re-infection is early and universal in patients who are viremic at the time of transplant. 5-yr survival after HCV recurrence in deceased donor liver transplant (DDLT) is lower than non-HCV related liver transplants. Histologic recurrence is seen 50% of these patients at 1 yr post transplant. Cumulative probability of graft cirrhosis is 30% at 5 years post transplant, as compared to 5% in chronic HCV infection in non transplanted population. Actuarial risk of decompensation once these transplant recipients develop cirrhosis is 42% at 1 yr, 62% at 5 yrs; whereas in non transplant HCV it is 5% and 10% at 1 and 3 yrs respectively. 3-yr survival after decompensation is less than 10% for recurrent HCV after liver transplantation. Of total number of patients transplanted for HCV related liver disease, 10-25% will need retransplantation within 5 years. All this data is from cadaveric liver transplants.[31,32,33]

Initial comparative data of severity of HCV recurrence following living donor liver transplant (LDLT) vs. Deceased donor liver transplant (DDLT) showed greater severity of recurrence and poorer 1 yr graft survival.[34,35] Subsequently, many trials have been published which show no difference in mean inflammation score or mean fibrosis score, with similar occurrence of cirrhosis and similar graft and patient survival at 4 yrs, in patients with recurrent HCV in LDLT vs. DDLT. [33,36,37,38,67].

Keypoints

1. Majority of studies points toward no differences in 1- and 5-yr graft and patient survival between LDLT and DDLT

2. No differences in 1- to 3-yr inflammation scores, fibrosis and cirrhosis.

Do all patients with HCV need treatment post liver transplant?

Treatment protocols for HCV post liver transplant can be broadly divided in 2 main categories: treatment for all irrespective of 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 sustained viral response (SVR) of 9.1%.[39] The incidence of complications has been 60-90% (dose reduction - 85%, discontinuation - 37%, 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 preemptive treatment which continued for 1yrafter 1^st negative HCV RNA report.[65] This study also showed similar survival between patients transplanted for HCV and non HCV cirrhosis.[65]

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.[18] 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%).[40] Acute cellular rejection was reported in 2% (0-4%) receiving IFN and 5% (2-25%) of those receiving PEG-IFN.

Keypoints

1. Pre-emptive/prophylactic antiviral therapy is poorly tolerated and has low efficacy

2. It is currently recommended to treat established disease i.e. raised ALT with HAI>4 and/or F>1.

Current treatment protocol of treatment of HCV post Liver Transplant

Treatment is recommended for established HCV recurrence post transplant only (HAI>4, F>1).[18] Two treatment protocols are followed; escalating dose regimen – Peg IFN (0.5-1.5 mcg/kg or 90/135/180 mcg weekly) + Ribavirin (400-1200 mg/day) or standard dose regimen (PEG IFN 1.5 mcg/kg or 180 mcg weekly + Ribavirin 800-1200 mg/day). Most centers prefer the standard dose over escalating regimen. Treatment should be started at fibrosis score 1-2 as response rates decrease with higher fibrosis scores at the start of treatment (48% vs. 19%).[41] The duration of treatment is recommended to be 48 weeks irrespective of the genotype.

Keypoints

1. Standard dose regimen (PEG IFN 1.5 mcg/kg or 180 mcg weekly + Ribavirin 800-1200 mg/day) is the recommended treatment protocol.

2. HAI>4, F>1 should be treated. Delaying treatment till higher fibrosis scores decreases the response rate.

3. 48 weeks treatment is recommended irrespective of HCV genotype.

Post liver transplant problems in HCV treatment

Treatment of HCV recurrence post liver transplant is difficult. Problems can be related to drug discontinuation / dose reduction of Peg IFN and/or Ribavirin, risk of graft rejection or other miscellaneous issues like Post Transplant Diabetes Mellitus (PTDM) CMV, occult HBV, etc.

Anaemia is seen in 36-81% LT recipients treated for chronic hepatitis C.[42] The mechanisms can be multiple: ribavirin induces hemolysis by accumulation of phosphorylated ribavirin in RBCs causing oxidative injury,[43] interferon induced myelosuppression contributing to anemia,[44] HCV interference in erythropoietin production (EPO) production by direct inhibition as well as ribavirin induced renal insufficiency.[45] Treatment is by using weight based dosing of ribavirin, use of erythropoietin(EPO) which is started pre-emptively when hemoglobin (Hb) <10gm% or when there is >2 gm% reduction in Hb. More vigilance is required in the elderly and in those on concurrent MMF.

Neutropenia and thrombocytopenia is 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.[46,47,48,49,50] Usual management is by reducing the dose/ frequency of PEG-IFN and restarting normal dosage once it comes back to normal. Granulocyte macrophage colony stimulating factor (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 0-25% in various published studies.[46,47,48,49,50] The proposed mechanism of rejection is that interferon enhances expression of HLADR antigens on donor bile duct epithelial cells and hepatocytes. Further, anti-viral therapy improves hepatocyte microsomal function leading to decreased immunosuppression levels.[42] Median time to rejection has been reported to be 3.5 months (range 0.3-15.7 months) after HCV RNA becomes undetectable.[51] The incidence of rejection is shown to be higher in responders vs. nonresponders. [51] Another study has reported a higher incidence of fibrosing cholestatic hepatitis (FCH) in non-responders after stopping IFN therapy.[52] Risk of chronic rejection is miniscule and overstated.

Post Transplant Diabetes Mellitus (PTDM) is seen in 7.2% of liver transplant recipients at 6 months post transplant. Incidence is higher with tacrolimus than cyclosporine, and 4 to 8 fold higher prevalence is seen in HCV related liver transplants than in non-HCV transplants. Exact mechanism is not known but both HCV direct effect and immune mediated effects have been proposed. It is recommended that insulin be used in thin patients and oral hypoglycemics in overweight patients.[53] Sulfonylureas and thiazolidinediones have been found to be safe.[53,54,55] 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 versus negative patients with HCV related liver transplant.[56] On the other hand CMV viral load is similar between HCV related and non HCV liver transplants.[56]

Keypoints

1. Anemia is seen in seen in a majority of patients on PEG + Riba treatment post transplant. Treatment is by erythropoietin.

2. Neutropenia is reversible by decreasing PEG-IFN dose. Gm-CSF is also used for increasing neutrophil counts.

3. Acute graft rejection is seen in 0-25% patients and mainly occurs in responders to anti-viral therapy

4. There is a risk of FCH on discontinuing anti-viral treatment in non-responders.

5. PTDM is more common in HCV related liver transplants. Insulin and oral hypoglycemics (sulfonylureas and thiazolidinediones) are safe in post transplant setting.

6. CMV status has no significant effect on HCV recurrence.

Conclusion

Hepatitis C infection accounts for maximum end stage liver disease patients. Management of chronic hepatitis C in peritransplant period requires specialized care by dedicated hepatologists. Patients with compensated/ Child class A cirrhosis 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 complications including risk of further worsening of liver disease 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 living donor and deceased donor liver transplants. 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 mcg/kg or 180 mcg weekly + Ribavirin 800-1200 mg/day) for 48 weeks irrespective of 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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