Treatment of HCV after liver transplantation
Chronic hepatitis C is the leading indication for adult liver transplantation in Australia, accounting for about 40% of transplants.74 Recurrence of hepatitis C after liver transplantation is universal and is a major clinical problem. Recurrent HCV pursues a more aggressive course after transplantation, with up to 80% of patients developing chronic hepatitis and 30% of patients progressing to cirrhosis within 5 years.75 Furthermore, in the setting of immunosuppression, 2%–5% of patients develop FCH within 6 months of transplantation.76 FCH is associated with very high-level viraemia, which is directly cytotoxic, causing rapid progression to jaundice, liver failure and death. Mortality rates of 80% are reported. Finally, although recurrent HCV infection is a major cause of allograft dysfunction after transplantation, it is not the only cause, and discrimination from other causes, including acute cellular rejection, biliary and vascular complications and drug hepatotoxicity, is challenging.
Treatment with DAAs offers the opportunity to clear HCV either before transplantation (preventing recurrence) or after transplantation (treating recurrence). Where possible, treatment should be initiated early after transplantation to prevent fibrosis progression; however, treatment is also indicated in people with established recurrence, including cirrhosis. People with FCH should be identified and treated immediately to prevent rapid progression to allograft failure.
Preventing recurrent HCV after transplantation: treatment of people on the transplant waiting list
Some people, such as those with HCC or very advanced liver failure, require liver transplantation regardless of whether hepatitis C is present or not, and receiving treatment while on the waiting list is unlikely to impact the timing or outcome of liver transplantation. A decision as to whether to treat a patient on the waiting list, or wait until after transplantation, should be made on a case-by-case basis by a liver transplant physician. Treatment regimen and duration should be chosen according to recommendations for treatment of compensated cirrhosis (for patients with HCC) or decompensated cirrhosis (see sections on treatment for chronic hep C and special populations: treatment of decompensated liver disease).
If a decision is made to treat a person while awaiting liver transplantation, a period of at least 30 days with undetectable HCV RNA during treatment is associated with a very low risk of recurrence of HCV after transplantation.58 People treated for ≥ 12 weeks, with a period of undetectable serum HCV RNA of ≥ 8 weeks, can have antiviral treatment stopped at transplantation. For people treated for < 12 weeks before transplant, treatment should continue after transplantation until a total treatment duration of 12 weeks has been achieved. The development of severe acute kidney injury may lead to an interruption of dosing if the person is taking a sofosbuvir-containing regimen. Potential drug–drug interactions in the post-transplant setting should be considered.
Treatment of HCV and compensated liver disease after transplantation
Recommendations for the treatment of HCV after liver transplantation are based on clinical trial data where available. We have tried to avoid extrapolation from studies performed in non-liver transplant patients, given the complexity associated with posttransplant immunosuppression. Therefore, treatment recommendations may differ from those for the non-transplant population, and may differ from the treatment regimens currently eligible for prescription under the PBS (Table 8). None of the currently available DAAs in Australia include a specific indication for treating HCV after liver transplantation.
Clinical trial data are limited. In the SOLAR-1 study, treatment with sofosbuvir plus ledipasvir plus 1000/1200 mg of ribavirin daily for 12 or 24 weeks was studied in 162 post-transplant patients with HCV Gt 1 (31% with Child–Pugh A cirrhosis).66 SVR was observed in 96%–98% (157/162) and there was no significant difference between 12 and 24 weeks of treatment. Similar SVR results were found for the combination of sofosbuvir and daclatasvir plus ribavirin for 12 weeks in patients with HCV Gt 1 and post-transplant HCV recurrence in the ALLY-1 study.77 This regimen was also effective in 10 of 11 patients (91%) with Gt 3 and is the only currently available regimen suitable for people with Gt 3 HCV. It is therefore recommended for post-transplant patients with HCV Gt 3. Treatment was well tolerated in these studies and there were no clinically significant drug–drug interactions between sofosbuvir plus ledipasvir or sofosbuvir plus daclatasvir and calcineurin inhibitors or mTOR inhibitors.
The combination of PrOD and ribavirin for 24 weeks’ duration was evaluated for the treatment of posttransplant Gt 1 HCV recurrence in 34 individuals with no or minimal fibrosis in an open-label, prospective, multicentre study.78 All those enrolled had received their transplant more than 12 months previously. SVR was achieved in 97%. The majority of patients received 600–800 mg of ribavirin daily. Treatment was well tolerated, and no one developed allograft rejection. This regimen is associated with drug–drug interactions that require dose modification of calcineurin inhibitors; use in combination with mTOR inhibitors is not recommended.
There are limited data on treatment of post-transplant patients with HCV Gt 2, 4, 5 or 6. Until such data are available, we recommend treatment with sofosbuvir plus ledipasvir plus ribavirin for 12 weeks for people with Gt 4 or 6, or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks for those with Gt 2–6.
Treatment of HCV and decompensated liver disease after transplantation
The treatment of decompensated liver disease due to recurrent HCV after liver transplantation has been evaluated in a multicentre, prospective study in which 52 patients with Gt 1 or 4 HCV were treated with sofosbuvir plus ledipasvir plus ribavirin for 12 versus 24 weeks (SOLAR-1).66 The ribavirin starting dose was 600 mg; increased dosing on-treatment was rare. SVR was observed in 85%–88% of patients (45/52) with Child–Pugh B cirrhosis and 60%–75% (6/9) with Child–Pugh C cirrhosis. Response rates were similar with 12 and 24 weeks of treatment. No study has examined a ribavirin-free regimen in post-transplant patients. There are no prospective clinical trial data that specifically evaluate treatment of post-transplant HCV in people with decompensated cirrhosis and HCV Gt 2, 3, 5 or 6. Until such data are available, we recommend treatment with sofosbuvir plus daclatasvir plus ribavirin 600 mg daily for 12 weeks, or sofosbuvir plus daclatasvir for 24 weeks if ribavirin is not tolerated (Table 8). In people with decompensated cirrhosis and HCV Gt 3 after liver transplantation, we recommend treatment with sofosbuvir plus daclatasvir plus ribavirin 600 mg for 24 weeks.
Treatment of fibrosing cholestatic hepatitis C
Diagnosis of FCH should be made according to established criteria.79 Treatment with DAAs results in rapid clinical improvement and high rates of SVR (Table 8). In 23 people with FCH, sofosbuvir with daclatasvir or ribavirin for 24 weeks resulted in rapid clinical improvement and survival in all.80 Post-treatment relapse occurred in one individual with HIV coinfection treated with sofosbuvir and daclatasvir. Six people with HCV Gt 1 and FCH were enrolled in Group 7 of the SOLAR-1 study of ledipasvir plus sofosbuvir plus ribavirin for 12 or 24 weeks and all had rapid clinical improvement and achieved SVR.56