For hepatitis C patients who receive liver transplants, a population that is challenging to treat with interferon-based therapy, treatment with new direct-acting antivirals (DAAs) leads to high cure rates.
The choice of which DAA to use depends on the hepatitis C virus (HCV) genotype and the severity of liver damage. Outcomes are better in people who have not yet developed severe damage in the new liver, suggesting that post-transplant treatment should be started sooner rather than later.
Liver transplant recipients have a high likelihood of successful treatment, but it is important to consider potential interactions with immunosuppressant drugs, notes Raymond Chung, MD, chief of Hepatology at Massachusetts General Hospital in Boston, speaking in an interview with MedPage Today. “Our ability to safely and successfully treat patients with new antiviral regimens has now led to the recommendation to treat all patients in the early post-transplant period.”
Chronic hepatitis C is the leading indication for adult orthotopic liver transplants in the United States. But HCV almost always infects the new liver graft soon after transplantation, which can cause rapid progression to cirrhosis, decompensation, or loss of the graft, Chung explained. Up to a quarter of HCV-infected transplant recipients progress to cirrhosis within 5 years.
“Recurrent HCV infection of the transplanted liver has historically been the most important threat to graft and patient survival.”
Unlike hepatitis B virus (HBV), there is currently no prophylactic therapy to prevent HCV re-infection of the liver graft. However, recent research suggests that the hepatitis C immune globulin Civacir holds promise.
During the interferon era, liver transplant patients with recurring HCV were difficult to treat, Chung said. Many patients had severe liver disease prior to transplantation, resulting in more adverse events and lower sustained virological response (SVR) rates if treated with interferon-based therapy prior to transplantation. Early post-transplant treatment was also poorly tolerated and increased the risk of graft rejection.
The advent of DAAs has greatly improved the prospects for successful treatment both before and after liver transplantation. But the optimal timing of treatment is subject to debate and varies with disease severity.
The HCV guidelines developed by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) include recommendations for patients who develop recurrent HCV infection after liver transplantation.
For transplant recipients with HCV genotypes 1 or 4, the guidelines recommend sofosbuvir/ledipasvir (Harvoni) or sofosbuvir (Sovaldi) and daclatasvir (Daklinza) for 12 weeks. Both should be taken with ribavirin — in some cases starting with a low dose that can be increased if tolerated. For patients who are ineligible or unwilling to take ribavirin, treatment duration should be extended to 24 weeks, the guidelines note.
Alternative regimens for genotype 1 patients consist of sofosbuvir and simeprevir (Olysio) with or without ribavirin for 12 weeks, and paritaprevir/ritonavir/ombitasvir/dasabuvir (Viekira Pak or Viekira XR, also known as the “3D” regimen) with ribavirin for 24 weeks.
For people with HCV genotype 2, AASLD/IDSA recommends sofosbuvir and daclatasvir, either with ribavirin for 12 weeks or without ribavirin for 24 weeks, or else sofosbuvir alone with ribavirin for 24 weeks.
For the difficult-to-treat genotype 3, the sole recommended regimen is sofosbuvir and daclatasvir with ribavirin for 12 weeks or without ribavirin for 24 weeks. No recommendations are given for genotypes 5 or 6.
Although the guidelines recommend sofosbuvir/velpatasvir (Epclusa) for non-transplant patients with all HCV genotypes, there is not enough data about how well it works in the post-transplant setting, especially with regard to interactions with immunosuppressant drugs. The same holds for the grazoprevir/elbasvir (Zepatier) combination.
In the ALLY-1 study, sofosbuvir and daclatasvir with ribavirin for 12 weeks cured 94% of people with recurrent HCV after transplantation and 83% of patients with pre-transplant decompensated cirrhosis.
The SOLAR-1 trial included transplant recipients with a range of liver disease severity. Sofosbuvir/ledipasvir with ribavirin taken for 12 or 24 weeks cured 96% of post-transplant patients with absent to moderate fibrosis (stage F0-F3) or Child-Pugh Class A compensated cirrhosis. But cure rates dropped to 85% for those with Child-Pugh Class B decompensated liver disease and to just 60% for those with the most severe Class C disease.
Likewise, in the SOLAR-2 trial, SVR rates using the same regimen taken for 12 or 24 weeks were at least 95% for transplant recipients without cirrhosis, with compensated cirrhosis, or with Child-Pugh Class B decompensated cirrhosis. But sustained response rates fell to just 50% with 12 weeks of treatment and 75% with 24 weeks among Class C patients.
The small CORAL-1 study, which enrolled liver transplant recipients with absent to moderate fibrosis (stage F0-F2), saw a sustained response rate of 97% using paritaprevir/ritonavir/ombitasvir/dasabuvir with ribavirin for 24 weeks.
Small studies and real-world clinical experience have also seen good cure rates for transplant recipients treated with sofosbuvir and simeprevir, with or without ribavirin, with SVR rates generally in the range of 80% to 90%.
Taken together, these studies indicate that treating hepatitis C before advanced cirrhosis develops in the new liver leads to better outcomes, the AASLD/IDSA guidelines state.
“Although the basis for the attenuated SVR rate observed in patients with more advanced HCV infection post-liver transplant is not known, research suggests that the optimal period to initiate therapy may be the first 6 to 12 months post-transplant to minimize the likelihood of having to treat patients with more advanced liver disease.”
A challenge of post-transplant HCV treatment is preventing or managing interactions between DAAs and immunosuppressant drugs used to prevent organ rejection. According to the guidelines, sofosbuvir, daclatasvir, and ledipasvir require no advance dose adjustment when used with the common immunosuppressants cyclosporine or tacrolimus, but drug levels should be monitored. The paritaprevir-based regimen (which contains ritonavir) may require titrating doses of immunosuppressants. Simeprevir and grazoprevir/elbasvir are not recommended in combination with cyclosporine.
Successful DAA treatment can slow or halt liver disease progression, Chung noted, adding, though, that some questions remain about the best time to treat HCV in patients undergoing liver transplantation.
Liver transplant candidates are given a Model for End-Stage Liver Disease (MELD) score based on biomarkers of liver function. Those with higher scores are at greater risk of death and have a higher priority for receiving donor livers.
People with advanced liver disease who are treated while awaiting a transplant may see enough functional improvement that they no longer need a new liver. But sometimes treatment may improve liver function enough that patients fall to a lower priority on the waiting list, but not enough that they no longer need a transplant — a situation that has been called “MELD purgatory.”
“This is the subject of continued debate and discussion in the transplant community,” Chung said. “On the one hand, we may not want to treat patients with high MELD scores who are close to transplant, since treatment could lower the priority on the list without obviating the patient’s need for transplantation. However, for those with much lower MELD scores, successful treatment could permit their removal from the list.”
“Regardless, the decision to treat should be individualized, since some patients with low MELD scores may be profoundly disabled by symptoms that are not reflected in the score, and they may be better off deferring therapy so as to remain eligible for receipt of donor organs infected with HCV.”
Studies have shown that hepatitis C patients who receive HCV-positive liver grafts do as well as those who get HCV-negative livers.
This approach is considered too risky for people who don’t already have hepatitis C, but the high likelihood of successful post-transplant treatment opens up a new source of donor organs for hepatitis C patients who need liver transplants, Chung said.