Rethinking the algorithm for HCV treatment and transplantation

Researchers of a new study published in the World Journal of Gastroenterology are hoping to further refine the approach to and the optimal timing of direct-acting antiviral (DAA) treatment in patients with hepatitis C (HCV) who are candidates for liver transplantation.

While the second-generation DAA agents have changed the HCV landscape by introducing a highly effective, well tolerated treatment option, many clinicians often face a dilemma as to whether to treat a patient before or after liver transplantation.

The authors of this new study, led by Chiranjeevi Gadiparthi, MD, of the Tennessee Health Sciences Center, Memphis, TN, noted that while sustained virological response (SVR) rates may improve liver function enough to negate the need for liver transplantation, a decrease in the Model for End-State Liver Disease (MELD) Score without an improvement in quality of life may put patients at risk of dropping off of the wait-list for a potentially curative transplantation.

Despite an overall decline in incidence during recent years, chronic HCV is still a major cause of liver disease in the US, as well as one of the leading indications for liver transplantation. The new DAA agents offer a favorable safety profile and high rates of SVR, but the optimal timing in patients who are candidates for liver transplantation is still subject to debate.

In the days of ribavirin and pegylated interferon, SVR was shown to significantly reduce the rates of cirrhosis, decompensation, hepatocellular carcinoma (HCC), and liver-related and all-cause mortality. The regimen was poorly tolerated, however, and clinical efficacy was low. It could also not be administered to patients with decompensated cirrhosis.

Currently, DAA-based therapy has been showing favorable results in patients with advanced liver disease both before and after transplantation. In the landmark SOLAR-1 trial, a combination of sofosbuvir, ledipasvir, and ribavirin achieved high rates of SVR at 12 weeks (SVR12) in patients with advanced liver disease, including decompensated cirrhosis, before and after transplantation.

Seven patients in the trial required re-transplantation, including four who underwent transplantation prior to completion of therapy. Six of those seven achieved SVR12, indicating that DAAs have high efficacy for the prevention of HCV recurrence following transplantation.

The ASTRAL studies have also shown that DAAs are highly effective in different ethnic groups, high-risk HCV populations (eg, the elderly), and in patients who had failed prior therapies.

While the major DAA studies enrolled patients with decompensated cirrhosis, the proportion of patients with MELD scores >20 was quite low. While the results were favorable, the authors noted they should be cautiously applied to patients with severe hepatic impairment.

In patients for whom liver transplantation may be the only curative option (eg, those with advanced liver disease or HCC), the treatment may not be beneficial. In addition, the authors wrote, “…after achieving viral clearance before liver transplantation, HCV patients are no longer able to accept the organs from HCV-positive donors, further shrinking the already limited donor pool. This is particularly relevant in the midst of the opioid epidemic, where the young and otherwise HCV-positive donors are becoming increasingly available due to deaths related to overdose.”

In areas where HCV is highly prevalent, pre-transplantation treatment has the potential to extend the transplant waiting period and increase the risk of wait-list dropout. Treatment in these patients should be done with an eye toward the proportion of HCV-positive donors in the local and regional areas.

Patients with HCV who are cured prior to transplantation can still receive organs from HCV-positive donors, but re-treatment for recurrent HCV infection will be required. This incurs additional health care costs beyond transplantation. However, the authors noted that the cost of HCV treatment is several-fold lower than transplantation, and the combination offers a mortality benefit and cost-savings for avoiding additional hospitalizations.

MELD purgatory

Current algorithms for liver transplantation allocation are mainly prioritized around a MELD score. Patients with higher MELD scores typically receive transplantations first.

While treatment with DAA agents may improve MELD scores to the point where the patient no longer requires liver transplantation, some patients experience a decrease in MELD scores without a significant boost to quality of life or hepatic dysfunction. They are then at risk of waitlist dropout or death, which is referred to as the ‘MELD purgatory.’

“To avoid ‘MELD purgatory,’ we suggest a modified algorithm summarizing the approach to optimal timing of HCV therapy in [liver transplantation] candidates,” the authors wrote. “At present, evidence favors DAA-based HCV therapy in patients with lower MELD scores and mild hepatic impairment in the pre-transplant period. Additionally, with exception to those needing immediate [transplantation], carefully selected patients with moderate hepatic decompensation may also benefit from HCV therapy prior to transplantation.”

To read more about this study, click here.