Is DAA treatment for hepatitis C reducing the need for liver transplants?

People successfully treated for hepatitis are less likely to need liver transplants and less likely to die while on a transplant waiting list, according to studies presented at the 2016 AASLD Liver Meeting in November. A related analysis looked at the optimal timing of treatment for people awaiting transplants in order to avoid 'MELD purgatory'.

Over years or decades chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis, hepatocellular carcinoma (HCC), hepatic decompensation and the need for a liver transplant. In recent years hepatitis C has been a leading indication for liver transplantation in Europe and the US.

Successful hepatitis C treatment can slow or halt liver disease progression. Direct-acting antivirals (DAA) used in interferon-free regimens have made treatment easier, faster and much more effective. All-oral DAA treatment has only been widely available since 2014, but it may be starting to have an effect on how many people with hepatitis C need liver transplants.

Donghee Kim and colleagues of Stanford University School of Medicine looked at mortality among people living with hepatitis C with decompensated cirrhosis awaiting liver transplants before and after the introduction of DAA therapy.

This analysis included more than 20,000 adult liver transplant candidates with end-stage liver disease identified from the US national Organ Procurement and Transplantation Network (OPTN) database.

Cohort 1 (n = 6002 including 2410 with HCV) consisted of individuals on a waiting list as of 1 January 2004, cohort 2 (n = 6598 including 2416 with HCV) was made up of those listed as of 1 January 2009 and cohort 3 (n = 8779 including 2783 with HCV) consisted of those listed as of 1 January 2014 – the last of which had DAAs available after sofosbuvir (Sovaldi) was introduced at the end of 2013.

Overall, 35% of the transplant candidates had hepatitis C. Roughly 30% had alcoholic liver disease in all cohorts, but the proportion with non-alcoholic steatohepatitis (NASH) rose over time, from 0.3% in cohort 1 to 9.9% in cohort 2 and 17.2% in cohort 3. In both the HCV and non-HCV populations more than half were men and patient age increased over time. In both populations the average MELD score was higher – indicating worse liver function impairment – in cohort 3 (14) than in cohorts 1 and 2 (13).

More people with HCV withdrew from the waiting list over time (6.3% in cohort 1, 4.2% in cohort 2 and 2.7% in cohort 3), and more did so because they improved enough to no longer need a transplant (0.3%, 1.6% and 2.2%, respectively). In the non-HCV population, overall withdrawal rose from 3.3% in cohort 1 to 6.2% and 6.9% in cohorts 2 and 3, and the proportion withdrawing due to improved condition followed a similar pattern (1.0%, 2.8% and 3.0%, respectively).

Nearly two-thirds of people with HCV in all three cohorts were alive one year after the study start date (64.1% in cohort 1, 63.1% in cohort 2 and 63.5% in cohort 3). About 12% in all three HCV cohorts died while on the waiting list (11.8%, 11.5% and 11.5%, respectively). One-year survival and death rates were similar in the non-HCV population.

The one-year mortality rate while on the waiting list was 10% lower for people with HCV in cohort 2 compared to cohort 1, and 22% lower for cohort 3 compared to cohort 2 – a statistically significant difference. Among the non-HCV population there was only a non-significant 3% reduction in the risk of death between cohorts 2 and 3, suggesting better hepatitis C treatment might help explain the greater improvement seen in the HCV population.

This pattern was more marked for people with HCV with the highest baseline MELD liver function scores (> 20), for whom the risk of death was 43% lower for cohort 3 compared to cohort 2, again statistically significant. In the non-HCV population the death rate for people with high MELD was 16% lower, a non-significant trend.

Looking at changes in MELD scores over time, the researchers found that scores rose less in both the HCV and non-HCV population with low baseline MELD in the most recent cohort. But the greatest improvement was seen among people with HCV with baseline scores > 20: those in cohort 1 saw a +4.39 point annual increase, compared with +3.70 in cohort 2 and +2.40 in cohort 3, suggesting reduced disease progression. Among the non-HCV population with high MELD scores, the annual change did not differ significantly.

These findings, the researchers concluded, show "improved survival and disease severity for HCV-positive liver transplant candidates in the DAA era, driven by patients with high MELD."

Transplant waiting lists

In a related study, Jennifer Flemming of Queens University in Ontario and colleagues analysed liver transplant waiting list trends to explore the potential impact of DAA treatment.

The researchers used data from the Scientific Registry of Transplant Recipients, which provides analytic support for OPTN, looking at more than 47,500 adults who were wait-listed for liver transplants between 2003 and 2015 due to hepatitis C, hepatitis B or NASH. They were considered to have decompensated cirrhosis if they had hepatocellular carcinoma or a MELD score > 15.

Individuals were divided based on whether they were wait-listed between 2003 and 2010 (interferon era), 2011 and 2013 (first-generation HCV protease inhibitors plus interferon/ribavirin) or 2014 and 2015 (interferon-free DAAs).

The study showed that the likelihood of people with hepatitis C being wait-listed for decompensated cirrhosis decreased by 5% in the protease inhibitor era and by 32% in the interferon-free DAA era compared to the interferon era, both of which were statistically significant.

Wait-listing for decompensation due to hepatitis B also decreased, by 24%, from the earliest to the latest period; during this time hepatitis B virus antiviral therapy has improved but there is still no reliable cure. In contrast, wait-listing for decompensation due to NASH rose dramatically, by 81% over the entire study period. In 2015 the incidence of wait-listing for decompensated cirrhosis due to HCV and NASH were similar, at 2.73 and 2.80 per 100,000 people.

"The rate of liver transplant wait-listing for HCV complicated by decompensated cirrhosis has decreased by over 30% in the era of DAA therapy and is now equal to that of NASH," the researchers concluded. "Further reductions in wait-listing are anticipated with increased testing, linkage to care, and access to DAA therapy."

Optimal timing of HCV treatment

The prospect of liver function improvement after successful hepatitis C treatment raises the possibility that effective DAA therapy could reduce patients' MELD scores enough to lower their priority or make them ineligible for a liver transplant, but not enough so that they no longer need one – a situation that has been dubbed 'MELD purgatory'.

Jagpreet Chhatwal of Massachusetts General Hospital and colleagues looked at the optimal timing of hepatitis C treatment for people with decompensated cirrhosis on the transplant waiting list with regard to this trade-off, aiming to identify who would benefit or not benefit from pre-transplant HCV treatment.

Noting that a randomised controlled trial of pre-transplant treatment for liver transplant candidates would be prohibitively large and time-consuming, they used mathematical models to simulate a 'virtual trial' comparing long-term outcomes of pre- versus post-transplant oral DAA treatment.

The SIM-LT model took into account several variables including patient demographics, pre- and post-transplant liver disease progression, treatment efficacy, changes in MELD scores, likelihood of liver transplantation, changes in transplant waiting lists, mortality rates and quality of life. The model also considered the reduced likelihood of receiving an HCV-infected donor liver if more people with hepatitis C are cured with DAAs.

The analysis considered people with a mean age of 50 years, HCV genotypes 1 or 4 and MELD scores between 10 and 40. Efficacy was based on results from the SOLAR-1 and SOLAR-2 trials, which showed that sofosbuvir/ledipasvir (Harvoni) plus ribavirin cured at least 85% of pre-transplant patients with decompensated cirrhosis and at least 95% of liver transplant recipients with less severe cirrhosis due to recurrent HCV.

The model predicted that post-transplant life expectancy would increase for people with MELD scores of 10 to 27 who received HCV treatment prior to transplantation. However, among people with MELD scores of 30 to 40, pre-transplant treatment was associated with reduced life expectancy. Pre-transplant treatment also increased quality-adjusted life years up to a MELD score of 27, after which it led to a decrease.

Looking at different United Network for Organ Sharing (UNOS) regions, the upper MELD cut-off for improved life expectancy was 23 in the southeastern Region 3, with the shortest wait time, and 27 in the northeastern Region 9, with the longest wait time.

"Optimal MELD score threshold below which to treat HCV in patients on the transplant waiting list is between MELD scores 23-27, depending on the UNOS region," the researchers concluded. "Our results may help inform clinicians about the timing of HCV treatment in liver transplant candidates."

However, they cautioned, "recommendations may still need to be individualized for special situations," as their results may not apply in cases where transplant urgency is not determined by MELD score, and the model did not consider people with HCC.