PRO: Patients With Decompensated Cirrhosis Listed for Liver Transplantation Should Be Treated Pretransplant

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

CTP

Child‐Turcotte‐Pugh class

DAA

direct‐acting antiviral

G

genotype

HCV

hepatitis C virus

LT

liver transplantation

MELD

Model for End‐Stage Liver Disease

NS5A

nonstructural protein 5A

SVR

sustained virological response

SVR12

SVR at posttreatment week 12

Key Points

• Patients with decompensated cirrhosis secondary to hepatitis C virus (HCV), especially those with less severe symptoms, can achieve high rates of sustained viral response; however, therapy may need to be modified to optimize efficacy and safety.

• Treatment in some patients listed for liver transplantation (LT) can result in clinical improvement to the point that they can be removed from the transplant list.

• HCV should be treated in patients with a Model for End‐Stage Liver Disease (MELD) score less than 15 and could be considered in those with a MELD score less than 27.

In the United States, the Centers for Disease Control and Prevention estimates that approximately 3.5 million people are chronically infected with hepatitis C virus (HCV), with the highest prevalence in individuals born between 1945 and 1965. The number of patients with chronic HCV with cirrhosis is expected to continue to rise.1 Over the past three decades, treatment for HCV has evolved with improved efficacy in patients with cirrhosis. Compensated cirrhosis is defined as patients with well‐preserved liver function and the absence of signs and symptoms of portal hypertension such as ascites, encephalopathy, peripheral edema, variceal bleeding, or jaundice. These patients are typically classified as Child‐Turcotte‐Pugh (CTP) class A. In contrast, patients with decompensated cirrhosis will have one or more of the aforementioned signs or symptoms and are defined as CTP B or CTP C. LT is believed to offer the best long‐term prognosis in those with decompensated cirrhosis; however, access to this lifesaving opportunity is limited by high demand and organ availability. Goldberg et al.2 found that 26% of patients with decompensated cirrhosis had HCV. Because HCV is a common cause for decompensated cirrhosis, viral eradication could improve hepatic function without transplantation. Unfortunately, these patients represent one of the most challenging groups to treat.2

Direct‐Acting Antivirals Can Cure HCV In Patients With Advanced Liver Disease

Since the discovery and characterization of HCV in 1989, there has been an evolution in treatment regimens (Fig. 1). Interferon‐based therapy led to cure; however, these drugs were contraindicated in patients with decompensated cirrhosis because of a high risk for complications and incredibly low response rates.

Figure 1.

Chronology of HCV therapy.

For patients without cirrhosis and those with compensated cirrhosis, several oral drug combinations have shown sustained virological response (SVR) rates of greater than 95%. However, not all oral therapies can be used in decompensated cirrhosis. Specifically, protease inhibitor‐containing therapy is contraindicated in decompensated cirrhosis because of unreliable hepatic metabolism and a risk for hepatic toxicity.

This is not true for all oral therapies. Nonstructural protein 5A and 5B (NS5A/NS5B) therapy has made treating patients with decompensated cirrhosis possible. These drugs are eliminated by the kidneys and can, therefore, be used in patients with liver dysfunction.

The ALLY‐1 study assessed the efficacy of pan‐genotypic daclatasvir/sofosbuvir plus ribavirin in two parallel cohorts: (1) patients with advanced cirrhosis (of which we have particular interest), and (2) those with posttransplantation recurrence of HCV. The overall SVR at posttreatment week 12 (SVR12) in advanced cirrhosis groups was 83%; however, within this group, patients with CTP A were included. When accounting for SVR12 within the different CTP classes, there was a significantly lowered SVR12 achieved (56%) for CTP C compared with CTP A or B (93%), suggesting a suboptimal response within this particular subgroup. A limitation to this study, however, is the small sample size of patients (n = 4) with MELD greater than 20. Within this group of patients, the efficacy of treatment cannot be established by this study. It is worth noting that the response rate for genotype 3 (G3) patients within the advanced cirrhosis group was 83%, yielding similar results to the ASTRAL‐4 trial that showed a higher (85%) SVR12 when ribavirin was added to velpatasvir/sofosbuvir.3

The SOLAR‐2 study addressed the efficacy of ledipasvir/sofosbuvir plus ribavirin in patients with HCV G1 or G4 with advanced liver disease (CTP B or C). Among pretransplant G1 patients, SVR was achieved in 87% of CTP B with 12 weeks of therapy and in 96% with 24 weeks of therapy. For those patients with CTP C, SVR was achieved in 85% and 78% with 12 and 24 weeks of therapy, respectively. Among pretransplant G4 patients, SVR rates for CTP‐B was 67% (2/3) and 100% (2/2) for 12 and 24 weeks, respectively. For CTP C, SVR was 0% (0/1) and 50% (1/2) for 12 and 24 weeks. SOLAR‐2 again proved that HCV can be eliminated in decompensated cirrhosis but was limited by the small sample size of the G4 group.4

The ASTRAL‐4 trial evaluated the efficacy of pan‐genotypic velpatasvir/sofosbuvir with and without ribavirin for decompensated (CTP‐B) patients with genotypes 1 to 6. Results of this study showed high SVR rates among the three treatment arms. The overall SVR12 were 83% for velpatasvir/sofosbuvir for 12 weeks, 94% for velpatasvir/sofosbuvir plus ribavirin for 12 weeks, and 86% for velpatasvir/sofosbuvir for 24 weeks. Improvements in CTP and MELD scores from baseline were also observed with improvement highest in patients with baseline MELD of 15 or greater.5 Notably, G3 patients had a lower SVR12 (50%) for both the velpatasvir/sofosbuvir 12‐ and 24‐week treatment arms compared with 85% for the velpatasvir/sofosbuvir plus ribavirin group. It may be beneficial to suggest the addition of ribavirin for G3 patients.

Direct‐Acting Antiviral Therapy In Decompensated Cirrhosis Is Safe

Clinical trial data not only proved efficacy, but also demonstrated that these agents could be used safely. First, most patients have an improvement in CTP and MELD score by SVR12 (negative HCV RNA 12 weeks after stopping treatment). There were episodes of decompensation, as well as death, in these trials; however, most were related to the severity of cirrhosis, not the therapy. No death was considered study drug related. The addition of ribavirin does increase the risk for serious anemia (hemoglobin <10 g/dL).

Currently, there are two U.S. Food and Drug Administration–approved regimens for decompensated patients: ledipasvir/sofosbuvir for G1 and G4, and velpatasvir/sofosbuvir for G1 through G6. We make the assertion that the treatment of decompensated patients and those awaiting LT with direct‐acting antivirals (DAAs) is possible. The studies discussed earlier have demonstrated efficacy in treating this subgroup of patients, although results (SVR) are not as high compared with patients with compensated cirrhosis.

Treatment Before Transplantation Can Result In Delisting

The question of treating patients awaiting LT with high MELD score is one of an ongoing debate because treatment may improve their MELD score and put them below the threshold for LT, but not help patients improve their overall health.6 However, we assert that this is not one size fits all. For patients with a MELD less than 15, the likelihood of transplantation is low. Pretransplantation treatment can result in effective delisting.7 However, a threshold of 15 may be too conservative. With the shortage of donor livers in certain regions, pretreatment with DAA could reduce the need for LT, prevent graft infection, and improve post‐LT outcomes.6, 8, 9, 10 In a microsimulation study using data from the United Network for Organ Sharing and the SOLAR‐1 and −2 trials, Chhatwal et al.11 suggest that the optimal threshold for pretransplantation treatment of decompensated patients is a MELD score between 23 and 27. This further supports the fact that patients below this threshold will benefit from pretransplantation treatment.

In the current era of DAAs, it remains difficult to determine the most suitable patients for HCV treatment in the setting of decompensated cirrhosis. However, we believe patients with low MELD scores should be treated. The following criteria may help clinicians decide whether to pursue antiviral therapy (Table 1).

Table 1.

Criteria to Determine Treatment Decision

Patients who should be treated: MELD score <15 for patient listed/eligible for transplantation MELD score <20 for patients not eligible for transplantation Compliant and motivated patients with good support

Patients who should not be treated: Awaiting combined liver and kidney transplantation Previous NS5A DAA failure Multiple comorbidities MELD score >20 Active liver cancer

Patients With Meld Score Of Less Than 15 Should Be Treated

In conclusion, our review of the literature and current clinical trial data support the treatment of some patients with decompensated cirrhosis based on sound clinical judgment and close monitoring of their condition. Transparent and extensive discussion must be had with patients and their family prior to starting treatment to clearly explain the expectations and goals. Hepatitis C treatment may benefit patients with decompensated cirrhosis with a low MELD score (<27).