Treatment of Patients with HCV-Related Cirrhosis with Peginterferon and Ribavirin: Swinging the Pendulum Towards Treatment.

Abstract

Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared to those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared to non-responders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients who achieve an SVR should be monitored because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.

Chronic infection with the hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide.(1) Long-term sequelae include the development of cirrhosis, hepatocellular carcinoma (HCC) and hepatic decompensation. Progression to cirrhosis marks an ominous milestone in the disease process. Following the development of cirrhosis, 5% of individuals will decompensate and 1% to 3% will develop HCC annually.(2–6) Recent data have demonstrated that successful eradication of HCV in patients with cirrhosis was associated with reversal of cirrhosis, (7) and a reduction in the rate of hepatic decompensation, liver transplant and liver-related death.(8–10) Therefore, patients with cirrhosis stand to benefit greatly from therapy with the goal being sustained viral clearance. The unfortunate reality is that rates of sustained virological response (SVR) are substantially lower in patients with cirrhosis compared to those without cirrhosis. Additional concerns of poor tolerance, the risk of serious life-threatening infections due to neutropenia, and the risk of precipitating hepatic decompensation lead many clinicians to use suboptimal therapy in this population. Only a few studies have evaluated the current standard of care in patients with cirrhosis, which is full dose peginterferon in combination with weight-based ribavirin. The majority of these studies have limited sample sizes which included selected subjects from single centers. Additionally, patients with histologic evidence of bridging fibrosis were combined with those with cirrhosis. Furthermore, many of the studies lacked adequate reporting of long-term treatment outcomes.

The current report, although retrospective and subject to selection bias, attempts to address some of these shortcomings. The primary aims of the study were to assess the efficacy and outcome of standard therapy in 568 patients with HCV-related cirrhosis from 26 centers in Spain. (Ref. paper) Patients were treated with either pegylated interferon alfa 2a (n=315) or 2b (n=253) in combination with weight-based ribavirin at the investigator’s discretion. Cirrhosis was confirmed by liver biopsy in three-quarters of subjects, by Fibroscan in 1.6% and by clinical assessment in the remainder. One third of the patients had been previously treated. Patients with decompensated liver disease (Child Turcotte Pugh [CTP] score >6) or significant cytopenia at baseline (neutrophil count <1,500/mm³ and platelet count <100,000/mm³) were excluded. The primary efficacy endpoint was the rate of SVR. Clinical outcomes were defined as the development of ascites, hepatic encephalopathy, an increased in CTP score by ≥2 points, development of HCC, variceal hemorrhage, need for liver transplantation, or death either unrelated or liver-related. Patients were monitored for HCC by ultrasound every 6 months. Overall, an SVR occurred in 30.7% of patients. Pre-treatment factors associated with an SVR were non-genotype 1, viral load <6 × 10⁵ IU/ml, absence of ultrasound signs of portal hypertension and the overall dose of therapy received for ≥80% of the scheduled time. Over a median follow-up of 35 months, 23% of subjects developed a clinical event including 29 deaths. The important finding was that subjects who achieved an SVR had a significantly better survival compared to non-responders, 98% versus 86%, and less decompensation at 5 years, 91% versus 59%, respectively. However, attaining an SVR did not prevent the development of HCC. Factors independently associated with the development of a clinical event were absence of an SVR, baseline serum albumin <3.9 g/dL and evidence of esophageal varices on endoscopy.

This study supports others that have shown that standard therapy can be safely used in HCV patients with compensated cirrhosis.(11–15) (ref paper) However, tolerance was poor with close to one third of patients having to discontinue therapy early. Although full dose peginterferon and weight-based ribavirin would in theory be the preferred regimen to use in cirrhotic patients, the SVR rate of 30.6% was comparable to the 30% SVR rate reported with full dose peginterferon alfa-2a monotherapy.(16) Differences in baseline criteria may explain the similar SVR rates obtained with the two regimens. The current study enrolled a higher proportion of patients with HCV genotype 1 infection and patients who had prior treatment failures. These two factors have been recognized to be associated with lower SVR rates. In the only randomized study to compare peginterferon alfa-2b to peginterferon plus ribavirin in subjects with cirrhosis, lower doses of both peginterferon and ribavirin were used.(12) Nevertheless, the results showed that the proportion of subjects who achieved an SVR was higher in the combination arm compared to the monotherapy arm, 21.6% versus 9.8%, but the difference was not statistically significant, perhaps due to the relatively small sample size. Thus, the optimal regimen to treat patients with cirrhosis has not been established and in the absence of further data either regimen may be appropriate in cirrhotic patients. However, the low SVR rates obtained with HCV genotype 1 infection with peginterferon monotherapy favors the use of combination therapy.

In this study, better therapeutic adherence during the first 12 weeks of therapy resulted in a higher SVR rate. The importance of treatment adherence was also highlighted in an analysis that explored dose reductions and discontinuations during the lead-in phase of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C).(17) Dose reductions in peginterferon or stopping ribavirin during the initial 20 weeks were associated with a significant decrease in the SVR rate. Therefore, regardless of regimen used, efforts should be directed at optimizing patient adherence and maintaining full dose therapy for as long as safely possible in patients with cirrhosis. Cytopenias are a major cause of dose reduction in this population. Therefore, future studies directed toward the role of growth factors in cirrhotic patients are warranted.

SVR rates with full dose peginterferon and ribavirin in patients with cirrhosis are consistently lower compared to those without cirrhosis.(18), (19) The real world SVR rate of 30.6% obtained in this study mirrors the rate of 33% reported in cirrhotic patients enrolled in three large multicenter trials but was significantly lower than that of patients without cirrhosis, 60%, in that analysis.(18) The reason patients with cirrhosis respond less well to therapy is not clear. It was believed that the lower response to treatment was due to the need for more frequent dose reductions and discontinuations rather than a lower antiviral response. Indeed the rates of discontinuation were lower in responders compared to non-responders in this study. However, a recent analysis from the HALT-C trial suggested that disease severity was the major factor that impaired virologic response independent of dose reduction. Furthermore, the post hoc analysis of cirrhotic patients treated with peginterferon alfa-2a plus ribavirin revealed that the rate of viral clearance was the most important predictor of a SVR even in cirrhotic patients.(18) Cirrhotic patients were shown to have significantly slower rates of viral clearance compared to those with bridging fibrosis and without either bridging fibrosis or cirrhosis. Why rates of viral clearance are slower in patients with cirrhosis is unknown and may relate to host genetic factors. Thus, early viral kinetics can be used to predict the response to treatment in patients with cirrhosis. The positive predictive value of a rapid virological response (RVR) defined as a negative HCV RNA test at week 4 is high ranging from 84% to 95%, in contrast the negative predictive value of an RVR was only 67.6%, too low to be used as a stopping rule. In this study, the authors suggested that an HCV RNA reduction of <1 log by week 4 had a negative predictive value of 100%. However, it should be noted that this was a subanalysis involving less than 50% of the cohort. Therefore, the utility of this parameter for stopping therapy by week 4 in cirrhotic patients should be confirmed in other studies before it can be adopted in clinical practice.

In addition to poor tolerance and lower SVR rates, another reason physicians may have been reluctant to treat patients with cirrhosis was the lack of data indicating any meaningful clinical benefit. However, several recent studies have reported that achievement of an SVR in patients with cirrhosis was associated with reversal of fibrosis, a reduction in the incidence of hepatic decompensation and liver-related death compared to patients who did not achieve an SVR. Additionally, most patients remain HCV RNA negative with long-term follow-up. These findings strongly shift the risk benefit assessment in favor of treating patients. Although these results are encouraging leading some to view this as a cure, patients with cirrhosis may still decompensate after achieving an SVR. More importantly, the risk of developing HCC persists for at least five years after an SVR and while lower, was not different between those with an SVR and those without.(10) This finding underscores the need for continued screening for HCC and monitoring for clinical decompensation in patients with cirrhosis even after achieving an SVR. Who are the patients likely to run into trouble? Results from this study and other suggest that patients with more advanced disease as evidenced by low synthetic parameters and presence of portal hypertension (those with esophageal varices) are at higher risk for clinical events and perhaps warrant closer monitoring. (Ref paper)

In summary, results from this study adds to the growing body of evidence demonstrating the safety and benefit of treating patients with compensated cirrhosis. Despite the low SVR rates, the long-term benefits of an SVR clearly swings the pendulum towards treatment of cirrhotic patients. Future studies should focus on optimizing the treatment regimen in this difficult to treat population particularly in patients with HCV genotype 1 infection with the aim of achieving an SVR. Cirrhotic patients who obtain an SVR remain at risk for complications of the disease particularly the development of HCC and should be monitored. Newer more effective therapies are urgently needed for patients with cirrhosis. In this regard, the results of trials evaluating direct acting antiviral agents may offer a ray of hope. Patients with compensated cirrhosis should not be excluded from these trials.

Abbreviations:

HCV

hepatitis C virus

HCC

hepatocellular carcinoma

SVR

sustained virological response

CTP

Child Turcotte Pugh

HALT-C

hepatitis C antiviral long-term treatment against cirrhosis

RVR

Rapid Virological Response