Hepatitis C virus (HCV) treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.
The course of chronic hepatitis C virus (HCV) progression can take decades and differs among individuals. Many patients are unaware of their HCV infection and some will develop only mild inflammation and fibrosis of the liver. Yet, a significant number of these patients will develop cirrhosis, decompensated cirrhosis and hepatocellular carcinoma (HCC). Many studies have shown that attaining sustained viral response (SVR) in both groups decreases all cause mortality and reduces the risk of HCC development. HCV treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.
Elie Ghoulam MD, MS Post-Doctoral Research Fellow, Section of Hepatology, Rush University Medical Center, Chicago, IL Nancy Reau, MD Professor of Medicine Chief, Section of Hepatology, Associate Director, Solid Organ Transplantation, Rush University Medical Center, Chicago, IL
INTRODUCTION
Hepatitis C virus (HCV) was previously identified as non-A non-B hepatitis until its existence was proven in 1989.1. Hepatitis C is a contagious, blood borne, ssRNA virus and exists in multiple genotypes.2 Risk factors for acquiring include injection drug use, inadequate sterilization of medical equipment and transfusion of unscreened blood and blood products.3 HCV can also be transmitted sexually and vertically, but these modes of transmission are less efficient. Globally, 130-150 million people have HCV.3 According to the Centers for Disease Control and Prevention (CDC), an estimated 3.2 million people in the United States (USA) are living with chronic hepatitis C infection, many of whom are unaware of their infection.4 There is a high seroprevelance of HCV infection in persons born from 1945-1965, one-half of whom already had severe fibrosis or cirrhosis based on a study by Klevens et al. This data prompted the CDC to recommend one- time hepatitis C virus antibody testing in this group of people.5,6
The course of chronic HCV disease progression occurs over decades and is varied among individuals.7 Factors that impact disease progression are older age, male gender, diabetes, obesity, steatosis, iron overload, genotype 3, alcohol intake and human immunodeficiency virus (HIV) or hepatitis B (HBV) coinfection.8,9,10 Over the first 20 years of infection, most patients do not develop liver disease beyond inflammation and moderate fibrosis.10 A percentage of these patients will then progress to cirrhosis, possibly decompensated or symptomatic, and HCC.8 The chances of developing decompensated cirrhosis in the cirrhotic populations are 11.7% with a four-year survival of 50%. The risk of developing HCC is 1%-5% annually.8,11
Hepatitis C therapy has evolved significantly since first using interferon and ribavirin. This evolution has allowed the expansion of therapy to groups of individuals previously without treatment options. Although, even in the interferon era, individuals with well compensated cirrhosis could contemplate therapy, there were occasions of decompensation and significant toxicity. All-oral options have now made therapy commonplace for those with asymptomatic cirrhosis and an option to consider in those with decompensation.
The clinical benefit of viral eradication in those with advanced liver disease has been unarguably established through several long-term observational trials. Development of cirrhosis, decompensation and HCC are all considerably reduced after sustained viral response (SVR) with either interferon based or all oral direct acting antiviral (DAA) therapy. The rate of liver transplant wait-listing for HCV secondary to decompensated cirrhosis has decreased by 32% as a result of DAA therapy.12 Not only has there been demonstrable benefit to liver-related mortality, but all- cause mortality is also improved with viral eradication.13 However, clinicians still need to be aware that not all patients with cirrhosis are the same. Those with symptomatic cirrhosis (decompensated cirrhosis) are at higher risk for adverse events and drug toxicity. Historically, treatment of this group of individuals was contraindicated. As the toxicity and efficacy of therapy improved, we have been able to expand therapy to increasingly sicker patients, although the benefit of doing so remains controversial.
Recognizing Cirrhosis
Our guidance recommends staging each patient with hepatitis C.14 Cirrhosis can be quite subtle, and can easily be missed.
Cirrhosis
Cirrhosis is defined as the late stage of progressive hepatic fibrosis characterized by change of hepatic architecture and the formation of regenerative nodules.15 In its advanced stages it is considered to be irreversible, but in its earlier stages it may improve or even reverse if specific treatments aimed at the underlying etiology of liver disease are addressed.16
Signs and symptoms of cirrhosis can be nonspecific such as anorexia, weight loss, weakness, fatigue or signs and symptoms of hepatic decompensation such as jaundice, pruritus, upper gastrointestinal bleeding, abdominal distension from ascites and confusion due to hepatic encephalopathy.16
Physical findings consist of spider angiomatas, palmar erythema, gynecomastia, testicular atrophy, amenorrhea, parotid/lacrimal gland hypertrophy, Dupuytren’s contractures, clubbing and jaundice.16
Laboratory abnormalities may be striking such as elevated serum bilirubin or coagulopathy. However, laboratory findings may be subtler such as a platelet count &tl;150 or AS>ALT. Several clinical calculators can help identify those at higher risk for cirrhosis such as APRI or FIB4.17
Diagnosis
If cirrhosis is evident clinically (nodularity on imaging, splenomegaly, low platelets, ascites, encephalopathy, jaundice, etc.), no further assessment is required. However, most patients with advanced disease lack these clinical cues. Several non-invasive means have been validated to assess for fibrosis. All have diagnostic utility, yet a combination of concordant serum markers and elastography is felt to have the most reliability outside of biopsy.14
Compensated vs Decompensated Cirrhosis
Patients who develop complications of cirrhosis are considered to have decompensated cirrhosis and those who have not developed major complications are classified as having compensated cirrhosis.18 The median survival of patients with compensated cirrhosis is >12 years.18 Patients that develop varices but not variceal bleeding are still considered as having compensated cirrhosis but have a 2.1 percent increase in one-year mortality.18 Several factors can predispose to decompensation in a patient with cirrhosis. Risk factors include bleeding, infection, alcohol intake, medications, dehydration, obesity and constipation.19,20
Predictive Models
Two predictive models, the Child-Pugh classification (CP) and Model for End-Stage Liver Disease (MELD) score, are most commonly used today in attempt to predict the prognosis of cirrhotic patients. Based on clinical and laboratory information, these models have been derived from multiple studies.21,22
Child-Pugh Classification
The variables included in the CP classification are the serum albumin and bilirubin, ascites, encephalopathy and prothrombin time. The score ranges from 5 to 15. Patients with a score of 5 or 6 have Child-Pugh class A cirrhosis (well-compensated cirrhosis), those with a score of 7 to 9 have Child-Pugh class B cirrhosis (significant functional compromise) and those with a score of 10 to 15 have Child-Pugh class C cirrhosis (decompensated cirrhosis).21
The Child-Pugh classification system is not only used in staging of cirrhosis but has been found to correlate with survival of patients not undergoing surgery with decrease survival rates as you progress from Child-Pugh A to C.23 It is also associated with likelihood of developing complications of cirrhosis. Child-Pugh C patients are much more likely to develop variceal bleeding for example than Child-Pugh A.24
MELD Score
Another model to predict prognosis in patients with cirrhosis is the MELD score 22. Based on bilirubin levels, creatinine, INR and the etiology of cirrhosis, the MELD score has been adopted for use in prioritizing patients awaiting liver transplantation and has an expanding role in predicting outcomes in patients with liver disease in the non-transplantation setting as well. In January 2016, Organ Procurement and Transplantation Network Policy 9.1 (MELD Score) was updated to include serum sodium as a factor in the calculation of the MELD score 25. The MELDNa score can be calculated online.
Consider Consequences of Cirrhosis
Individuals with advanced liver disease are at risk for complications of portal hypertension and liver cancer. Once cirrhosis is recognized, it is advised to obtain abdominal imaging with ultrasonography to screen for hepatocellular cancer (HCC). If ultrasound is of poor quality, cross sectional imaging should be done.
Ascites may be clinically evident, but is not infrequently identified first on imaging done for liver cancer screening. The development of ascites carries significant impact on prognosis, decreasing expected 5-year survival to <60%. If the ascites is refractory to diuretics, associated with dilutional hyponatremia or type 2 hepatorenal syndrome (HRS), the anticipated 1-year survival is 30%.26
Several clinical algorithms exist to help identify those cirrhotics that are at higher risk for complications of portal hypertension. Those individuals with liver stiffness scores <20 kPa and serum platelet count >150,000/ mm3 are unlikely to have high-risk varices. Recently updated AASLD guidelines27 recommended performing an upper endoscopy to evaluate for gastroesophageal varices for all individuals that do not meet those criteria. If high-risk for bleeding (the presence of medium/large varices), primary prophylaxis with either non-selective beta-blockers or band ligation should be initiated.
Other routine health maintenance includes vaccinating against hepatitis A (HAV), hepatitis B, yearly influenza and avoidance of hepatotoxins. Patients with a CP score of >7 or MELD score >18 are at high risk for complications and should be co-managed by an experienced clinician.28
HCV and Genotypes and Treatment
Although pan genotypic therapy exits, the genotype of HCV remains an important variable as this may determine the efficacy and duration of therapy.14
Treatment of HCV in Patients with Compensated Cirrhosis
Individuals with HCV cirrhosis that lack symptoms (ascites, variceal bleeding, coagulopathy, jaundice, encephalopathy) are considered compensated. The Child-Pugh Class (CP) can be used to confirm prognosis. CP A is considered well compensated.29
No therapeutic agent is contraindicated in a patient with compensated cirrhosis, however certain regimens are recommended depending on genotype and treatment experience. Recommended regimens are generally prioritized due to shorter duration and the omission of ribavirin (RBV) to achieve higher efficacy. The most up to date therapeutic recommendations can be found in the American Association for the Study of Liver Disease/ Infectious Disease Society of America (AASLD/ IDSA ) guidance document.14 Table 1 summarizes the recommended and alternative, or not recommended, treatment choices for treatment naïve and treatment experienced (exposed to interferon, ribavirin or sofosbuvir) patients with cirrhosis.
Treatment of HCV with Decompensated Cirrhosis
The treatment of patients with CP class B or C cirrhosis is controversial, as most will require liver transplantation for optimal long-term survival. In patients who are not transplant candidates, the goal is to achieve SVR with the hope that there will be an improvement in clinical condition. For patients who are transplant candidates, the goals are not as straightforward. SVR before transplantation prevents re-infection of the new liver which could improve post-transplant outcomes and survival of the graft.14,30 However, viral eradication pre- transplant prevents the use of HCV exposed organs and treatment post-transplant is safe and effective.
Marginal hepatic function limits treatment options. In the era of IFN-based therapies, treatment in decompensated cirrhosis was contraindicated.31 All-oral therapy has significantly better efficacy and safety, however drug toxicity must still be considered. Although safe and effective in CP class A, protease inhibitors are not advised for those with CP class B/C cirrhosis.
Accordingly, the AASLD, IDSA and the European Association for the Study of the Liver (EASL) guidelines recommend only all-oral DAA regimens containing sofosbuvir, ledipasvir, daclatasvir and RBV as show in Table 2.31
Individuals with decompensated cirrhosis are at high risk for complications. It is advised that treatment should be performed by a highly experienced medical practitioner, preferably associated with a transplant center.14,30
Post-Cure Monitoring
It is important to recognize that although SVR substantially lowers the risk of progression or liver cancer, it does not eliminate this risk. All patients with cirrhosis, despite demonstration of regression by biopsy or non-invasive measurements, still require longitudinal follow-up. Liver cancer screening remains necessary as risk for malignancy remains. Recent analysis of a large Veterans Administration (VA) database demonstrates that age, gender and diabetes increase this risk.32
CONCLUSION
Compensated HCV cirrhosis has excellent long-term prognosis and a chance of reversal if SVR is attainable. Decompensated cirrhosis carries high risk of mortality and should be performed by highly experienced HCV providers. Early referral for transplant for patients with CTP >7 and MELD >18 is key for better patient outcomes as early treatment of HCV can prevent many life threatening complications and reduce HCC risk.