Co-existing Hepatitis C and Alcoholic Liver Disease: A Diminishing Indication for Liver Transplantation?

Co-existing Hepatitis C and Alcoholic Liver Disease: A Diminishing Indication for Liver... Abstract Aims To provide an overview of published literature on the interaction of alcohol and hepatitis C virus (HCV) in the accelerated progression of liver disease to cirrhosis as relates to decision-making for the management of the liver transplant candidate and recipient. Methods General PubMed search was employed along with expert input to identify the relevant articles on the topic. The authors also utilized both backward and forward citation review of the relevant articles and reviews to identify articles on identified topic. Results In HCV cases, heavy alcohol use has been associated with more severe fibrosis, but even low rates of use may have deleterious effects. Patients with chronic hepatitis C and alcoholic liver disease can be cured of the HCV—theoretically positively impacting outcome and reducing the need for liver transplantation. Current antiviral therapy achieves virologic cure or sustained viral response (SVR) in over 90% of cases. Antiviral therapy is so effective that most liver transplant candidates or recipients can be cured of HCV either prior to or after transplantation. However, despite successful antiviral therapy, liver disease may progress after SVR due to the effects of ongoing alcohol use. Conclusion Antiviral therapy in patients with HCV plus alcohol should improve pre- and post-transplant outcomes, but providers must remain firm in limiting use of alcohol to avoid progression of liver disease post HCV cure. Short Summary Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant. INTRODUCTION Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world, and cirrhosis due to chronic hepatitis C is historically the most common indication for liver transplantation. The number of those actively infected with HCV within the United States is estimated to be between 2.7 and 3.9 million. HCV commonly coexists with abusive alcohol use patterns. Alcohol and HCV interact to accelerate progression to advanced fibrosis and cirrhosis. Thus, both causes of liver injury need to be simultaneously addressed by clinicians who are considering these patients for liver transplantation. Current HCV treatment with direct-acting antiviral drugs (DAAs) is nearly universally effective across all HCV genotypes and over the full spectrum of HCV liver disease. Patients with coexistent chronic hepatitis C and alcoholic liver disease can be cured of the HCV—theoretically positively impacting clinical outcome and reducing the need for liver transplantation. With eradication of HCV, the control of the alcoholic liver disease will be the key to the overall clinical outcome of these patients. CO-EXISTENCE OF HEPATITIS C INFECTION AND ALCOHOL ABUSE HCV infection and alcohol abuse commonly co-exist. The prevalence of HCV infection in the general population has been estimated at close to 2% (Alter et al., 1999). In individuals with heavy alcohol use, the prevalence of HCV infection is several-fold higher (Befrits et al., 1995; Coelho-Little et al., 1995). The estimates of the prevalence of hepatitis infection in patients with alcohol abuse are higher in alcoholic patients with liver disease, with ranges from ~18% up to 50% in some studies (Regev and Jeffers, 1999). This compares with lower reports of 0–14% HCV prevalence in alcoholic patients without clinically apparent liver disease (Regev and Jeffers, 1999). Patients with alcoholic abuse patterns with HCV are more likely than patients with HCV alone to develop clinical liver complications. ACCELERATION OF PROGRESSION IN LIVER DISEASE WITH ALCOHOL AND HCV Molecular and epidemiological evidence support the conclusion that the combination of hepatitis C and alcohol accelerates the progression of liver fibrosis compared to either etiology alone. The combined effect of hepatitis C and alcohol is not simply additive; due to different mechanisms of liver injury there is a multiplicative increase in damage (Singal and Anand, 2007). Alcohol-related mechanisms may include direct toxicity of alcohol, condensation of cytoskeletal proteins, alcohol-induced oxidative injury, accumulation of excessive iron further enhancing oxidative injury and neutrophilic infiltration of the liver. HCV-related mechanisms of injury additionally include pro-inflammatory cytokines and chemokines, HCV-induced hepatocellular necrosis, and immunomodulation by the virus (Szabo, 2003; Singal and Anand, 2007). In some studies, but not all, alcohol was shown to increase HCV viral replication (Anand and Thornby, 2005). In theory, alcohol could potentially increase the numbers of ‘quasispecies’ or viral diversity, which might increase risk for resistance emerging during antiviral drug therapy (Sherman et al., 1999). For these reasons, any alcohol use is strongly discouraged during antiviral treatment. Alcohol alone, increases risk for cirrhosis. As little as 6 drinks per week in women (84 g of alcohol) and 13 drinks per week in men (182 g of alcohol) has been associated with increased risk for cirrhosis (Becker et al., 1996). Risk for cirrhosis increases with increasing alcohol intake. For example, an intake of 28–41 standard drinks per week (between 392 and 574 g per week) increased risk for cirrhosis by 17-fold in women and 7-fold in men (Becker et al., 1996). Only a handful of studies have examined the relationship of quantify and frequency of alcohol to progression of liver disease in patients with chronic hepatitis C. As a result, it is not known whether there is a minimum safe amount of alcohol for an individual with chronic hepatitis C. Heavy to regular moderate use of alcohol (typically at minimum >3 drinks daily or >40 g per day) has been clearly shown to influence risk for chronic hepatitis C to progress to cirrhosis (Poynard et al., 1997; Serfaty et al., 1997; Wiley et al., 1998). In a cross-sectional study of 800 patients with chronic hepatitis C, Monto found that heavy alcohol use (>50 g daily) was associated with more severe fibrosis, but increases in fibrosis also occurred with low to moderate alcohol use (Monto et al., 2004). The impact of low to moderate alcohol intake on hepatic fibrosis in patients with chronic hepatitis C was further investigated by Westin et al. They evaluated 78 individuals with chronic hepatitis C and low to moderate alcohol use and assessed for progression of fibrosis between historical biopsies. Patients with alcohol consumption above the median alcohol consumption for the study population showed increased progression of fibrosis when compared with the patients whose alcohol consumption was below the median. The alcohol use within the higher use group was on average 11.6 g per day with a range from 5.2 to 17.8 g per day. In contrast, the alcohol use within the lower use group was on average 1.1 g per day with a range from 0.2 to 2.6 g per day. The increased fibrosis in the moderate alcohol drinkers supports the conclusion that even intermittent moderate alcohol can accelerate fibrosis progression with HCV (Westin et al., 2002). Given the uncertainties in defining a safe amount of minimal alcohol use in patients with chronic hepatitis C, both the American Association for the Study of Liver Disease and the European Association for the Study of Liver Disease recommend that patients with chronic hepatitis C avoid use of alcohol in their published clinical guidelines. HCV TREATMENT REGIMENS Figure 1a and b displays the currently available, all oral, DAA regimens for the treatment of chronic hepatitis C. Rates of sustained viral response (Fig. 2a and b) are greater than 90% with all of these regimens when used in the populations listed. It is highly likely that most patients listed for the combination of chronic hepatitis C and alcoholic liver disease will either be free of HCV at time of listing or could be made HCV free by treatment after listing. Decisions on whom to treat and when to treat with DAAs are currently the topic of discussion and clinical research. It is our opinion that withholding DAA treatment might be appropriate for waitlisted patients with MELD upgrade for hepatocellular carcinoma or those with very high MELD scores (>25). These patients might be best served by treatment after transplant as this strategy affords them the opportunity to be transplanted with a liver from an HCV positive donor. Fig. 1. View largeDownload slide (a) Summary of HCV treatment regimens approved for genotype 1 as of January 2017. (b) Summary of HCV treatment regimens approved for genotypes 2, 3 and 4 as of January 2017. Fig. 1. View largeDownload slide (a) Summary of HCV treatment regimens approved for genotype 1 as of January 2017. (b) Summary of HCV treatment regimens approved for genotypes 2, 3 and 4 as of January 2017. Fig. 2. View largeDownload slide (a) Rates of SVR for genotype 1 by treatment regimen, available as of January 2017. (b) Rates of SVR for genotypes 2, 3 and 4 by treatment regimen, available as of January 2017. Fig. 2. View largeDownload slide (a) Rates of SVR for genotype 1 by treatment regimen, available as of January 2017. (b) Rates of SVR for genotypes 2, 3 and 4 by treatment regimen, available as of January 2017. Certain underlying clinical features may dictate the choice of DAA treatment. Many patients with cirrhosis will have concomitant renal disease—as of this writing, sofosbuvir is not currently recommended for use in patients with creatinine clearance less than 30 mL/min. Although the combinations of sofosbuvir plus either ledipasvir or velpatasvir are approved for use in advanced cirrhosis (Child-Turcotte-Pugh B or C) other regimens are not, and those containing a protease inhibitor may be contraindicated. Although the need for ribavirin is often questioned, in most regimens where patients have had prior courses of DAA therapy or have advanced liver disease, ribavirin is included. The exception might be the emerging new triple and dual second and third generation combination DAA regimens. With the latter combinations, ribavirin may add little to no additional benefit in terms of sustained virologic response (SVR) or virologic cure. IMPACT OF ALCOHOL USE ON EFFECTIVENESS OF HCV TREATMENT Data is limited for the effects of alcohol on SVR rates. In the interferon era of treatment of chronic hepatitis C alcohol use was an exclusion criteria from clinical trials and historically alcohol abstinence was required prior to clinicians offering this complicated and toxic therapy. Most studies showed that ongoing excessive use of alcohol adversely affected the likelihood of achieving SVR, possibly due to early discontinuation (Anand et al., 2006). Studies also suggested that as amount of alcohol increased, SVR decreased (Loguercio et al., 2000). The requirement for injections, coupled with the intolerability and neuropsychiatric side effects of interferon undoubtedly contributed to non-compliance and poor treatment outcomes. The new era of all oral direct-acting antiviral drugs to treat HCV is characterized by ease of use, enhanced safety, high tolerability and markedly improved efficacy. As a result, patients with ongoing alcohol use tolerate and complete therapy and experience high rates of SVR. The impact of alcohol use on SVR was evaluated in a recent analysis of 15,151 patients who initiated DAA treatment and completed the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire. AUDIT-C scores were categorized as 0 (abstinence), 1–3 (low-level drinking) and 4–12 (unhealthy drinking) in men or 0, 1–2 and 3–12 in women. In that sample, 10,387 (68.5%) were categorized as abstinent, 3422 (22.6%) as low-level drinking and 1342 (8.9%) as unhealthy drinking. There were no significant differences in SVR rates between abstinent (SVR 91%; 95% CI: 91–92%), low-level drinking (SVR 93%; 95% CI 92–94%) or unhealthy drinking (SVR 91%; 95% 89–92) categories in univariable analysis or in multivariable logistic regression models (Tsui et al., 2016). Given these results, concomitant alcohol use may not be a reason to deny HCV treatment, given that HCV eradication may improve clinical outcome. On the other hand, the treating provider must emphasize to the HCV patient using alcohol that alcohol alone can lead to cirrhosis and that alcohol should be avoided to reduce risk for disease progression after SVR. MANAGEMENT OF THE PATIENT WITH DECOMPENSATED CIRRHOSIS With high rates of SVR expected even with advanced fibrosis, treating those with compensated cirrhosis to avoid transplant is an accepted strategy. However, treating those with decompensated disease (CPT B and C) is an area of debate. Patients with decompensated disease have lower rates of SVR and exposure to DAAs may favor development of resistance. Viral resistance to DAA treatment could complicate future management, particularly after liver transplantation. Also, clearing HCV by DAA treatment would eliminate the option for transplantation with an HCV positive donor, since most third-party payers will only allow one course of DAA treatment. In addition, SVR in a decompensated patient may not improve liver function or reverse portal hypertension. The patient may be left with ongoing poor quality of life and ‘MELD purgatory’—a low MELD score but ongoing issues with poor liver function, portal hypertension and clinical complications. A stable low MELD may eliminate access to a liver from a deceased donor, since liver transplantation in the United States is typically performed in patients with very high MELD scores. Selecting candidates for DAA treatment from the group of patients with decompensated disease is an ongoing challenge. EVALUATION OF THE PATIENT WHO DETERIORATES AFTER SVR The liver function, liver fibrosis and clinical picture of patients with fibrosis or compensated cirrhosis should stabilize or improve after SVR. Those with co-morbid alcoholism or alcohol abuse will require ongoing clinical and social follow-up to maintain sobriety to prevent liver deterioration and progression to decompensated disease. Clinicians need to be aware that underlying alcohol use/abuse is a factor that may promote deterioration after SVR. Alcohol avoidance may be the key to the ultimate benefit of DAA treatment of HCV in the patient with alcohol use/abuse. Patients with advanced fibrosis have the least hepatic reserve and are most likely to deteriorate clinically with alcohol-induced liver injury. Advanced fibrosis may be suspected by laboratory indices, imaging, or non-invasive staging. Progressive liver dysfunction should also prompt assessment for any unrecognized underlying liver disease such as non-alcoholic steatohepatitis (NASH), concomitant viral disease (HBV), genetic conditions (hemochromatosis, Wilson disease or alpha one antitrypsin deficiency). Patients with advanced fibrosis or cirrhosis who achieve SVR should undergo screening for hepatocellular carcinoma (HCC). Risk for HCC may decrease with SVR, but remains increased above the general population and long term lifelong surveillance may be warranted. TRANSPLANT OUTCOMES WITH HCV CO-OCCURRING WITH ALCOHOL Approximately 11% of the 54,687 adult liver transplants performed in the United States during 1994–2009 were for the indication of combined alcohol and chronic hepatitis C (approximately 6000) (Singal et al., 2013). This is compared to a reported 15,000 (28%) for chronic hepatitis C alone and 9000 (16%) for alcohol alone. It is highly likely that there is significant underreporting of alcohol use in the patients transplanted for chronic hepatitis C alone. It is anticipated that liver transplantation for the indication of cirrhosis due to chronic HCV could decline around the year 2020. HCV infection adversely affects outcome after liver transplantation. In an early study from the UNOS database of over 11,000 cases transplanted between 1992 and 1998, the 1, 3 and 5 year survivals for HCV positive transplant recipients were 86.4%, 77.8% and 69.9%, compared to 87.5%, 81.8% and 76.6% for HCV negative transplant recipients (Forman et al., 2002). The inferior outcomes in recipients with HCV infection are likely related to allograft hepatitis with accelerated fibrosis and progression to cirrhosis (Berenguer et al., 2000). There is limited information comparing outcomes for the combination of chronic hepatitis C and alcohol compared to either chronic hepatitis C or alcohol alone. A single center Spanish study found that outcomes after liver transplant were worse for HCV alone when compared to alcohol alone or HCV combined with significant alcohol consumption (Aguilera et al., 2009). The study reported outcomes in 337 patients followed for up to 7 years. The authors reported that 170 had an etiology of HCV alone, 107 had alcohol alone and 60 had a combined etiology of alcohol and HCV. They defined significant alcohol consumption as >50 g/day (about 3–4 standard drinks) for a period of >5 years or >80 g/day (about 5–6 standard drinks) for a shorter period. The HCV with alcohol group was found to be younger with median age of 49.5 (32.5–66.5) compared with median age 59 (29–68) for the HCV alone group and median age 53 (32–67) for the alcohol alone group. The improved outcomes for the HCV with alcohol group may have been related to a greater percentage receiving antiviral treatment (32% vs. 18%) and younger age (Aguilera et al., 2009). The younger age of the HCV plus alcohol group at the time of transplant supports the concept that the combination of alcohol and HCV accelerates disease progression. The perception that alcohol accelerates HCV disease progression among providers and patients may translate into better control of alcohol use post-transplant. Rates of recurrent alcohol use after transplant (considered significant at >1 drink per week for at least 6 months) were 3% (4/133) for HCV alone, 8% (4/50) for HCV with alcohol and 18% (15/83) for the alcohol alone (Aguilera et al., 2009). Another retrospective study, compared characteristics of liver transplant recipients for indication of alcoholic cirrhosis with (n = 32) or without HCV (n = 56) (Goldar-Najafi et al., 2002). The group with cirrhosis due to alcohol plus HCV was younger (median age 46 vs. 56) and had a shorter reported duration of disease (median 15 years vs. 25 years), again supporting the conclusion that alcohol combined with HCV is typically associated with acceleration of liver disease. One-year survival after transplantation was similar between the two groups—93% in alcohol alone and 97% in alcohol with HCV. Rates of recurrent alcohol abuse after transplantation was 8.9% for alcohol alone (median follow-up time of 5 years) and 9.4% for the combined alcohol with HCV (median follow-up time of 10 months). One large retrospective analysis from the UNOS dataset compared outcomes in 17,700 patients transplanted for HCV alone, 9600 for alcohol alone, and 6800 for the combination of HCV and alcohol collected from 1991 to 2010 (Singal et al., 2013). Although limited by lack of details regarding degree of alcohol use, when adjusted for recipient and donor characteristics, the results demonstrated poorest outcome for patients transplanted for the indication of chronic hepatitis C plus alcohol (Singal et al., 2013). Based on the high level of SVR rates anticipated with new DAAs, the entity of HCV with alcohol will be expected to diminish in coming years which hopefully will translate into overall improved outcomes with liver transplant. POST-TRANSPLANT TREATMENT OF HCV Given the emerging data demonstrating minimal impact of alcohol use on rates of SVR with DAAs, it is anticipated that patients transplanted for the combination of chronic hepatitis C and alcoholic liver disease will experience the same high rates of viral clearance as the patients transplanted for chronic hepatitis C alone. The SOLAR 1 and SOLAR 2 studies, using the combination 12 weeks DAA regimen of sofosbuvir and ledipasvir with ribavirin, demonstrated SVR rates in transplant recipients of 96% for those with non-cirrhotic fibrosis, 96% for CTP A, 85% for CTP B and 60% for CTP C. The falloff in SVR with increasing severity of cirrhosis is also noted in non-transplant populations. Thus, institution of treatment early after recovery from transplant, prior to graft injury and fibrosis, is currently highly recommended (Charlton et al., 2015). FUTURE OF INDICATIONS FOR LIVER TRANSPLANTATION Currently, the leading indication for liver transplantation is HCV—December 2013 data showed 29% of those on the waitlist were for the primary indication of HCV. The proportion of HCV cases has been relatively stable since 2003 (Kim et al., 2015). The second highest indication for liver transplantation over that same period of time was alcoholic liver disease, representing 24% of cases (Kim et al., 2015). Future studies should focus not only on the impact of alcohol on post-SVR outcomes but also other factors, including alcohol, that may promote progression of disease. For example, is there a difference in clinical outcome in waitlist patients with active ongoing HCV infection compared to waitlist patients who have cleared their HCV infection. What factors promote disease progression after SVR? What post-SVR factors, such as HCC development or cirrhosis complications, predict risk for liver transplantation despite achieving SVR? Concomitant ongoing alcohol use will need to be more accurately reported to help guide where to try to impact risk for disease progression. CONCLUSION Historically, Hepatitis C and alcohol together have commonly co-existed in patients with advanced liver disease. The widespread availability of effective HCV treatment will change the prevalence of this clinical entity—HCV will disappear and potentially the progressive liver disease will be driven by factors related to alcoholic liver disease. With clearance of HCV changes in liver function in either native liver or allograft need to be carefully assessed for other factors promoting disease progression. Although, alcohol does not seem to influence the chance to achieve SVR with current DAA treatment, providers must remain firm in recommendations regarding limiting use of alcohol to avoid progression in liver disease despite clearance of the HCV. We do not want to be left with the statement, ‘The treatment (HCV) was a success but the patient drank himself (herself) to death!’ CONFLICT OF INTEREST STATEMENT Dr. Gregory Everson received research grants and served on advisory boards for GILEAD, ABBVIE, MERCK, JANSSEN and BMS. Dr. Amanda Wieland has no conflicts of interest for this manuscript. REFERENCES Aguilera V, Berenguer M, et al.  . ( 2009) Cirrhosis of mixed etiology (hepatitis C virus and alcohol): posttransplantation outcome—comparison with hepatitis C virus-related cirrhosis and alcoholic-related cirrhosis. Liver Transpl  15: 79– 87. Google Scholar CrossRef Search ADS PubMed  Alter MJ, Kruszon-Moran D, et al.  . ( 1999) The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med  341: 556– 62. Google Scholar CrossRef Search ADS PubMed  Anand BS, Currie S, et al.  . ( 2006) Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenterology  130: 1607– 16. Google Scholar CrossRef Search ADS PubMed  Anand BS, Thornby J. ( 2005) Alcohol has no effect on hepatitis C virus replication: a meta-analysis. Gut  54: 1468– 72. Google Scholar CrossRef Search ADS PubMed  Becker U, Deis A, et al.  . ( 1996) Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology  23: 1025– 9. Google Scholar CrossRef Search ADS PubMed  Befrits R, Hedman M, et al.  . ( 1995) Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand J Gastroenterol  30: 1113– 8. Google Scholar CrossRef Search ADS PubMed  Berenguer M, Ferrell L, et al.  . ( 2000) HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol  32: 673– 84. Google Scholar CrossRef Search ADS PubMed  Charlton M, Everson GT, et al.  . ( 2015) Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology  149: 649– 59. Google Scholar CrossRef Search ADS PubMed  Coelho-Little ME, Jeffers LJ, et al.  . ( 1995) Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. Alcohol Clin Exp Res  19: 1173– 6. Google Scholar CrossRef Search ADS PubMed  Forman LM, Lewis JD, et al.  . ( 2002) The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology  122: 889– 96. Google Scholar CrossRef Search ADS PubMed  Goldar-Najafi A, Gordon FD, et al.  . ( 2002) Liver transplantation for alcoholic liver disease with or without hepatitis C. Int J Surg Pathol  10: 115– 22. Google Scholar CrossRef Search ADS PubMed  Kim WR, Lake JR, et al.  . ( 2015) OPTN/SRTR 2013 Annual Data Report: liver. Am J Transplant  15: 1– 28. Google Scholar CrossRef Search ADS PubMed  Loguercio C, Pierro M. Di, et al.  . ( 2000) Drinking habits of subjects with hepatitis C virus-related chronic liver disease: prevalence and effect on clinical, virological and pathological aspects. Alcohol Alcohol  35: 296– 301. Google Scholar CrossRef Search ADS PubMed  Monto A, Patel K, et al.  . ( 2004) Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology  39: 826– 34. Google Scholar CrossRef Search ADS PubMed  Poynard T, Bedossa P, et al.  . ( 1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet  349: 825– 32. Google Scholar CrossRef Search ADS PubMed  Regev A, Jeffers LJ. ( 1999) Hepatitis C and alcohol. Alcohol Clin Exp Res  23: 1543– 51. Google Scholar CrossRef Search ADS PubMed  Serfaty L, Chazouilleres O, et al.  . ( 1997) ‘Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study.’. Hepatology  26: 776– 9. Google Scholar CrossRef Search ADS PubMed  Sherman KE, Rouster SD, et al.  . ( 1999) Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease. Hepatology  30: 265– 70. Google Scholar CrossRef Search ADS PubMed  Singal AK, Anand BS. ( 2007) Mechanisms of synergy between alcohol and hepatitis C virus. J Clin Gastroenterol  41: 761– 72. Google Scholar CrossRef Search ADS PubMed  Singal AK, Hmoud BS, et al.  . ( 2013) Outcome after liver transplantation for cirrhosis due to alcohol and hepatitis C: comparison to alcoholic cirrhosis and hepatitis C cirrhosis. J Clin Gastroenterol  47: 727– 33. Google Scholar CrossRef Search ADS PubMed  Szabo G. ( 2003) Pathogenic interactions between alcohol and hepatitis C. Curr Gastroenterol Rep  5: 86– 92. Google Scholar CrossRef Search ADS PubMed  Tsui JI, Williams EC, et al.  . ( 2016) Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents. Drug Alcohol Depend  169: 101– 9. Google Scholar CrossRef Search ADS PubMed  Westin J, Lagging LM, et al.  . ( 2002) Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat  9: 235– 41. Google Scholar CrossRef Search ADS PubMed  Wiley TE, McCarthy M, et al.  . ( 1998) Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology  28: 805– 9. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Medical Council on Alcohol and Oxford University Press. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alcohol and Alcoholism Oxford University Press

Co-existing Hepatitis C and Alcoholic Liver Disease: A Diminishing Indication for Liver Transplantation?

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Abstract

Abstract Aims To provide an overview of published literature on the interaction of alcohol and hepatitis C virus (HCV) in the accelerated progression of liver disease to cirrhosis as relates to decision-making for the management of the liver transplant candidate and recipient. Methods General PubMed search was employed along with expert input to identify the relevant articles on the topic. The authors also utilized both backward and forward citation review of the relevant articles and reviews to identify articles on identified topic. Results In HCV cases, heavy alcohol use has been associated with more severe fibrosis, but even low rates of use may have deleterious effects. Patients with chronic hepatitis C and alcoholic liver disease can be cured of the HCV—theoretically positively impacting outcome and reducing the need for liver transplantation. Current antiviral therapy achieves virologic cure or sustained viral response (SVR) in over 90% of cases. Antiviral therapy is so effective that most liver transplant candidates or recipients can be cured of HCV either prior to or after transplantation. However, despite successful antiviral therapy, liver disease may progress after SVR due to the effects of ongoing alcohol use. Conclusion Antiviral therapy in patients with HCV plus alcohol should improve pre- and post-transplant outcomes, but providers must remain firm in limiting use of alcohol to avoid progression of liver disease post HCV cure. Short Summary Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant. INTRODUCTION Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world, and cirrhosis due to chronic hepatitis C is historically the most common indication for liver transplantation. The number of those actively infected with HCV within the United States is estimated to be between 2.7 and 3.9 million. HCV commonly coexists with abusive alcohol use patterns. Alcohol and HCV interact to accelerate progression to advanced fibrosis and cirrhosis. Thus, both causes of liver injury need to be simultaneously addressed by clinicians who are considering these patients for liver transplantation. Current HCV treatment with direct-acting antiviral drugs (DAAs) is nearly universally effective across all HCV genotypes and over the full spectrum of HCV liver disease. Patients with coexistent chronic hepatitis C and alcoholic liver disease can be cured of the HCV—theoretically positively impacting clinical outcome and reducing the need for liver transplantation. With eradication of HCV, the control of the alcoholic liver disease will be the key to the overall clinical outcome of these patients. CO-EXISTENCE OF HEPATITIS C INFECTION AND ALCOHOL ABUSE HCV infection and alcohol abuse commonly co-exist. The prevalence of HCV infection in the general population has been estimated at close to 2% (Alter et al., 1999). In individuals with heavy alcohol use, the prevalence of HCV infection is several-fold higher (Befrits et al., 1995; Coelho-Little et al., 1995). The estimates of the prevalence of hepatitis infection in patients with alcohol abuse are higher in alcoholic patients with liver disease, with ranges from ~18% up to 50% in some studies (Regev and Jeffers, 1999). This compares with lower reports of 0–14% HCV prevalence in alcoholic patients without clinically apparent liver disease (Regev and Jeffers, 1999). Patients with alcoholic abuse patterns with HCV are more likely than patients with HCV alone to develop clinical liver complications. ACCELERATION OF PROGRESSION IN LIVER DISEASE WITH ALCOHOL AND HCV Molecular and epidemiological evidence support the conclusion that the combination of hepatitis C and alcohol accelerates the progression of liver fibrosis compared to either etiology alone. The combined effect of hepatitis C and alcohol is not simply additive; due to different mechanisms of liver injury there is a multiplicative increase in damage (Singal and Anand, 2007). Alcohol-related mechanisms may include direct toxicity of alcohol, condensation of cytoskeletal proteins, alcohol-induced oxidative injury, accumulation of excessive iron further enhancing oxidative injury and neutrophilic infiltration of the liver. HCV-related mechanisms of injury additionally include pro-inflammatory cytokines and chemokines, HCV-induced hepatocellular necrosis, and immunomodulation by the virus (Szabo, 2003; Singal and Anand, 2007). In some studies, but not all, alcohol was shown to increase HCV viral replication (Anand and Thornby, 2005). In theory, alcohol could potentially increase the numbers of ‘quasispecies’ or viral diversity, which might increase risk for resistance emerging during antiviral drug therapy (Sherman et al., 1999). For these reasons, any alcohol use is strongly discouraged during antiviral treatment. Alcohol alone, increases risk for cirrhosis. As little as 6 drinks per week in women (84 g of alcohol) and 13 drinks per week in men (182 g of alcohol) has been associated with increased risk for cirrhosis (Becker et al., 1996). Risk for cirrhosis increases with increasing alcohol intake. For example, an intake of 28–41 standard drinks per week (between 392 and 574 g per week) increased risk for cirrhosis by 17-fold in women and 7-fold in men (Becker et al., 1996). Only a handful of studies have examined the relationship of quantify and frequency of alcohol to progression of liver disease in patients with chronic hepatitis C. As a result, it is not known whether there is a minimum safe amount of alcohol for an individual with chronic hepatitis C. Heavy to regular moderate use of alcohol (typically at minimum >3 drinks daily or >40 g per day) has been clearly shown to influence risk for chronic hepatitis C to progress to cirrhosis (Poynard et al., 1997; Serfaty et al., 1997; Wiley et al., 1998). In a cross-sectional study of 800 patients with chronic hepatitis C, Monto found that heavy alcohol use (>50 g daily) was associated with more severe fibrosis, but increases in fibrosis also occurred with low to moderate alcohol use (Monto et al., 2004). The impact of low to moderate alcohol intake on hepatic fibrosis in patients with chronic hepatitis C was further investigated by Westin et al. They evaluated 78 individuals with chronic hepatitis C and low to moderate alcohol use and assessed for progression of fibrosis between historical biopsies. Patients with alcohol consumption above the median alcohol consumption for the study population showed increased progression of fibrosis when compared with the patients whose alcohol consumption was below the median. The alcohol use within the higher use group was on average 11.6 g per day with a range from 5.2 to 17.8 g per day. In contrast, the alcohol use within the lower use group was on average 1.1 g per day with a range from 0.2 to 2.6 g per day. The increased fibrosis in the moderate alcohol drinkers supports the conclusion that even intermittent moderate alcohol can accelerate fibrosis progression with HCV (Westin et al., 2002). Given the uncertainties in defining a safe amount of minimal alcohol use in patients with chronic hepatitis C, both the American Association for the Study of Liver Disease and the European Association for the Study of Liver Disease recommend that patients with chronic hepatitis C avoid use of alcohol in their published clinical guidelines. HCV TREATMENT REGIMENS Figure 1a and b displays the currently available, all oral, DAA regimens for the treatment of chronic hepatitis C. Rates of sustained viral response (Fig. 2a and b) are greater than 90% with all of these regimens when used in the populations listed. It is highly likely that most patients listed for the combination of chronic hepatitis C and alcoholic liver disease will either be free of HCV at time of listing or could be made HCV free by treatment after listing. Decisions on whom to treat and when to treat with DAAs are currently the topic of discussion and clinical research. It is our opinion that withholding DAA treatment might be appropriate for waitlisted patients with MELD upgrade for hepatocellular carcinoma or those with very high MELD scores (>25). These patients might be best served by treatment after transplant as this strategy affords them the opportunity to be transplanted with a liver from an HCV positive donor. Fig. 1. View largeDownload slide (a) Summary of HCV treatment regimens approved for genotype 1 as of January 2017. (b) Summary of HCV treatment regimens approved for genotypes 2, 3 and 4 as of January 2017. Fig. 1. View largeDownload slide (a) Summary of HCV treatment regimens approved for genotype 1 as of January 2017. (b) Summary of HCV treatment regimens approved for genotypes 2, 3 and 4 as of January 2017. Fig. 2. View largeDownload slide (a) Rates of SVR for genotype 1 by treatment regimen, available as of January 2017. (b) Rates of SVR for genotypes 2, 3 and 4 by treatment regimen, available as of January 2017. Fig. 2. View largeDownload slide (a) Rates of SVR for genotype 1 by treatment regimen, available as of January 2017. (b) Rates of SVR for genotypes 2, 3 and 4 by treatment regimen, available as of January 2017. Certain underlying clinical features may dictate the choice of DAA treatment. Many patients with cirrhosis will have concomitant renal disease—as of this writing, sofosbuvir is not currently recommended for use in patients with creatinine clearance less than 30 mL/min. Although the combinations of sofosbuvir plus either ledipasvir or velpatasvir are approved for use in advanced cirrhosis (Child-Turcotte-Pugh B or C) other regimens are not, and those containing a protease inhibitor may be contraindicated. Although the need for ribavirin is often questioned, in most regimens where patients have had prior courses of DAA therapy or have advanced liver disease, ribavirin is included. The exception might be the emerging new triple and dual second and third generation combination DAA regimens. With the latter combinations, ribavirin may add little to no additional benefit in terms of sustained virologic response (SVR) or virologic cure. IMPACT OF ALCOHOL USE ON EFFECTIVENESS OF HCV TREATMENT Data is limited for the effects of alcohol on SVR rates. In the interferon era of treatment of chronic hepatitis C alcohol use was an exclusion criteria from clinical trials and historically alcohol abstinence was required prior to clinicians offering this complicated and toxic therapy. Most studies showed that ongoing excessive use of alcohol adversely affected the likelihood of achieving SVR, possibly due to early discontinuation (Anand et al., 2006). Studies also suggested that as amount of alcohol increased, SVR decreased (Loguercio et al., 2000). The requirement for injections, coupled with the intolerability and neuropsychiatric side effects of interferon undoubtedly contributed to non-compliance and poor treatment outcomes. The new era of all oral direct-acting antiviral drugs to treat HCV is characterized by ease of use, enhanced safety, high tolerability and markedly improved efficacy. As a result, patients with ongoing alcohol use tolerate and complete therapy and experience high rates of SVR. The impact of alcohol use on SVR was evaluated in a recent analysis of 15,151 patients who initiated DAA treatment and completed the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire. AUDIT-C scores were categorized as 0 (abstinence), 1–3 (low-level drinking) and 4–12 (unhealthy drinking) in men or 0, 1–2 and 3–12 in women. In that sample, 10,387 (68.5%) were categorized as abstinent, 3422 (22.6%) as low-level drinking and 1342 (8.9%) as unhealthy drinking. There were no significant differences in SVR rates between abstinent (SVR 91%; 95% CI: 91–92%), low-level drinking (SVR 93%; 95% CI 92–94%) or unhealthy drinking (SVR 91%; 95% 89–92) categories in univariable analysis or in multivariable logistic regression models (Tsui et al., 2016). Given these results, concomitant alcohol use may not be a reason to deny HCV treatment, given that HCV eradication may improve clinical outcome. On the other hand, the treating provider must emphasize to the HCV patient using alcohol that alcohol alone can lead to cirrhosis and that alcohol should be avoided to reduce risk for disease progression after SVR. MANAGEMENT OF THE PATIENT WITH DECOMPENSATED CIRRHOSIS With high rates of SVR expected even with advanced fibrosis, treating those with compensated cirrhosis to avoid transplant is an accepted strategy. However, treating those with decompensated disease (CPT B and C) is an area of debate. Patients with decompensated disease have lower rates of SVR and exposure to DAAs may favor development of resistance. Viral resistance to DAA treatment could complicate future management, particularly after liver transplantation. Also, clearing HCV by DAA treatment would eliminate the option for transplantation with an HCV positive donor, since most third-party payers will only allow one course of DAA treatment. In addition, SVR in a decompensated patient may not improve liver function or reverse portal hypertension. The patient may be left with ongoing poor quality of life and ‘MELD purgatory’—a low MELD score but ongoing issues with poor liver function, portal hypertension and clinical complications. A stable low MELD may eliminate access to a liver from a deceased donor, since liver transplantation in the United States is typically performed in patients with very high MELD scores. Selecting candidates for DAA treatment from the group of patients with decompensated disease is an ongoing challenge. EVALUATION OF THE PATIENT WHO DETERIORATES AFTER SVR The liver function, liver fibrosis and clinical picture of patients with fibrosis or compensated cirrhosis should stabilize or improve after SVR. Those with co-morbid alcoholism or alcohol abuse will require ongoing clinical and social follow-up to maintain sobriety to prevent liver deterioration and progression to decompensated disease. Clinicians need to be aware that underlying alcohol use/abuse is a factor that may promote deterioration after SVR. Alcohol avoidance may be the key to the ultimate benefit of DAA treatment of HCV in the patient with alcohol use/abuse. Patients with advanced fibrosis have the least hepatic reserve and are most likely to deteriorate clinically with alcohol-induced liver injury. Advanced fibrosis may be suspected by laboratory indices, imaging, or non-invasive staging. Progressive liver dysfunction should also prompt assessment for any unrecognized underlying liver disease such as non-alcoholic steatohepatitis (NASH), concomitant viral disease (HBV), genetic conditions (hemochromatosis, Wilson disease or alpha one antitrypsin deficiency). Patients with advanced fibrosis or cirrhosis who achieve SVR should undergo screening for hepatocellular carcinoma (HCC). Risk for HCC may decrease with SVR, but remains increased above the general population and long term lifelong surveillance may be warranted. TRANSPLANT OUTCOMES WITH HCV CO-OCCURRING WITH ALCOHOL Approximately 11% of the 54,687 adult liver transplants performed in the United States during 1994–2009 were for the indication of combined alcohol and chronic hepatitis C (approximately 6000) (Singal et al., 2013). This is compared to a reported 15,000 (28%) for chronic hepatitis C alone and 9000 (16%) for alcohol alone. It is highly likely that there is significant underreporting of alcohol use in the patients transplanted for chronic hepatitis C alone. It is anticipated that liver transplantation for the indication of cirrhosis due to chronic HCV could decline around the year 2020. HCV infection adversely affects outcome after liver transplantation. In an early study from the UNOS database of over 11,000 cases transplanted between 1992 and 1998, the 1, 3 and 5 year survivals for HCV positive transplant recipients were 86.4%, 77.8% and 69.9%, compared to 87.5%, 81.8% and 76.6% for HCV negative transplant recipients (Forman et al., 2002). The inferior outcomes in recipients with HCV infection are likely related to allograft hepatitis with accelerated fibrosis and progression to cirrhosis (Berenguer et al., 2000). There is limited information comparing outcomes for the combination of chronic hepatitis C and alcohol compared to either chronic hepatitis C or alcohol alone. A single center Spanish study found that outcomes after liver transplant were worse for HCV alone when compared to alcohol alone or HCV combined with significant alcohol consumption (Aguilera et al., 2009). The study reported outcomes in 337 patients followed for up to 7 years. The authors reported that 170 had an etiology of HCV alone, 107 had alcohol alone and 60 had a combined etiology of alcohol and HCV. They defined significant alcohol consumption as >50 g/day (about 3–4 standard drinks) for a period of >5 years or >80 g/day (about 5–6 standard drinks) for a shorter period. The HCV with alcohol group was found to be younger with median age of 49.5 (32.5–66.5) compared with median age 59 (29–68) for the HCV alone group and median age 53 (32–67) for the alcohol alone group. The improved outcomes for the HCV with alcohol group may have been related to a greater percentage receiving antiviral treatment (32% vs. 18%) and younger age (Aguilera et al., 2009). The younger age of the HCV plus alcohol group at the time of transplant supports the concept that the combination of alcohol and HCV accelerates disease progression. The perception that alcohol accelerates HCV disease progression among providers and patients may translate into better control of alcohol use post-transplant. Rates of recurrent alcohol use after transplant (considered significant at >1 drink per week for at least 6 months) were 3% (4/133) for HCV alone, 8% (4/50) for HCV with alcohol and 18% (15/83) for the alcohol alone (Aguilera et al., 2009). Another retrospective study, compared characteristics of liver transplant recipients for indication of alcoholic cirrhosis with (n = 32) or without HCV (n = 56) (Goldar-Najafi et al., 2002). The group with cirrhosis due to alcohol plus HCV was younger (median age 46 vs. 56) and had a shorter reported duration of disease (median 15 years vs. 25 years), again supporting the conclusion that alcohol combined with HCV is typically associated with acceleration of liver disease. One-year survival after transplantation was similar between the two groups—93% in alcohol alone and 97% in alcohol with HCV. Rates of recurrent alcohol abuse after transplantation was 8.9% for alcohol alone (median follow-up time of 5 years) and 9.4% for the combined alcohol with HCV (median follow-up time of 10 months). One large retrospective analysis from the UNOS dataset compared outcomes in 17,700 patients transplanted for HCV alone, 9600 for alcohol alone, and 6800 for the combination of HCV and alcohol collected from 1991 to 2010 (Singal et al., 2013). Although limited by lack of details regarding degree of alcohol use, when adjusted for recipient and donor characteristics, the results demonstrated poorest outcome for patients transplanted for the indication of chronic hepatitis C plus alcohol (Singal et al., 2013). Based on the high level of SVR rates anticipated with new DAAs, the entity of HCV with alcohol will be expected to diminish in coming years which hopefully will translate into overall improved outcomes with liver transplant. POST-TRANSPLANT TREATMENT OF HCV Given the emerging data demonstrating minimal impact of alcohol use on rates of SVR with DAAs, it is anticipated that patients transplanted for the combination of chronic hepatitis C and alcoholic liver disease will experience the same high rates of viral clearance as the patients transplanted for chronic hepatitis C alone. The SOLAR 1 and SOLAR 2 studies, using the combination 12 weeks DAA regimen of sofosbuvir and ledipasvir with ribavirin, demonstrated SVR rates in transplant recipients of 96% for those with non-cirrhotic fibrosis, 96% for CTP A, 85% for CTP B and 60% for CTP C. The falloff in SVR with increasing severity of cirrhosis is also noted in non-transplant populations. Thus, institution of treatment early after recovery from transplant, prior to graft injury and fibrosis, is currently highly recommended (Charlton et al., 2015). FUTURE OF INDICATIONS FOR LIVER TRANSPLANTATION Currently, the leading indication for liver transplantation is HCV—December 2013 data showed 29% of those on the waitlist were for the primary indication of HCV. The proportion of HCV cases has been relatively stable since 2003 (Kim et al., 2015). The second highest indication for liver transplantation over that same period of time was alcoholic liver disease, representing 24% of cases (Kim et al., 2015). Future studies should focus not only on the impact of alcohol on post-SVR outcomes but also other factors, including alcohol, that may promote progression of disease. For example, is there a difference in clinical outcome in waitlist patients with active ongoing HCV infection compared to waitlist patients who have cleared their HCV infection. What factors promote disease progression after SVR? What post-SVR factors, such as HCC development or cirrhosis complications, predict risk for liver transplantation despite achieving SVR? Concomitant ongoing alcohol use will need to be more accurately reported to help guide where to try to impact risk for disease progression. CONCLUSION Historically, Hepatitis C and alcohol together have commonly co-existed in patients with advanced liver disease. The widespread availability of effective HCV treatment will change the prevalence of this clinical entity—HCV will disappear and potentially the progressive liver disease will be driven by factors related to alcoholic liver disease. With clearance of HCV changes in liver function in either native liver or allograft need to be carefully assessed for other factors promoting disease progression. Although, alcohol does not seem to influence the chance to achieve SVR with current DAA treatment, providers must remain firm in recommendations regarding limiting use of alcohol to avoid progression in liver disease despite clearance of the HCV. We do not want to be left with the statement, ‘The treatment (HCV) was a success but the patient drank himself (herself) to death!’ CONFLICT OF INTEREST STATEMENT Dr. Gregory Everson received research grants and served on advisory boards for GILEAD, ABBVIE, MERCK, JANSSEN and BMS. Dr. Amanda Wieland has no conflicts of interest for this manuscript. 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Alcohol and AlcoholismOxford University Press

Published: Mar 1, 2018

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