A Glimpse of the Future
William F. Balistreri, MD
December 27, 2013
A Rapid Pace of Progress in Hepatology
The clinical practice of hepatology promises to change dramatically in the next few years. This optimistic view is based on the excitement generated by research presented at The Liver Meeting® -- the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
Investigators highlighted the pace of progress in understanding common forms of liver disease, such as viral hepatitis, cholestasis, and fatty liver disease. Of specific interest, presentations focused on the availability of novel diagnostic and therapeutic options, which present a strong, cogent argument for an enhanced screening methodology to ensure optimal outcomes for our patients.
Here is my "top 10" list of the concepts emerging from this year's meeting.
A Future Without Hepatitis C
The successful development of targeted therapies for patients with chronic hepatitis C virus (HCV) was clearly evident. Several companies are jockeying to be the first to offer an all-oral, interferon (IFN)-free strategy. On the near horizon is the promise that a cocktail of agents, constructed on the basis of synergistic mechanisms of action, will be available for clinicians to wisely, effectively, and safely treat patients with HCV infection. A major advance, in my opinion, is the validation of regimens that are devoid of IFN and, in some cases, ribavirin.
Chayama and colleagues documented the safety and efficacy of an IFN/ribavirin-free, all-oral therapy with daclatasvir (60 mg once daily) and asunaprevir (100 mg twice daily) in IFN-ineligible, -naive, or -intolerant patients and in those who did not respond to standard treatment for HCV genotype 1b.
Daclatasvir is a novel NS5A replication complex inhibitor with pangenotypic antiviral activity. Asunaprevir is a potent NS3 protease inhibitor with antiviral activity against genotypes 1, 4, 5, and 6. This regimen was associated with high (87%) sustained virologic response (SVR) rates after 12 weeks in both groups of patients. Treatment with this dual therapy was well tolerated.
Another all-oral triple combination -- daclatasvir, asunaprevir, and BMS-791325 (a nonnucleoside NS5B inhibitor) -- achieved SVR rates > 90% in pilot cohorts of noncirrhotic patients with HCV genotype 1 infection. Everson and colleagues evaluated this regimen in larger cohorts that included cirrhotic patients. Patients received a twice-daily regimen of daclatasvir (30 mg), asunaprevir (200 mg), and BMS-791325 (either 75 mg or 150 mg) for 12 weeks. This investigational combination, which likewise avoids the use of both IFN and ribavirin, allowed a high percentage (92%) of patients infected with HCV to achieve SVR, including 87% of cirrhotic patients. The most frequent adverse effects in both groups were headache, diarrhea, fatigue, and nausea.
Lawitz and colleagues reported successful results with another strategy. They administered the investigational combination of ABT-450, an HCV NS3/4A protease inhibitor (150 mg, dosed with ritonavir 100 mg), with ABT-267, an NS5A inhibitor (25 mg). Both compounds have shown potent antiviral activity in vitro against HCV genotypes 1-4 and 6. This combination, given once daily for 12 weeks, reduced viral loads to undetectable levels 12 weeks after the end of treatment in 95% of treatment-naive patients and in 90% of patients who had been previously treated but did not respond. The regimen was generally well tolerated. There were no serious adverse events related to the study drugs, and no patients stopped treatment because of adverse events.
Other reported regimens included a once-daily combination of simeprevir plus sofosbuvir (2 novel agents that were recently approved by the US Food and Drug Administration), with or without ribavirin, in patients with cirrhosis and noncirrhotic HCV genotype 1 treatment-naive and previous null responders. One study reported the effect of sofosbuvir and ribavirin for the treatment of recurrent HCV infection after liver transplantation, and another study reported that sofosbuvir and ribavirin can be administered before transplant to prevent recurrence of HCV infection after liver transplantation.
Screening Specific Populations for HCV
HCV eradication cannot begin until an effective case identification strategy is in place. The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force have recently recommended 1-time HCV screening for all Americans born during 1945-1965 ("baby boomers") to reduce HCV-related morbidity and mortality.
US veterans. US veterans in Department of Veterans Affairs care typically have a higher HCV infection rate than the general public -- 6.1% for veterans vs 2.5% for all Americans. Backus and colleagues assessed the extent of complete birth cohort screening for HCV among veterans and estimated the potential clinical impact. Of 5,500,392 veterans, 55% (2.9 million) were screened for HCV at least once (Table).
Table. Anti-HCV and HCV Prevalence, by Year of Birth
|Year of |
|Proportion of Birth |
For those in the 1945-1965 birth cohort, HCV infection prevalence rates decline according to the year of first screening. In veterans first screened between 1999 and 2003, the prevalence fell sharply from 33.2% to 10.3%. Thereafter, prevalence rates fell more gradually, from 9.5% of those screened in 2004 to 5.7% in 2012.
The observation that anti-HCV and HCV infection prevalence are markedly elevated among those born during 1945-1965 compared with those born before or after this period supports the recommended emphasis on birth cohort testing. The investigators postulated that unless the disease is recognized and treatment considered, 1.7 million veterans with HCV are at risk for cirrhosis and 400,000 for hepatocellular carcinoma; therefore, more than 1 million individuals are at risk for death from HCV-related disease.
Emergency department patients. Galbraith and colleagues screened for HCV in baby-boomer patients presenting to an urban academic hospital emergency department (ED). They identified a high prevalence of chronic HCV infection among previously unaware baby boomers, with approximately 1 of every 8 screened ED patients exhibiting positive reactivity. These pilot results highlight the ED as an important venue for HCV screening.
Pregnant women. The American College of Obstetricians and Gynecologists recommends HCV screening only in pregnant women "with significant risk factors." Chen and colleagues estimated the potential for missed diagnosis under current targeted screening practices and evaluated the correlations between chronic HCV infection and pregnancy outcomes. A substantial proportion (72%) of pregnant women with chronic HCV had no traditional, codeable risk factors, and thus could be overlooked under the present targeted screening guidelines.
HCV-positive women have a significantly increased risk for adverse pregnancy outcomes, including early or threatened labor, pulmonary embolism, antepartum hemorrhage, and poor fetal growth. The investigators suggested that expansion of HCV screening practices in pregnant women should be considered, especially if emerging therapeutic strategies are safer for use in pregnancy than IFN- and ribavirin-based regimens.\
Outcomes of Chronic HCV Infection
Natural history. The German HCV-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large and homogenous cohort of young women followed from the date of HCV inoculation. Previous follow-up studies at 20 years and 25 years after infection suggested slow rates of fibrosis progression in this unique cohort. A prospective community-based multicenter studyreevaluated liver disease progression in 718 patients from the original anti-D cohort at 35 years after infection.
Patients with self-limited HCV infection were compared with those who did not eliminate the virus. In the overall cohort, 9% of patients showed clinical signs of cirrhosis at 35 years after infection. The women with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best long-term clinical outcomes. Liver disease progression largely depended on HCV infection status.
This study provides further evidence for a mild but significant disease progression at 35 years after infection in the German HCV-contaminated anti-D cohort.
Benefits of HCV eradication. For patients with chronic HCV infection, achieving an undetectable viral load reduces the risk for death by 45% and the risk for liver-related adverse events by 27%. McCombs and colleagues[11,12] documented the impact of viral load suppression and treatment on morbidity and mortality in patients with HCV infection receiving care through the US Veterans Health Administration.
They identified and examined the clinical records of 128,769 patients who were enrolled in the database in 1999-2010. Only 24% of patients initiated treatment, and among those treated patients, only 16% achieved an undetectable viral load at some point after starting treatment.
\Reactivation of Hepatitis B Attendant to Immune Suppression
Seto and colleagues presented an interim analysis of hepatitis B virus (HBV) reactivation in patients with a history of HBV exposure who were undergoing chemotherapy. High rates of HBV reactivation were observed in HBsAg-negative, anti-HBc-positive individuals undergoing rituximab-containing chemotherapy within the first year of therapy commencement, with most occurring within the first 6 months. The earliest surrogate marker of reactivation was the serum HBV DNA level. Entecavir treatment controlled HBV reactivation in all cases.
Assessing the Global and Regional Burden of Liver Disease
Cowie and colleagues categorized deaths attributable to viral hepatitis and other liver diseases worldwide, reasoning that establishing the relative contributions of the underlying causes of deaths due to liver cancer and cirrhosis is essential for appropriate targeting of public health and clinical responses at the global, regional, and national levels.
They used country-level and regional cause-of-death data to analyze the proportion of cirrhosis and liver cancer deaths attributable to HBV, HCV, alcohol, and other causes. An estimated 752,000 deaths occurred from liver cancer and 1.03 million deaths from cirrhosis in 2010, making chronic liver disease a leading cause of mortality. In the United States in 2010, an estimated 70,000 people died of these causes. HCV was the predominant cause (40%) of liver cancer/cirrhosis deaths in the United States.
On a global basis, HBV was estimated to be responsible for 45% of liver cancer deaths and 30% of deaths from cirrhosis, and HCV accounted for 26% and 28%, respectively. Alcohol abuse was estimated to be responsible for approximately one fourth of deaths from liver cancer and cirrhosis.
These data indicate that liver cancer and cirrhosis result in the deaths of 1.75 million persons each year, with chronic viral hepatitis causing approximately three fourths of these deaths. Greater priority to recognition and treatment of chronic viral hepatitis and other causes of liver disease is clearly needed to address this large burden of disease and death. The differing predominant causes of chronic liver disease identified across different regions requires prioritization of prevention responses to address global health priorities and projections, such as the potential major impact of the new antiviral strategies for HCV.
Insight Into the Mechanism, Diagnosis, and Treatment of NAFLD
An altered fecal microbiome has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Puri and colleagues set out to more clearly characterize the microbiome and metabolome of patients with NAFLD.
They performed 16S ribosomal RNA multitag pyrosequencing for fecal microbiome and mass spectrometry for small-molecule metabolomic profiling from plasma and feces. They found that NAFLD was associated with significant changes in fecal and systemic metabolites of microbial origin or contribution, despite no significant differences in microbial biodiversity. Puri and colleagues postulate pathophysiologic implications to explain their findings, including microbial influences on altering membrane permeability and aromatic amino acid metabolism, as well as induction of cellular stress.
These findings offer the potential for novel therapeutic approaches as well as biomarker discovery to noninvasively distinguish NAFLD from nonalcoholic steatohepatitis (NASH).
The goal of several recent studies has been to develop valid diagnostic and prognostic tools for use in patients with fatty liver disease. Cross-sectional studies have shown an association between steatohepatitis and serum levels of keratin 18 fragments (CK18). Jain and colleagues assessed serial changes in serum CK18 levels in relationship to changes in liver histology. The changes in serum CK18 levels strongly predicted changes in all histologic components of NAFLD over 96 weeks of observation. They suggest that serum CK18 is a potentially useful biomarker for predicting histologic improvement in children and adolescents with NAFLD.
Other than lifestyle changes, a paucity of options for the treatment of patients with NAFLD have been validated. Polyunsaturated fatty acids (PUFA) are known to reduce insulin resistance, triglyceride levels, lipogenesis, oxidant stress, and inflammation, all key features of NASH.
Sanyal and colleagues reported the results of a phase 2b prospective, double-blind, randomized, placebo-controlled trial of ethyl eicosapentaenoic acid (EPA-E), a highly purified synthetic PUFA, in patients with NASH. Although EPA-E was found to be safe and produced a modest improvement in serum triglyceride levels, this agent did not improve the histologic features or biomarkers of inflammation or fibrosis among patients with NASH.
Pathophysiology of Acute Liver Failure
Acute liver failure (ALF) is a syndrome of intense systemic inflammatory response characterized by multiorgan system failure and, frequently, death if liver transplantation is not performed. In patients with ALF, platelet-derived microparticles and sub-micron-sized membrane fragments (involved in intercellular signaling and hemostasis) increase in proportion to the severity of the inflammatory response and organ failure, suggesting a possible pathogenic role.
Stravitz and colleagues assessed 1598 patients in the ALF Study Group Registry and determined that the development of thrombocytopenia, a previously uncharacterized feature of the ALF syndrome, occurs simultaneously with increases in plasma microparticles. They postulate that a reduction in platelets and an increase in platelet microparticles, which parallel the severity of the systemic inflammatory response, may predict the development of multisystem organ failure and a poor outcome. They further speculate that platelet fragmentation into microparticles may mediate the systemic complications of ALF.
Therapeutic Options for Patients With Biliary Atresia
Biliary atresia, a rapidly fibrosing cholangiopathy that obstructs the extrahepatic bile duct, is the most common cause of end-stage liver disease in children and the most frequent indication for pediatric liver transplantation. The primary treatment is surgical excision of the fibrotic biliary remnant followed by Roux-en-Y hepatoportoenterostomy, which has a reported success rate for restoring bile drainage of approximately 50%. Despite treatment, the intrahepatic cholangiopathy progresses, and more than 70% of patients ultimately require liver transplantation. Therefore, there is a need for adjunct therapies to improve survival with the native liver.
On the basis of their anti-inflammatory effects, corticosteroids have been proposed and are frequently used in clinical practice in the management of biliary atresia. Bezerra and colleagues conducted the Steroids in Biliary Atresia Randomized Trial (START) to determine whether adding high-dose corticosteroid therapy to surgical intervention is superior to surgical therapy alone.
Children with biliary atresia (n = 140) were enrolled from 14 US centers participating in the ChiLDREN Network, which is sponsored by the National Institute for Diabetes and Digestive and Kidney Disorders. They were randomly assigned to receive intravenous methylprednisolone/oral prednisolone (4 mg/kg/day for 2 weeks, then 2 mg/kg for 2 weeks, followed by a tapering protocol over the next 9 weeks) or placebo within 72 hours of hepatoportoenterostomy.
High-dose corticosteroid therapy did not result in significantly improved bile drainage at 6 months or greater transplant-free survival up to 2 years of age in children with biliary atresia. Bezerra and colleagues concluded that corticosteroid therapy after hepatoportoenterostomy for patients with biliary atresia cannot be recommended.
Herbal and Dietary Supplement-Induced Liver Injury
Navarro and colleagues compared and contrasted the clinical features and outcomes in patients with herbal and dietary supplement (HDS)-induced and drug-induced liver injury (DILI) enrolled in the Drug-Induced Liver Injury Network (DILIN). Between 2003 and 2013, of more than 800 patients enrolled in DILIN, 16% of the cases of liver injury were attributed to an HDS, 35% of which were attributed to bodybuilding products. The proportion of cases attributed to HDS products increased from 7% in 2004-2005 to 20% in 2010-2012; this increase occurred with bodybuilding (from 2% to 7%) and other HDS products (from 5% to 12%).
Liver injury caused by bodybuilding products had unique clinical features:
• This association occurred exclusively in men;
• The patients were younger (33 vs 49 years);
• Serum alanine aminotransferase levels were lower (median, 194 IU/L vs 1100 for other HDS and 634 for DILI);
• Serum total bilirubin levels at onset were higher (median, 9.8 mg/dL) than for other HDS, and bodybuilding product-induced injury led to more prolonged jaundice; and
• There were no deaths or transplants in this group. In contrast, liver transplantation was required in 13% of other HDS-related cases and 2% died of liver failure, and in the conventional DILI group, only 3% required transplant and 3% died.
This study emphasizes the need for enhanced general awareness of the potential for HDS-induced liver injury. The specific ingredients responsible for injury must be identified.
A Solution to Organ Shortage
A futuristic approach to tissue repair was presented by Atala, offering hope for patients with diseased or injured organs through regenerative medicine and tissue engineering. He stated that we may soon be able to apply, in a practical fashion, the principles of cell transplantation, material sciences, and bioengineering to construct biological substitutes that can restore and maintain normal function in diseased liver tissue. He also emphasized that stem cells offer a potentially limitless source of cells for tissue engineering applications, opening additional therapeutic options for patients with liver disease.
Chayama K, Suzuki Y, Ikeda K, et al. All-oral combination of daclatasvir plus asunaprevir in interferon ineligible naive/intolerant and nonresponder Japanese patients chronically infected with HCV genotype 1b: results from a phase 3 trial. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 211.
Everson GT, Sims KD, Thuluvath PJ, et al. Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve patients with chronic HCV genotype 1 infection. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract LB-1.
Lawitz E, Hezode C, Varunck P, et al. Interferon- and ribavirin-free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naive patients and prior null responders. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 75.
Jacobson I, Ghalib R, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract LB-3.
Charlton MR, Ganes EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent Hepatitis C infection after liver transplantation: Preliminary results of a prospective, multicenter study. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract LB-2.
Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 213.
Backus LI, Belperio PS, Loomis TP, Halloran JP, Han SB, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care in 2012. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 21.
Galbraith JW, Franco RA, Rodgers JS, et al. Screening in emergency department identifies a large cohort of unrecognized chronic hepatitis C virus infection among baby boomers. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract LB-6.
Chen PH, Limketkai BN, Kim B, Woreta TA. Effects of chronic hepatitis C on pregnancy and perinatal outcomes. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 19.
Wiese M, Fischer J, Loebermann M, et al. Evaluation of liver disease progression in the German HCV (1b)-contaminated anti-D cohort at 35 years after infection. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 142.
McCombs J, Matsuda T, Tonnu-Mehara I, et al. Impact of treatment on long-term morbidity and mortality in chronic hepatitis C patients receiving care through the US Veterans Health Administration. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 246.
McCombs J, Matsuda T, Tonnu-Mihara I, et al. The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry. JAMA Intern Med. 2013 Nov 5. [Epub ahead of print]
Seto WK, Chan TS, Hwang YY, et al. Interim analysis of hepatitis B reactivation in patients with prior HBV exposure undergoing rituximab-containing chemotherapy: a prospective study. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 34.
Cowie BC, MacLachan JH. The global burden of liver disease attributable to hepatitis B, hepatitis C, and alcohol: increasing mortality, differing causes. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 23.
Puri P, Siddiqui MS, Sargeant C, et al. Metabiomic signature of human non-alcoholic fatty liver disease provides insights into potential microbial contribution to disease status. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 80.
Jain AK, Deppe RB, Yates KB, et al. Serum keratin fragment 18 (CK18) levels significantly predict changes in liver histology in children and adolescents with nonalcoholic fatty liver disease (NAFLD): Results from the TONIC trial. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 114.
Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings W, Chojkier M. A phase 2B double-blind placebo controlled study of two doses of EPA-E in patients with nonalcoholic steatohepatitis. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract LB-13.
Stravitz RT, Ellerbe C, Durkalski V, Reuben A, Lee WM. Thrombocytopenia in acute liver failure (ALF): a marker of multi-organ system failure and poor prognosis. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 110.
Bezerra JA, Spino C, Magee JC, et al. High-dose corticosteroid therapy following portoenterostomy in infants with biliary atresia does not improve outcome: The multi-center, randomized, double-blind, placebo-controlled START Trial. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 111.
Navarro VJ, Barnhart HX, Bonkovsky HL, et al. The rising burden of herbal and dietary supplement induced hepatotoxicity in the U.S.A. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Abstract 113.
Atala A. Regenerative medicine: new approaches to healthcare. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC. Thomas E. Starzl Transplant Surgery State-of-the-Art Lecture.