Diagnosis of Covert Hepatic Encephalopathy Without Specialized Tests

Clin Gastroenterol Hepatol. 2013 Dec 19. pii: S1542-3565(13)01966-6. doi: 10.1016/j.cgh.2013.12.020. [Epub ahead of print]

Nabi E¹, Thacker LR², Wade JB³, Sterling RK¹, Stravitz RT¹, Fuchs M¹, Heuman DM¹, Bouneva I¹, Sanyal AJ¹, Siddiqui MS¹, Luketic V¹, White MB¹,Monteith P¹, Noble NA¹, Unser A¹, Bajaj JS⁴.

Abstract

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) impairs quality of life (QOL) and can be difficult to diagnose. Patient-administered methods that do not require specialized tests or equipment might increase rates of detection. We performed a longitudinal study to determine whether demographic data and responses to a validated QOL questionnaire, the Sickness Impact Profile (SIP), can identify patients with CHE.

METHODS: Patients with cirrhosis without prior overt HE were recruited from outpatient liver clinics at Virginia Commonwealth University Medical Center, from August 2008 through February 2012. We performed cognitive tests on 170 patients (mean age, 55 y; mean model for end-stage liver disease score, 9; 50% with hepatitis C-associated and 11% with alcohol-associated cirrhosis). Patients were also given the SIP questionnaire (136 questions on 12 QOL topics, requiring a yes or no answer) at enrollment, 6 months, and 12 months. The proportion of patients that responded "yes" to each question was compared between those with and without CHE. Patient variables (non-cognitive), demographics (age, education, sex, alcoholic etiology), and SIP questions that produced different responses between groups were analyzed by logistic regression and receiver operating characteristic analyses.

RESULTS: Based on cognitive test results, 93 patients (55%) had CHE when the study began. They had a higher proportion of "yes" responses to 54 questions on the SIP questionnaire, across all categories. We developed a formula to identify patients with CHE based on age, sex, and responses to 4 SIP questions (a SIP CHE score). Baseline SIP CHE scores >0 identified patients with CHE with 80% sensitivity and 79% specificity. Of the 98 patients that returned for the 6-month evaluation, 50% had CHE (the SIP CHE identified these with 88% sensitivity). Of the 50 patients that returned for the 12-month evaluation, 32% had CHE (the SIP CHE score identified these with 81% sensitivity).

CONCLUSIONS: We developed a system to identify patients with CHE based on age, sex, and responses to 4 SIP questions; this formula identified patients with CHE with >80% sensitivity over a 12-month period after the initial enrollment. Patient-administered CHE screening strategies that do not include specialized tests could increase detection of CHE and improve therapy.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: A, AB, BCM, BDT, C, CHE, DST, E, EB, HCV, HM, HRQOL, M, NASH, NCT-A/B, ROC, RP, SI, SIP, SIP subcategories (SR, SSRI, W, alertness behavior, ambulation, block design test, body care and movement, cirrhosis, cognition, communication, covert hepatic encephalopathy, digit symbol test, eating), emotional behavior, health-related quality of life, hepatitis C virus, household management, minimal hepatic encephalopathy, mobility, non-alcoholic steatohepatitis, number connection test-A/B, psychometric tests, receiver operating characteristic, recreation and pastimes, selective serotonin reuptake inhibitors, sickness impact profile, sleep and rest, social interaction, work

PMID: 24362049 [PubMed - as supplied by publisher]

Source

Risk of Hepatobiliary Cancer After Solid Organ Transplant in the United States

Clin Gastroenterol Hepatol. 2013 Dec 19. pii: S1542-3565(13)01964-2. doi: 10.1016/j.cgh.2013.12.018. [Epub ahead of print]

Koshiol J¹, Pawlish K², Goodman MT³, McGlynn KA⁴, Engels EA⁵.

Abstract

BACKGROUND & AIMS: Studies of liver cancer risk in recipients of solid organ transplants have generally been small, yielding mixed results, and little is known about biliary tract cancers among transplant recipients.

METHODS: We identified incident hepatobiliary cancers among 201,549 US recipients of solid organs, from 1987 through 2008, by linking data from the US transplant registry with 15 cancer registries. We calculated standardized incidence ratios (SIRs), comparing risk relative to the general population. We also calculated incidence rate ratios (RRs), comparing risk for hepatocellular carcinoma (HCC) and total (intrahepatic and extrahepatic) cholangiocarcinoma among subgroups of recipients.

RESULTS: Of transplant recipients, 165 developed hepatobiliary cancers (SIR, 1.2; 95% confidence interval [CI], 1.0-1.4). HCC risk was increased among liver recipients (SIR, 1.5; 95% CI, 1.0-2.2), especially 5 or more y after transplant (SIR, 1.8; 95% CI, 1.0-3.0). Cholangiocarcinoma was increased among liver (SIR, 2.9; 95% CI,1.6-4.8) and kidney recipients (SIR, 2.1; 95% CI, 1.3-3.1). HCC was associated with hepatitis B virus (RR, 3.2; 95% CI, 1.3-6.9), hepatitis C virus (RR, 10; 95% CI, 5.9-16.9), and non-insulin-dependent diabetes (RR, 2.5; 95% CI, 1.2-4.8). Cholangiocarcinoma was associated with azathioprine maintenance therapy (RR, 2.0; 95% CI, 1.1-3.7). Among liver recipients, primary sclerosing cholangitis (PSC) was associated with increased risk of cholangiocarcinoma, compared to the general population (SIR, 21; 95% CI, 8.2-42) and compared to liver recipients without PSC (RR, 12.3; 95% CI, 4.1-36.4).

CONCLUSIONS: Risks for liver and biliary tract cancer are increased among organ transplant recipients. Risk factors for these cancers include medical conditions and medications taken by recipients.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: BMI, CI, ECC, HBV, HCC, HCV, ICC, ICD-O-3, International Classification of Disease for Oncology, 3rd edition, PBC, PSC, RR, SIR, body mass index, confidence interval, epidemiology, extrahepatic cholangiocarcinoma, hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, rate ratio, standardized incidence ratio, transplantation

PMID: 24362053 [PubMed - as supplied by publisher]

Source

Physician nonadherence with a hepatitis C screening program

Qual Manag Health Care. 2014 Jan-Mar;23(1):1-9. doi: 10.1097/QMH.0000000000000007.

Southern WN, Drainoni ML, Smith BD, Koppelman E, McKee MD, Christiansen CL, Gifford AL, Weinbaum CM, Litwin AH.

Abstract

BACKGROUND: Testing for patients at risk for hepatitis C virus (HCV) infection is recommended, but it is unclear whether providers adhere to testing guidelines. We aimed to measure adherence to an HCV screening protocol during a multifaceted continuous intervention.\

SUBJECTS AND METHODS: Prospective cohort design to examine the associations between patient-level, physician-level, and visit-level characteristics and adherence to an HCV screening protocol. Study participants included all patients with a visit to 1 of the 3 study clinics and the physicians who cared for them. Adherence to the HCV screening protocol and patient-level, physician-level, and visit-level predictors of adherence were measured.

RESULTS: A total of 8981 patients and 154 physicians were examined. Overall protocol adherence rate was 36.1%. In multivariate analysis, patient male sex (odds ratio [OR] = 1.18), new patient (OR = 1.23), morning visit (OR = 1.32), and patients' preferred language being non-English (OR = 0.87) were significantly associated with screening adherence. There was a wide variation in overall adherence among physicians (range, 0%-92.4%). Screening adherence continuously declined from 59.1% in week 1 of the study to 13.7% in week 15 (final week). When implementing complex clinical practice guidelines, planners should address physician attitudinal barriers as well as gaps in knowledge to maximize adherence.

PMID: 24368717 [PubMed - in process]

Source

Healthcare reform and Hepatitis C: A convergence of risk and opportunity - report from Millman supported by Janssen

Provided by NATAP

Pdf of report attached here for download

Bruce S. Pyenson, Kathryn V. Fitch, Kosuke Iwasaki, Tyler Engel | 19 December 2013
Changes from the Patient Protection and Affordable Care Act (ACA) are dominating the healthcare landscape. These changes under ACA are very important for people infected with hepatitis C virus (HCV). 2013 has seen increasing federal public health efforts aimed at diagnosing people with HCV. Baby boomers, the generation with the most HCV-infected people, has started to become eligible for Medicare. Further, new treatments for HCV are under development. Undiagnosed individuals and uninsured individuals may represent a population that payers and stakeholders have not yet experienced. This paper discusses how increased diagnosis, increased Medicare eligibility, and newly insured individuals with HCV will affect the U.S. healthcare system.

Source

Top 10 Highlights From The Liver Meeting

Medscape Gastroenterology

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^[1] 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^[2] 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^[3] 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.^[4] One study^[5] reported the effect of sofosbuvir and ribavirin for the treatment of recurrent HCV infection after liver transplantation, and another study^[6] 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^[7] 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 Birth	Proportion of Birth Cohort Screened	Anti-HCV Prevalence	HCV Prevalence
Before 1945	42%	2.9%	1.7%
1945-1965	64%	13.1%	9.9%
After 1965	58%	1.9%	1.1%

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^[8] 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^[9] 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 study^[10]reevaluated 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^[13] 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^[14] 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^[15] 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^[16] 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^[17] 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^[18] 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^[19] 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^[20] 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,^[21] 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.

References

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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]

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

Source

Second-wave IFN-based triple therapy for HCV genotype 1 infection: simeprevir, faldaprevir and sofosbuvir

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 60–68, February 2014

Review Article

You have free access to this content

Tarik Asselah^1,2,3,*, Patrick Marcellin^1,2,3

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12424

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: antiviral potency;  direct-acting antivirals; pills burden; resistance;  safety

Abstract

With the approval of second-wave direct-acting antivirals simeprevir, sofosbuvir and faldaprevir in 2014–2015, for genotype 1 hepatitis C, patients and doctors will have more treatment options. During a first period, these treatments will still be used with peginterferon and ribavirin. The second wave of IFN-based triple therapy will have benefits and risk. These treatments have the following advantages: higher efficacy with more patient candidates for a shorten treatment duration (12–24 weeks, instead of 48 weeks). These new treatments appear to have a better safety profile than first generation, with no additional increase in anaemia over peginterferon/ribavirin. Then, these treatments are to take for patients with a decrease in pill burden (these three direct-acting antivirals are given orally one pill a day). Simeprevir and sofosbuvir may be approved in the US and Europe, in 2014, at the time this manuscript will be released. Approval of faldaprevir will follow. These direct-acting antivirals with many others will hopefully be combined in future interferon-free regimens. The goal of this review to summarize the results and safety of simeprevir, faldaprevir and sofosbuvir, to advise physicians and to inform patients on the benefits and risks of these second-wave IFN-based regimens for HCV genotype infection.

The goal of treatment of chronic hepatitis C is to obtain a sustained virological response (SVR) defined as undetectable HCV RNA in serum 24 weeks after the end of treatment. SVR results in the eradication of HCV infection and improvement of the histological outcome[1]. Twelve-week post-treatment follow-up appears to be as relevant as 24 weeks to define SVR [2]. Potentially, each step of the viral cycle is a target for drug development. All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase, NS5A replication complex and NS5B RdRp – are essential for HCV replication, and are potential drug discovery targets. In 2011, two direct-acting antivirals (DAAs) were approved for HCV genotype 1 chronic infection, telaprevir and boceprevir and opened a new area for HCV therapy. These two first-generation NS3/4 protease inhibitors (PI), given in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV), opened a window for the development of several DAAs. Since then, several DAA with different viral targets, including NS3 protease inhibitors, nucleoside/nucleotide analogue and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors are under development (Table 1) [3].

Table 1. Investigational HCV Regimens in Phase III Trials.

During a first period, starting from early next year with the arrival of second-wave DAAs simeprevir, sofosbuvir and faldaprevir, we will continue to use PEG-IFN plus RBV. In a second period, treatment strategies that combine several drugs with different mechanisms of action could hopefully result in IFN- and/or RBV-sparing regimens. The goal of this review is to summaries the results and safety profile of the second wave of IFN-based triple therapy for HCV genotype 1 infection.

Simeprevir

Genotype 1 naïve patients (Quest-1 and Quest-2 studies)

Two phase III randomized, double-blind, placebo-controlled clinical trials (Quest 1 and Quest 2) in GT1-naïve patients were reported [4-6]. Patients in the treatment groups were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virological response to therapy (Fig. 1A). Patients in the control groups were given placebo for 12 weeks combined with PR for 48 weeks.

Figure 1. Clinical trials with simeprevir. (A) QUEST-1, QUEST-2 and PROMISE: trail design and endpoints; phase III, randomized, double-blind, placebo-controlled trial to evaluate SMV 150 mg qd administered with PEG-IFN/RBV, compared with placedo+PegIFN/RBV, in treatment-naïve (QUEST-1 and QUEST-2), prior-relpasers (PROMISE), HCV genotype 1-infected patients. Patients stratiffied by HCV subtype and IL28B genotype. RGT criteria: if HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 12, complete treatment at week 24. Stopping rules: if HCV RNA >1000 IU/mL at week 4, stop SMV/placebo; if HCV RNA <2log10 IU/mL reduction at week 12, or confirmed >25 IU/mL at week 24 or 36, stop all treatment. Primary endpoint: SVR12 (HCV RNA <25 IU/mL undetected at EOT and HCV RNA <25 IU/mL 12 weeks after planned EOT. (B) Results of simeprevir phase III trials for genotype 1 naïve patients (QUEST-1, QUEST-2 studies). In Quest-1, SVR12 was achieved in 80% in the simeprevir arm (210/264) compared with 50% in the placebo arm (65/130, P < 0.001). SVR12 rates achieved in QUEST-2 were similar to QUEST-1, with 81% in the simeprevir arm attaining SVR12 compared to 50% in the placebo arm (P< 0.001). (C) Results for patients candidates for a short treatment duration. In QUEST-1 about 85% of patients who received simeprevir qualified for the shorter 24-week course of therapy, SVR12 among these patients was 91%. For Quest-2, the majority of patient (91.4%) in the simeprevir arm qualified for the shorter 24-week therapy course and SVR12 among these patients was 86%. (D) Results in QUEST-1 and QUEST-2 according to genotype 1 subtype (1a and 1b) and the presence of Q80K.

Efficacy

Efficacy data from Quest-1 and Quest-2 are reported in Figure 1B. These two studies were pooled because they were nearly identical in design; pooled results showed an SVR 12 rate of 80% in the treatment group and 50% in the control group. SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses. SVR rates were lower in patients with bridging fibrosis and cirrhosis.

In Quest-1, 85% of patients treated with simeprevir met the RGT criteria and were eligible for 24 weeks of treatment, among whom 91% achieved SVR12. In Quest-2, 91.4% of patients met RGT criteria and were eligible for 24 weeks of treatment, among whom 86% achieved SVR12 (Fig. 1C).

In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups (Fig. 1D). In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment group vs 43% in the control group for the two pooled trials.

HCV G1 relapsers to prior PEG-IFN/RBV (Promise study)

In the Promise trial, patients had received 24 weeks or more of a PEG-IFN-based treatment and had relapsed within 1 year after the last medication dose (Fig. 1A) [7, 8].

Efficacy

The SVR12 rate was 79% in the treatment group and 36% in the control group. Among patients treated with simeprevir, 92.7% were eligible to complete therapy at 24 weeks and achieved an SVR12 of 83% (Fig. 2). The SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group. In those without the Q80K polymorphism, the SVR12 rates were 78% in the treatment group vs 24% in the control group for the relapser trial.

Figure 2. Results for simeprevir in genotype 1 relapsers patients (PROMISE). Overall, 79% in the simprevir arm achieved SVR12 compared with 37% in the placebo arm. About 93% of patients were qualified to stop treatment at week 243. Those who were genotype 1a attained SVR12 rates of 70%, while those with genotype SVR12 rates approaching 86%

Safety

A total of four deaths occurred in the treatment groups, and they were judged to be unrelated to treatment. In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, vs 3% of those in the control group during the initial 12 weeks (Table 2). A total of three patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; one patient experienced major depression and two patients experienced photosensitivity reactions.

Table 2. Safety profile of simeprevir in phase III trials

Other common adverse events were rash [218 (28%) treatment groups; 79 (20%) control groups], influenza-like illness [203 (26%) treatment groups; 84 (21%) control groups], pruritus [168 (22%) treatment groups; 58 (15%) control groups] and nausea [173 (22%) treatment groups; 70 (18%) control groups].

Interestingly, enrolment has been completed rapidly for an ongoing phase III, open-label, single-arm study to evaluate the safety and efficacy of simeprevir plus PEG-IFN alfa-2a and RBV administered for 12 weeks in treatment-naïve subjects with chronic genotype 1 HCV infection (EudraCT number: 2012-004905-29) (Fig. 3).

Figure 3. A phase 3, open-Label, single-arm study to evaluate the safety and efficacy of simeprevir plus PEG-IFN alfa-2a and RBV administrated for 12 weeks in treatment-naïve subjects with chronic genotype 1 HCV infection. Trial designed to evaluate short treatment duration (12 weeks) in patients with rapid response (evaluated at week 2 and week 4) and without bridging fibrosis or cirrhosis

Faldaprevir

Genotype 1-naïve patients (STARTVerso^™1&2)

Faldaprevir is a protease inhibitor in association with PEG-IFN plus RBV [9, 10], but also being investigated in an IFN-free regimen [11].

Two multicentre, randomized, double-blind, placebo-controlled phase III studies (N = 1314) had a similar design (summarized in Fig. 4A)[12, 13]. In arms 2 and 3, patients achieving early treatment success (ETS) stopped all treatment at week 24. FDV plus PEG-IFN/RBv increased SVR12 compared with PR alone (Fig. 4B and C). SVR12 rates were lower in patients from North America than in patients from other regions (Fig. 4D).

Figure 4. Clinical trials with faldaprevir. (A) STARTVerso-1 and STARTerso-2: Trial design and endpoint. Adult, treatment-naïve patients with chronic GT-1 HCV infection were randomized 1:2:2 to receive 24 or 48 weeks of PR plus: placebo for 24 weeks (arm 1, N = 265). FDV 120 mg QD for 12 weeks or 24 weeks (arm 2, N = 523). In STARTverso 1, patients who achieved early treatment success (ETS, HCV RNA <25 IU/mL at week 4 and undetectable at week 8) stopped FDV for 24 weeks. FDV 240 mg QD for 12 weeks (arm 3, N= 526). Randomized/treated: STARTVerso 1 N = 656/652; STARTverso 2 N = 658/657. *in STARTVerso 2 all patients in arm 2 received 24 weeks of faldaprevir, at which stage patients who achieved ETS can stop all treatment. ETS, early treatment success, defined as HCV RNA <25 IU/mL at week 4 and undetectable at week 8 (Roche COBAS^® Taqman HCV/HPS assay). PR, pegylated interferon alfa-2a 180 μg/week and weight-based ribavirin. (B) Results of faldaprevir phase III trials for genotype 1 naïve patients (STARTVerso 1, STARTVerso 2 studied). Globally, SVR 12 was achieved in 73% in the fladaprevir 120 mg ang 72% in the 240 mg arm, compared with 50% in the placebo arm. (C) Results for patients candidates for a short treatment duration. Among FDV-treat patients, 84% achieved ETS and were eligible to stop all treatment at week 24. In patients with an ETS, SVR12 was achieved by 83% overall; 88% of patients who received 12 weeks of FDV (120 mg or 240 mg) and total of 24 weeks of PR. (D) Results according to origin (Europe, Asia, North America)

Most differences in SVR in the STARTVerso1 and STARTVerso2 trials are explained by baseline characteristics: reasons for virological failure are similar when adjusting for different factors impacting response (race, HCV genotype, IL28B genotype, HCV RNA level, GGT level and presence of cirrhosis). However, there was a higher discontinuation rate for reasons other than virological failure in North America, indicating different AE management and treatment discontinuation, which impacted the overall response. FDV efficacy was similar at 120 and 240 mg doses and with 12 or 24 weeks of treatment.

Among FDV-treated patients, 84% achieved ETS and were eligible to stop all treatments at week 24. In patients with an ETS, SVR12 was achieved by: 83% overall; 88% of patients who received 12 weeks of FDV (120 or 240 mg) and a total of 24 weeks of PR., FDV safety profile is shown in Table 3. Finally, the addition of FDV to PR was efficacious in treatment-naïve patients infected with HCV GT-1. FDV plus PR showed increases in SVR regardless of GT1 sub-type, IL28B genotype, liver disease stage and other factors associated with response to PR. The treatment regimen has the potential to improve tolerability and convenience compared with first-generation protease inhibitors.

Table 3. Safety profile of faldaprevir in STARTVerso 1 and STARTVerso 2

Treatment-experienced patients with G1 HCV chronic infection (START-Verso3)

Design of STARTVerso3, a phase III trial assessing the efficacy and safety of FDV (240 mg QD) plus PR in treatment-experienced patients with chronic HCV GT-1 infection is presented in Figure 5A [14]. It is a multicentre, randomized, double-blind, placebo-controlled phase III trial (N = 678). FDV 240 mg plus PR was effective in treatment-experienced patients with HCV GT-1 infection (Fig. 5B). The majority (87%) of prior relapsers receiving FDV achieved ETS and were eligible to stop treatment at week 24. The low SVR12 rates in the placebo groups (14% prior relapsers; 3% prior partial responders) reflect the difficult-to-treat population enrolled. Comparison with other DAA studies is limited by the early futility rule (>2 log₁₀ decrease in HCV RNA at week 4). The low SVR12 rate in patients on placebo who met the futility criteria indicates that even in its absence, the SVR12 rates in the placebo arms would have been lower than previously reported rates. No additional benefit was observed by treating patients with FDV 240 mg for 24 weeks vs 12 weeks. Virological breakthrough was higher in prior null responders with HCV GT-1a compared with GT-1b. Q80K polymorphism did not affect GT-1a SVR12 following FDV treatment. FDV 240 mg + PR was well tolerated with a safety profile similar to PR alone. Lower rates of hyperbilirubinaemia were observed with a lower dose of 120 mg FDV in the STARTVerso1 and two studies. Finally, FDV plus PR demonstrated a significant and clinically meaningful improvement in SVR12 rates over PR. These results suggest that FDV plus PR provides an effective and well-tolerated treatment regimen in previously difficult-to-treat, treatment-experienced patients infected with HCV GT-1.

Figure 5. STARTVerso 3 trial design and results. (A) Trial design. (B) Results in previous relapsers, partial responders and null responders

HIV-HCV co-infected patients (STARTVerso 4)

FDV was highly efficacious and well tolerated in difficult-to-treat patients co-infected with HIV and HCV GT-1 [15]. FDV resulted in a total SVR4 rate of 74% in all patients. A high proportion of patients (80%) achieved ETS and 88% of these patients achieved SVR4. Response rates were comparable across FDV doses and durations and among patients who received either 24 or 48 weeks of PR. The safety profile of FDV in HIV and HCV GT-1 co-infected patients was similar to that observed in HCV GT-1 mono-infected patients.

Sofosbuvir

Sofosbuvir with PEG-IFN/RBV for HCV G1 infection

For G1, two strategies have been developed: (i) 12 weeks sofosbuvir, PEG-IFN/RBV and (ii) new IFN-free regimens with sofosbuvir and ledipasvir (NS5A inhibitor).

The NEUTRINO trial was a single-group, open-label phase III study of sofosbuvir plus PEG-IFN/RBV in 327 naïve patients infected with HCV genotypes 1, 4, 5 or 6 [16]. Most of the patients who were included in the study had HCV genotype 1 (89%); 9% had genotype 4 and 2% had genotypes 5 or 6. All patients received sofosbuvir, PEG-IFN/RBV for 12 weeks. The trial design is represented in Figure 6A and the results in Figure 6B. Sofosbuvir was given orally at a dose of 400 mg, once a day, along with RBV, also given orally in a dose based on weight. Patients who weighed less than 75 kg received 1000 mg/d, and heavier patients received 1200 mg/d. Patients received PEG-IFN alfa-2a subcutaneously (180 μg/week).

Figure 6. The NEUTRINO trial: design and results. (A) Trial Design: single-group, open-label phase III study of 12 weeks of sofosbuvir plus PEG-IFN/RBV in 327 naïve patients infected with HCV genotype 1, 4, 5, or 6. (B) Results: A total of 295 of the 327 patients (90%) had an SVR12

A total of 295 of the 327 patients (90%) had an SVR12. According to the HCV genotype: 89% for patients with HCV genotype 1 (92% for G1a and 82% for G1b) and 96% (27/28) for those with G4 had SVR. The single patient with G5 and all six patients with G6 in this trial had an SVR.

Treatment discontinuation because of adverse events was uncommon among patients receiving sofosbuvir regimens, with rates of 2%. The most common adverse events in all study groups were fatigue, headache, nausea and insomnia (Table 4).

Table 4. Safety profile of simeprevir

Other PEG-IFN-based regimens

Danoprevir, daclatasvir, asunaprevir, MK-5172

The combination of danoprevir, PEG-IFN and RBV leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase [17]. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway. Daclatasvir (a potent NS5A replication complex inhibitor) seems to increase the antiviral potency of peginterferon and ribavirin [18]. Asunaprevir (PI) has also been studied in association with PEG-IFN and RBV [19]. Forthermore, high SVR were observed with MK-5172 with PEG-IFN and ribovirin (20).

Conclusion

With the approval of second-wave direct-acting antivirals simeprevir, sofosbuvir and faldaprevir in 2014-15 for genotype 1 hepatitis C, patients and doctors will have more treatment options. During a first period, the treatments will still be used with PEG-IFN and RBV. The second wave of IFN-based triple therapy will have benefits and risk. These treatments have the following advantages: higher efficacy with more patient candidates for a shortened treatment duration (12–24 weeks instead of 48 weeks). These new treatments appear to have a better safety profile than the first generation, with no additional increase in anaemia over peginterferon/ribavirine. An advantages is also a decrease in pill burden (these three direct-acting antivirals are given orally one pill a day).

Access to therapy is not equal worldwide, and we will still need PEG-IFN and RBV, and first-generation PI, until these second-wave IFN-based regimens become available. Unfortunately, we have to recall that a major medical need is HCV genotype 4-infected patients, and that the current standard of care is PEG-IFN and RBV for 48 weeks with an SVR near 50% [21]. Mechanisms associated with fibrosis progression and IFN-response remain major issues [22].

Fortunately, in the near future, we will benefit from an IFN-free regimen with several ongoing regimens (Table 5) [3, 11, 23, 24]. Off-label combination may be useful for difficult-to-cure patients (cirrhosis null responders), and promising data have been already reported as the Cosmos study with the combination of simeprevir and sofosbuvir [25].

Table 5. Perspectives for HCV treatment.

Disclosure

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen, Gilead, Roche and MSD. Patrick Marcellin is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen, Gilead, Roche and MSD.

References

Source

HCV F1/F2 patients: treat now or continue to wait

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 79–84, February 2014

Review Article

You have free access to this content

Mitchell L. Shiffman^1,2,*, Yves Benhamou^1,2

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12408

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: chronic hepatitis C virus;  faldaprevir;  sofosbuvir;  simeprevir

Abstract

The treatment of chronic HCV is evolving rapidly. In 2014, three new oral antiviral agents, simeprevir, faldeprevir and sofosbuvir will become available for patients with HCV genotype 1. These agents have far less side effects than the first generation protease inhibitors telaprevir and boceprevir. Treatment will therefore be easier for patients to tolerate but still require peginterferon and ribavirin (PEGINF/RBV). The first IFN free therapy, sofosbuvir (SOF) and ribavirin (RBV), will also become available in 2014. This treatment is highly effective for patients with HCV genotype 2. However, SVR rates with SOF/RBV appear to be similar to that achieved with PEGINF/RBV in patients with HCV genotype 3. The first IFN-free all oral antiviral therapy combination for patients with HCV genotype 1 may be available late in 2014 or early 2015. The factors which should be considered when deciding whether to treat a patient with HCV now or to delay treatment until IFN free therapies are available is discussed.

The treatment of chronic hepatitis C virus (HCV) continues to evolve at a rapid pace. Since the 2013 Paris Hepatitis Conference 1 year ago several new direct acting antiviral (DAA) agents have completed the clinical trials process and data supporting their efficacy and safety has or will soon be presented to the USA Food and Drug Administration, the European Medicines Agency and the health regulatory agencies in several other countries. By the time this manuscript appears at the 2014 Paris Hepatitis Conference we expect that simeprevir (SIM) and sofosbuvir (SOF) will have been approved and available for HCV treatment in the USA. We anticipate that faldaprevir (FAL) will be available during the first several months of 2014. All three of these agents should also be available in many European countries during 2014.

SIM and FAL are potent protease inhibitors (PIs) [1-4]. Both bind to the same site and inhibit the same NS3-4 protease as telaprevir (TVR) and boceprevir (BOC) and have a high rate of resistance if utilized as monotherapy. Clinical trials of both agents have been conducted in combination with peginterferon (PEG-IFN) and ribavirin (RBV) and both will likely be approved for use in patients with HCV genotype 1 who are either treatment naïve or who have failed previous treatment with PEGINF and RBV. Both of these PIs will be utilized according to the concepts of response guided therapy; similar to the way TPV has been utilized since that agent became available in mid-2011 [5]. SIM and FAL achieve high rates of rapid virological response (RVR) and this allows over 80% of patients to be treated for only 24 weeks. Sustained virological response (SVR) rates in the 75–85% range have been reported [1, 3]. SOF is a polymerase inhibitor and has antiviral activity against all HCV genotypes [6]. It is anticipated that this agent will be approved and utilized with PEG-IFN and RBV for treatment naive patients with HCV genotypes 1, 4, 5 and 6. RVR occurs in virtually all patients treated with SOF, PEG-IFN and RBV and SVR rates of 90% or better have been observed with just 12 weeks of treatment [6].

In 2014, the standard of care for the treatment of chronic HCV genotype 1 will continue to be the combination of a single DAA plus PEG-IFN and RBV [7]. The antiviral agent choices will include one of four protease inhibitors; TPV, BOC, SIM and FAL or the polymerase inhibitor SOF. The pharmacology, efficacy and side effect profile for each of these agents are detailed throughout this supplement to Liver International.

In 2014, an effective oral antiviral agent will for the first time be available for patients with HCV genotypes 2 and 3 [8]. The combination of SOF and RBV represents the first interferon free treatment for patients with chronic HCV. In patients with genotype 2 this treatment is highly effective. Virtually all patients achieve RVR and SVR rates with just 12 weeks of treatment are superior to that achieved with 24 weeks of PEG-IFN and RBV [6, 9]. In patients with HCV genotype 3, 12 weeks of SOF and RBV appears to have similar efficacy as 24 weeks of PEG-IFN and RBV. Extending the duration of SOF and RBV to 16 weeks appears to increase SVR especially in patients who have previously failed treatment with PEG-IFN and RBV and in patients with cirrhosis. We anticipate that the regulatory bodies will recommend that patients with HCV genotype 3 be treated for 16 weeks with SOF and RBV.

Several pharmaceutical manufacturers have independently developed either a PI, an NS5A replication complex inhibitor, a nucleoside polymerase inhibitor and/or a non-nucleoside polymerase inhibitor. When various combinations of these antiviral agents were evaluated in phase 2 clinical trials, with or without RBV, HCV RNA became undetectable very rapidly, and high rates of SVR were observed without resistance [10-13]. The results of these trials are reviewed throughout this supplement of Liver International. Phase 3 clinical trials of several interferon free oral antiviral therapies will be complete later in 2014. Table 1 summarizes those regimens we anticipate being approved and available for treatment of HCV genotype 1 during 2015.

Table 1. Interferon free all oral therapies for patients with HCV genotype 1 drugs that are expected to be available in 2015

At the 2013 Paris Hepatitis Conference the authors debated whether patients with chronic HCV should be treated in 2013 or wait for either a PI with less toxicity (which would be utilized with PEG-IFN and RBV) or an interferon free all oral antiviral regimen. These arguments were summarized in our contribution to the 2013 supplement to Liver International [14]. Frankly, the arguments to treat in 2014 or wait are not very different now than 1 year ago. The difference is that an interferon free therapy has arrived for patients with genotypes 2 and 3 and this is now only about 12–18 months away for patients with genotype 1. The current manuscript will re-evaluate the treatment landscape and provide arguments as to why some patients could be treated now and others could continue to defer therapy. These arguments should be considered by patients and physicians when deciding when to initiate HCV treatment.

Genotype 1

There was great enthusiasm in 2011 when the first protease inhibitors, TPV and BOC, were approved for the treatment of patients with chronic HCV. These two PIs when combined with PEG-IFN and RBV offered significant improvements in SVR and for the first time more patients were being cured instead of failing therapy [15-18]. An improvement in SVR compared with PEG-IFN and RBV was observed in nearly every patient population (treatment naïve or prior PEG-IFN and RBV failure) and subpopulation (race, degree of fibrosis, viral load or IL28B status). Unfortunately, these PIs substantially increased the toxicity of treatment compared with PEG-IFN and RBV. The biggest and most difficult to deal with side effect of TPV and BOC is anaemia. This occurs in approximately 40–50% of all persons treated with these PIs and is even more common when treating patients with cirrhosis [19]. Telaprevir also causes a rash in about 50% of patients [16, 18]. Although this is severe and progressive in only a limited number of patients several regulatory agencies insisted that physicians be informed of this potential toxicity and issued a ‘black box’ warning in 2012. Other side effects observed more frequently in patients treated with telaprevir include pruritus and gastrointestinal symptoms. TPV has to be taken with a high fat content meal or snack three times daily; although more recently data has demonstrated that this protease can be dosed twice daily without impacting efficacy [20]. BOC is associated with dysgeusia and is dosed three times daily. Both TPV and BOC have strong drug-drug interactions and several medications need to be either discontinued before the PI is started or the dosage and/or blood level of the alternate drug has to be closely monitored[21].

When first approved, the combination of TPV and BOC were disproportionately utilized in patients who had failed previous treatment with PEG-IFN and RBV and in patients with cirrhosis. In several centres treatment was even initiated in patients with cirrhosis and prior hepatic decompensation. In the largest cohort where this experience was described high rates of anaemia, significant morbidity and several mortalities were observed. The SVR observed in this cohort of patients with prior non-response and/or cirrhosis was only 41% [19, 22].

The two newer PIs, SIM and FAL and the PI SOF will also be utilized with PEG-IFN and RBV in patients with HCV genotype 1. However, these agents offer significant advantages over TPV and BOC. The most important of these is that none of these three agents cause additional anaemia compared with PEG-IFN and RBV [1-4, 6]. All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Neither SIM nor SOF were noted to have any adverse events with greater frequency than PEG-IFN and RBV [1, 2, 6]. FAL was noted to have a slightly higher incidence of rash [3, 4]. However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. FAL was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.

Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both SIM and FAL triple therapies were evaluated against a placebo control with PEG-IFN and RBV. As a result, the improvement in SVR with the PI over control could be compared for TPV, BOC, SIM and FAL [1, 3, 15, 16]. Such a comparison suggests that the RVR and SVR rates might be slightly higher in patients treated with SIM and FAL compared with telaprevir and boceprevir. The high RVR rates observed with SIM and FAL allowed over 80% of patients to be treated for only 24 weeks according to response guided therapy guidelines.

The success of treatment in patients treated with SIM and FAL, like the other PIs, is dependent upon an effective interferon response and this is modulated by IL28B genotype. The SVR exceeds 90% in patients with IL28B genotype CC and declines in patients with the CT and TT haplotypes [1, 3]. SIM and FAL have also been studied in patients who failed to achieve SVR with PEG-IFN and RBV [2, 4]. In general the SVR rates observed during retreatment follow a similar trend as reported for TPV and BOC and decline according to interferon responsiveness as defined by the previous treatment response. Patients with prior relapse had the highest SVR rates regardless of which PI was utilized. Patients with prior null response had the lowest SVR rates.

SOF, PEG-IFN and RBV is administered for only 12 weeks and in the phase 3 trial no placebo control was utilized [6]. Virtually all patients treated with SOF triple therapy achieved a RVR and the overall SVR rate was 89%. In patients with cirrhosis the SVR rate was 80% [6]. SOF triple therapy has not been evaluated in patients who failed either PEG-IFN and RBV or triple therapy with a PI [23, 24].

There is no doubt that the newer antiviral agents SIM, FAL and SOF will be easier to tolerate and they appear to be more effective than TPV and BOC. The major impediment to their widespread use will be that these agents will still require PEG-IFN. Many patients, particularly those with less fibrosis may therefore choose to delay therapy and opt for a future all oral antiviral regimen which is anticipated to be available by late 2014 or in 2015. In contrast, patients with cirrhosis will be more likely to seek treatment, and physicians will be more likely to treat these patients now with an interferon containing regimen that appears safer and is perceived to be superior. We fully expect that SOF, SIM and/or FAL triple therapy will be widely utilized in patients with cirrhosis in much the same manner as TPV and BOC were soon after these agents became available several years ago. The CUPIC study and other studies in patients with advanced cirrhosis clearly demonstrated that treating such patients with an interferon containing regimen is associated with significant morbidity and yields an SVR rate far below that observed in phase 3 clinical trials [19, 22]. We would expect somewhat similar results when SOF, SIM and/or FAL triple therapy are utilized in this population as well.

Genotypes 4, 5 and 6

Genotype 4 is the most common genotype of HCV in Egypt and many other middle eastern countries [23, 24]. HCV genotype 5 is most prevalent in South Africa and HCV genotype 6 is most common in Vietnam and its neighbouring countries. In the USA and many European countries genotype 4 accounts for a small, but not insignificant percentage of patients with HCV whereas HCV genotypes 5 and 6 appear limited to those persons who emigrated from areas of the world where these genotypes of HCV are more common. SOF, PEG-IFN and RBV is highly effective in patients with HCV genotypes 4, 5 and 6. Although only 35 patients with genotypes 4–6 were included in the single arm phase 3 trial, 96% of patients with genotype 4, and all 7 patients with genotypes 5 and 6 achieved an SVR [6].

It is currently unknown if the interferon free oral antiviral regimens being developed for HCV genotype 1 would also be effective in patients with genotypes 4, 5 and 6. These genotypes were not included in the ongoing phase 3 clinical trials and it would therefore be very unlikely that these first generation interferon free regimens would be approved for use in patients with these other genotypes. For this reason it seems logical to proceed with treatment in all patients with genotypes 4, 5 and 6 now utilizing SOF triple therapy.

Genotype 2

SOF and RBV yield superior SVR rates compared with PEG-IFN and RBV in patients with HCV genotype 2. In treatment naïve patients 12 weeks of SOF and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively [6, 8]. In patients who had previously failed PEG-IFN and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment [8]. Why the SVR rate with 12 weeks of SOF and RBV was lower in patients with cirrhosis who previously failed PEG-IFN therapy compared with a treatment naïve population remains unclear. Extending the duration of SOF from 12 to 16 weeks did increase the SVR in this subgroup of patients with cirrhosis and prior PEG-IFN non-response to 78% [8]. Given these results in the absence of PEG-IFN there appears to be no good reason why treatment with SOF and RBV should not be initiated in any patient with HCV genotype 2. Although 12 weeks of treatment will be sufficient in the majority of patients, this should probably be prolonged to 16 weeks in patients with cirrhosis and prior PEG-IFN non-response. Whether the regulatory bodies make this recommendation remains to be seen.

Genotype 3

Genotype 3 is now the most difficult of all the HCV genotypes to cure. The reasons for this remain unclear, but could be related to the much higher percentage of hepatic steatosis associated with this type of HCV [25]. The same is true when these patients are treated with SOF and RBV. The SVR rate observed with 12 weeks of SOF and RBV were only 34 and 61% for patients with and without cirrhosis and very similar to that observed with PEG-IFN and RBV [6, 8]. Prolonging the duration of SOF and RBV to 16 weeks increased the SVR rate in all patients with this genotype to 63–61% [8]. We expect the regulatory authorities will recommend that patients with HCV genotype 3 be treated with SOF and RBV for 16 weeks. Given that the SVR rates with SOF and RBV are suboptimal and either similar to or only marginally higher than observed with PEG-IFN and RBV the main reason to select the all oral combination is to avoid the side effects associated with PEG-IFN and RBV.

Additional DAA agents, which could be utilized with SOF and RBV, are currently being evaluated for patients with HCV genotype 3. Until these agents are shown to be effective and approved it is very reasonable to defer treatment in patients with genotype 3 and mild fibrosis. In contrast, patients and their physicians will be more likely and willing to use SOF and RBV, despite a suboptimal SVR, in patients with cirrhosis. It is rationale to assume that adding PEG-IFN to SOF and RBV would elevate the SVR rate in patients with genotype 3. A small preliminary study suggests this may be correct; 20/24 (83%) patients including 10/12 (83%) with cirrhosis achieved SVR following 12 weeks of treatment with SOF, RBV and PEG-IFN [26]. Until larger studies confirm these findings it is unclear if regulatory bodies and insurance carriers would approve and fund this combination, SOF triple therapy in patients with HCV genotype 3.

Mixing and matching antiviral agents

In 2014, both SIM and SOF will have been approved and available for use in the USA and many European countries. Both agents are highly effective against HCV genotype 1. In a small pilot study of patients with HCV genotype 1 and prior non-response all patients treated with the combination of SIM and SOF for 12 weeks achieved SVR [27]. To our knowledge, no additional formal studies utilizing these two agents is planned by their respective manufacturers. It is therefore unlikely that regulatory authorities and payers will authorize payment for this combination. However, if such approval could be obtained the combination of SIM and SOF would appear to be an excellent and safe combination with which to treat all patients with HCV genotype 1, especially those with advanced cirrhosis.

A few thoughts about cost

It is relatively intuitive that patients would rather be treated and physicians would rather prescribe several non-toxic oral DAAs than deal with the side effects of a PEG-IFN containing regimen. This is especially true if the SVR rates for the two regimens are similar. There is no doubt that a therapy that cures more patients with HCV can be shown to be more cost effective than a treatment with a lower cure rate. However, the payer, whether a private insurance carrier or a government entity may not will be willing to pay a substantially higher cost for medication that yields a similar SVR even though the more economical choice is associated with a higher side effect profile. There are many patients with chronic HCV that already have favourable response profiles. This includes a low serum HCV RNA level, mild fibrosis, prior relapse and IL28B genotype CC. The later patients already enjoy an SVR rate of over 90% and both retrospective and prospective data strongly suggest that this high SVR rate can be preserved with just 12 weeks of TPV triple therapy [28, 29]. Waiting for an interferon free all oral regimen may yield an easier treatment, but it is unlikely that this would be associated with any higher chance of SVR in certain subpopulations. Health care dollars are becoming more limited and tailoring treatment to each patient's response characteristics may be a more rational approach than treating all HCV patients with a more costly albeit easier regimen.

Conclusions

Continued improvement in our ability to ‘cure’ HCV has been made within the past year when we last reviewed the reasons to treat or wait in patients with mild fibrosis. Two new PIs and a polymerase inhibitor are now or will soon be available. In patients with genotypes 2 and 3 an interferon free all oral treatment is already or will soon be available. In patients with genotype 1 these new agents will still be utilized with PEG-IFN; but an IFN-free all oral option appears to be only another 12–18 months away.

This manuscript has summarized our current treatment for HCV and provided reasons for treating now as well as reasons why patients with mild fibrosis should continue to defer treatment. These reasons are summarized in Table 2. The vast majority of patients can be cured of HCV with our current PEG-IFN containing therapies and the only reason to wait is to avoid the side effects of IFN. However, as the duration of therapy is reduced to as little as 3 months the concern for interferon side effects becomes less of an issue. No two patients are the same and in the end it all comes down to presenting the patient with their choices and proceeding with what the patient is most comfortable doing.

Table 2. Factors that affect the decision to treat now or delay therapy

	Treat now	Delay treatment
Genotype 1	IL28B genotype CC or CT Low viral load Compensated cirrhosis Previous relapse or partial response with PEG-IFN/RBV	IL28B genotype TT Mild fibrosis Decompensated cirrhosis Previous null response with PEGINF/RBV Failure to achieve SVR with a protease inhibitor PEG-IFN/RBV
Genotype 4, 5 and 6	All patients without cirrhosis and stable cirrhosis	Decompensated cirrhosis
Genotype 2	All patients
Genotype 3	All patients with bridging fibrosis and cirrhosis	Patients with mild fibrosis

Disclosure

MLS is an advisor for Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gen-Probe, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis and Roche/Genentech; speaks on behalf of Bayer, Boehringer-Ingelheim, Gilead, Janssen, Merck, Roche/Genentech and Vertex and receives grant support from Abbvie, Achillion, Beckman-Colter, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Idenix, Intercept, Merck, Novartis and Vertex. YB has no conflicts of interest to declare.

References

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