Revolutionizing Treatment Outcomes in Hepatitis C: Managed Care Implications and Considerations—The New and Evolving Standards of Care

Published Online: March 24, 2015 Gary M. Owens, MD

Although the prevalence of hepatitis C virus (HCV) infection is declining, overall costs associated with HCV infection and the burden of advanced liver disease are projected to increase. The recent approval of all-oral, fixed-dose combination treatments for patients with HCV infection has resulted in unprecedented rates of treatment success, and in debate regarding treatment costs and appropriation. With all-oral therapies becoming the standard of care for HCV infection, high drug costs and improved clinical outcomes—now including the eradication of disease—must be weighed when selecting the most appropriate therapy. Patient “warehousing” has reached an all-time high as payers and providers strive to strike the fine balance between clinical efficacy and cost-effectiveness of currently available treatments, and this “wait and see” period may very well continue until an acceptable balance has been achieved. As such, it is imperative that managed care clinicians maintain an informed understanding of the disease burden and current climate of HCV infection in the United States.

Am J Manag Care. 2015;21:S97-S105

To date, the main objective of hepatitis C virus infection (HCV) treatment has been to achieve sustained virologic response (SVR; an undetectable viral load or “cure”). Achievement of an SVR is associated with better clinical outcomes related to liver disease—including cirrhosis, hepatocellular carcinoma (HCC), and the need for a liver transplant—and decreased allcause mortality compared with a lack of SVR achievement.1 With the addition of the 2 new direct-acting antivirals (DAAs) sofosbuvir and simeprevir in 2013, SVR rates up to 95% were experienced in patients after only 12 to 24 weeks of treatment with DAAs in combination with standard pegylated interferon (PEG-IFN)/ribavirin therapy, and in combination with each other. Approval of the fixed-dose combinations of ledipasvir and sofosbuvir and of paritaprevir/ritonavir, ombitasvir, and dasabuvir in late 2014 made available all-oral treatment options with high SVR rates for patients with HCV genotype 1. Several additional agents currently in late-stage clinical trials also show great promise for the treatment of chronic HCV infection.

Treatment decisions for patients with HCV infection are often challenging, and therapies used prior to the introduction of all-oral regimens can be complicated by a high incidence of adverse effects, treatment resistance, and medication adherence issues, often resulting in treatment discontinuation and non-achievement of an SVR, resulting in poorer overall outcomes. With a multitude of new therapies and treatment strategies now approved for clinical use and others continuously emerging, including interferon-free regimens and fixed-dose combination therapies, all-oral regimens are now becoming the standard of care. It is imperative for managed care clinicians and providers to improve their knowledge and competence surrounding the clinical and economic burden of HCV infection in the United States if they are to optimize their critical role in the management of patients.

The Economic Implications of HCV Infection and Its Management

Cost Burden of HCV Disease

Managed care clinicians and providers must carefully consider the cost-effectiveness of new and emerging treatments for HCV infection in the context of disease costs and the impact of treatment costs on patient outcomes. An informed understanding of both the burden and the costs associated with HCV infection and its complications is required for the effective management of patients. At the same time, the potential costs and values of new and emerging treatments must be taken into consideration. A recent analysis by Razavi and colleagues aimed to predict HCV disease progression and associated costs in the United States in the next few decades.2 Using a system dynamic model, which was developed with 36 cohorts to provide improved forecasting and flexibility, the prevalent population was tracked by the model beginning in 1950, and the sequelae population was forecasted to 2030. The model consisted of 17 five-year age cohorts and 1 age cohort for individuals at least 85 years of age; these were developed for each sex to provide maximum flexibility for changing inputs such as incidence rate, age at infection, and other variables. Future costs (2012-2030) were estimated using the 2011 annual medical inflation rate of 3.06% (2.88%-5.22%). The incidence of new infections in 2010 was forecasted at 16,020 (95% CI, 13,510- 19,510), compared with a reported incidence of 17,000. The viremic prevalence of HCV peaked at 3.3 million in 1994 and is expected to decline by two-thirds in 2030. The incidence of HCV infection has fallen significantly since its peak in 1989 due to the changing epidemiology of intravenous drug users,3 the implementation of HCV antibody screening of the blood supply in 1992,4 and universal donor screening for viral ribonucleic acid via nucleic acid testing in 1999.5 The authors stated that the total cost of $6.5 billion (in 2011 US$) is expected to increase and peak in 2024 at $9.1 billion.2 Although the prevalence of HCV infection is declining, and the 2030 prevalence is predicted to be one-third of the peak, the prevalence of advanced liver disease will continue to increase, along with the total healthcare costs associated with HCV infection. It was further projected that the prevalent populations with compensated and decompensated cirrhosis will peak in 2015 (626,500 cases) and 2019 (107,400 cases), respectively.2

Of note, the analysis by Razavi and colleagues did not consider the effects of recent changes in the HCV treatment landscape; however, the authors did point out that if the number of treated patients is doubled and kept constant between 2012 and 2030 at 126,000 per year, and the average SVR rate increases to 70%, the projected prevalent population would be fewer than 100,000 cases. They concluded that it is possible to achieve substantial reductions in HCV infection through active and appropriate management.²

One systematic literature search published in 2012 identified 50 studies that reported the costs of HCV sequelae in the United States, where costs were compiled and adjusted to 2010 constant US dollars using the medical component of the consumer price index. Several very substantial costs relating to the disease were delineated per person per year, including⁶:

• Liver transplants: $178,760 to $233,460
• HCC: $23,755 to $44,200
• Variceal hemorrhage: $25,595
• Compensated cirrhosis: $585 to $1110
• Refractory ascites: $24,755
• Hepatic encephalopathy: $16,430
• Diuretic sensitive ascites: $2450

Associated indirect costs of HCV infection, including lost earnings or work production due to hospitalization, ambulatory care, work loss owing to acute or chronic infection, and premature death, also carry substantial impact. Total indirect costs ranged from $51 million to $3.3 billion,7-11 with the lower end of the range including only the loss of work-related productivity income,9,11 and the higher end considering the loss of production due to early death (age 75 years).7 In many cases, indirect costs are greater than direct costs. For instance, a 2008 publication by the National Institutes of Health reported that indirect costs related to HCV infection ($1.78 billion in 2004) were 67% higher than the estimated direct costs.7

Of note, HCV genotype is frequently associated with disease severity and the likelihood of treatment response. At least 6 HCV genotypes have been identified worldwide, with substantial geographic variation in terms of prevalence.12 Genotypes 1a and 1b are the most common types in the United States and Europe. HCV 2a and 2b are also relatively common in these locations, and genotype 3a is frequently found in intravenous drug abusers in both the United States and Europe. Genotypes 4, 5, and 6 appear to be prevalent in North Africa and the Middle East, South Africa, and Hong Kong, respectively.12

HCV genotypes display distinct clinical characteristics. For example, although steatosis occurs with all HCV genotypes, patients with genotype 3a experience resolution of steatosis with viral clearance, unlike those with other genotypes.13,14 In addition, studies have demonstrated that genotype 1b may be associated with a more severe clinical course compared with other genotypes, including the development of HCC15,16; however, the exact role of HCV genotype in disease progression or severity has yet to be delineated.17

Cost Implications of Therapy in the Management of HCV: What Do the Data Tell Us?

Prior to 2011, the majority of published studies concluded that HCV treatments, including PEG-IFN/ribavirin and the first-generation protease inhibitors, were cost-effective.18 The recent approval of several novel agents for treatment of HCV infection, including the first-generation protease inhibitors boceprevir and telaprevir in 2011, and the DAAs simeprevir and sofosbuvir in 2013, have laid the foundation for an evolving HCV therapeutic landscape. The addition of boceprevir or telaprevir to PEG-INF/ribavirin standard therapy led to the achievement of an SVR in 50% to 80% of patients after 24 weeks of treatment, with higher rates in patients with genotype 2 or 3 compared with genotype 1.19 The availability of these agents, and those in late clinical studies, have led to new concerns about cost analyses and cost-effectiveness determinations. Although the costeffectiveness of traditional therapies (eg, PEG-IFN/ribavirin) is known, economic evaluations of DAAs are few at this time. Actual drug costs for newly approved agents are extremely high, leading to uncertainty regarding their true short- and long-term value in terms of healthcare costs versus benefits.20

Direct comparison of the relative efficacy of traditional agents versus DAAs is difficult due to a lack of headto- head trials. In a network meta-analysis of data from 21 studies that synthesized direct and indirect evidence from clinical trials, Ollendorf and Pearson aimed to describe the potential clinical and economic impact of the recently approved DAAs sofosbuvir and simeprevir in California compared with previous standard therapies. A cohort model was developed that assessed these effects over time periods of 1, 5, and 20 years. Outcomes were examined in hypothetical cohorts by genotype, prior treatment status, and interferon therapy eligibility.21

The authors concluded that therapeutic regimens that include sofosbuvir or simeprevir may substantially increase the number of patients achieving an SVR, but for some patient subsets, these agents could come at high cost due to the need for retreatment if an SVR is not achieved. For example, the model suggests that in treatment- naïve patients with HCV genotype 1, the increased drug costs would be offset by downstream savings from reductions in liver-related complications and a greater number of patients achieving an SVR. However, for other comparisons with previously standard treatments, the incremental cost required to achieve 1 additional SVR with a newer regimen may be greater than $300,000, and the average increase in treatment costs was estimated to be $70,000 per patient with newer agents.21

In patients with HCV genotype 1 infection, the firstgeneration protease inhibitors increased the sustained viral response 12 weeks after therapy (SVR12) from approximately 40% with PEG-IFN/ribavirin to about 70%.20,21 Unfortunately, the pill burden is substantial, ranging from 6 to 12 pills per day depending on the regimen, and adverse effects can be both bothersome and serious.22 Possible adverse effects include an increase in anemia, nausea, taste disturbance (boceprevir), and pruritis (telaprevir).20,23 Also of importance is the large number of drug-drug interactions associated with these agents.20 Despite these issues, triple therapy involving one of these agents with PEG-IFN/ribavirin was considered standard therapy until the arrival of simeprevir and sofosbuvir in 2013.20

In patients with HCV genotype 2 infection, the combination of sofosbuvir plus ribavirin is clinically more effective compared with standard treatment options. A large increase in SVR12 among untreated patients was observed in the randomized, open-label, phase 3 FISSION trial; the SVR12 value for patients receiving treatment was 90%. In the FISSION trial, SVR rates in patients receiving 12 weeks of sofosbuvir/ribavirin and in those receiving 24 weeks of PEG-IFN/ribavirin were both 67%.22 Neutropenia was not observed in patients receiving sofosbuvir, but occurred in 30% of patients receiving PEG-IFN/ribavirin. Discontinuation of treatment due to AEs occurred in 1% of patients receiving sofosbuvir/ribavirin and 11% of patients receiving PEGIFN/ ribavirin. In patients with genotype 3, response rates in the sofosbuvir/ribavirin group were lower compared with genotype 2 (56% vs 97%).22

Given the newly approved agents for treatment of HCV genotype 1 infection, patients with genotype 3 have become the more difficult patient population to treat. As noted earlier, correlations have been demonstrated between HCV genotype 3 infection and steatosis and HCC.24,25 In the randomized VALENCE study of 328 patients with HCV genotype 3 infection, Zeuzem and colleagues reported an SVR of 85% (95% CI, 80%-89%) in patients treated with sofosbuvir and ribavirin for 24 weeks, although lower rates were evident with shorter treatment durations.26 These results were irrespective of previous treatment status or presence of cirrhosis, and the severity and frequency of AEs were not different with 24 weeks of therapy compared with 12 or 16 weeks.26

In October 2014, the FDA approved the combination of ledipasvir and sofosbuvir, the first all-oral combination treatment for HCV genotype 1 infection.27 Studies suggest that this combination with or without ribavirin has the potential to cure most patients with HCV genotype 1 infection, irrespective of treatment history and including those with compensated cirrhosis.28

The combination of sofosbuvir and simeprevir in the management of HCV genotype 1 infection appears promising. In early November 2014, this combination therapy was approved by the FDA for treatment of patients with genotype 1 HCV infection.29 Both simeprevir and sofosbuvir have demonstrated efficacy when utilized in combination regimens to treat adults with HCV infection and concomitant complications such as compensated liver disease, cirrhosis, human immunodeficiency virus (HIV) coinfection, and HCC. These agents achieve an SVR within 12 to 24 weeks of treatment in up to 95% of patients.29 The COSMOS study enrolled patients with genotype 1 HCV infection who had previously failed PEG-IFN/ribavirin therapy or who were treatmentnaïve, and randomly assigned them to treatment with simeprevir plus sofosbuvir with or without ribavirin for 12 or 24 weeks. Rates of SVR12 were high (>90%) with the combination of simeprevir and sofosbuvir at 12 weeks, with or without ribavirin. This trial also demonstrated that in patients previously treated with other agents, the combination of simeprevir and sofosbuvir achieved an SVR12 of at least 90%.23 Treatment guidelines developed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD/IDSA) in 2014 recommend the use of these agents in combination or with standard PEG-IFN and/ or ribavirin for individualized management of HCV infection. Specific treatment recommendations depend on HCV genotype, previous treatment status, and disease sequelae, among other factors.30

A recent study evaluated the cost-effectiveness of sofosbuvir in combination with ribavirin versus a dual DAA combination with simeprevir. A decision-analytic Markov model was constructed to simulate the progression of a 50-year-old cohort of patients with HCV genotype 1 infection through natural history of disease and therapy with both of the treatment combinations, using a societal perspective over a lifetime horizon.31 Costs and quality-adjusted life-years (QALYs) associated with illness and treatments accumulated at the end of each stage (model year). The cost-effectiveness analysis accounted for drug costs, treatment-related medical care, re-treatment if an SVR was not achieved, and natural disease progression in the case of treatment failure. In the base case scenario, the dual DAA combination surpassed the combination of a DAA/ribavirin in the modeled 50-year cohort of both treatment-naïve and treatment-experienced patients, excluding those who had previously failed therapy with telaprevir or boceprevir. The dual oral combination of sofosbuvir and simeprevir resulted in lower costs and more QALYs compared with the DAA/ribavirin combination ($165,336 and 14.69 QALYs vs $243,586 and 14.45 QALYs, respectively). All-oral treatment dominated standard therapy in the base case analysis across a range of willingness-to-pay thresholds, producing an incremental cost-effectiveness ratio of $44,514 per QALY. The model was sensitive to drug costs, rates of SVRs, treatment-related medical care, re-treatment for individuals who do not achieve SVR, and the natural history of continued HCV infection following the failure of retreatment. The all-oral regimen was demonstrated to be the most cost-effective for subjects with HCV genotype 1 infection; however, it was also cost-effective for genotypes 2 and 3 (≥80,000/ QALY). These effects were maximized in younger treatment cohorts (<50 years of age).31 The degree of cost-effectiveness varied according to willingness-to-pay threshold and the cost of drug combinations.31,32

The authors calculated cost savings per SVR. The combination therapy resulted in cost savings of $91,590 per SVR compared with sofosbuvir and ribavirin in the base case analysis.31

Despite the paucity of direct comparison data with these new agents, it is clear that the changing treatment landscape for HCV infection brings with it effective strategies for virus eradication. Given the high up-front drug costs involved, it is critical that clinicians understand and distinguish between which treatments are most likely to result in positive outcomes for particular patient groups.

Going for Goal: The Cost-effectiveness of Achieving SVR/Cure

The goal of HCV infection management has focused on achieving an SVR, which indicates an undetectable viral load (ie, cure). Achievement of an SVR is associated with a greatly reduced risk of clinical outcomes related to liver disease, including cirrhosis, end-stage liver disease, HCC, and the need for liver transplantation. In addition, an SVR is associated with a decrease in all-cause mortality compared with a lack of SVR achievement.33

Unfortunately, the eradication of HCV infection comes with an extremely high price tag in terms of direct drug costs. The Table34,35 illustrates the approximate costs of various regimens used to treat patients with HCV infection genotype 1 (cost estimates are based on wholesale acquisition cost data).

Implications of New Drug Therapies on Managed Care

Current Status

Managed care payers and providers are currently in a “wait and see” position in terms of possessing all the information needed to distinguish between treatments for clinical efficacy and cost-effectiveness. Just a few months ago, patient “warehousing” (ie, holding off on HCV treatment) reached an all-time high. Prior to this, standard interferon-based therapies were considered the first-line treatment and were utilized across the board in treatment of patients with HCV infection. It is conceivable that this “wait and see” period will continue until payers and caregivers are comfortable with choosing the most clinically effective and cost-effective regimen for patients with consideration of individual status (eg, genotype, prior treatment status, extent of hepatic involvement).

According to study results published in late 2013, 90% of physicians are warehousing at least some of their patient caseload while waiting for more efficacious, tolerable therapies. Pharmaceutical companies are now in a race to release interferon-free treatments in addition to the newly available agents sofosbuvir and simeprevir.36

However, some evidence exists that this status is changing. Study results presented in October 2014 at the Academy of Managed Care Pharmacy’s (AMCP’s) Nexus meeting indicated that 90% of newly diagnosed patients begin treatment with a sofosbuvir-based regimen. In addition, 39% more patients began an HCV infection therapeutic regimen between December 2013 and May 2014 (n = 384) than between June 2013 and November 2013 (n = 276). This change in prescribing behavior, combined with a greater number of patients receiving treatment for HCV infection, has added substantial economic burden to overall pharmacy expenditure when drug costs alone are considered.37

Study results presented by Aggarwal et al at the same AMCP meeting evaluated the budget impact of new HCV infection treatments on US managed care in 5 states (Florida, Illinois, New York, Texas, and California). Of 426 coverage policies identified for the 4 treatments (telaprevir, boceprevir, sofosbuvir, and simeprevir), 69% were for telaprevir and boceprevir, and 31% were for sofosbuvir and simeprevir. They concluded that new HCV infection treatments such as sofosbuvir and simeprevir are associated with lower managed care access compared with older agents.38 These differences likely represent the lack of availability of cost-effectiveness data for sofosbuvir and simeprevir in specific clinical situations.

Future Implications

The healthcare and cost implications of new and emerging HCV infection treatments are still not clearly delineated, but it is evident that the main questions to be answered encompass the following: (1) What type of patient will most likely benefit from early treatment versus late? (2) Which treatment is most efficacious for which patients? and (3) What is the balance between efficacy and cost-effectiveness in individual patients with HCV infection that will tip the scales in the direction of achieving the most positive outcomes with the least economic impact? Research is under way to answer these questions.

Available results are encouraging in that all-oral and interferon-free regimens will prove cost-effective if treatments are individualized based on patient/disease characteristics. Of note, HCV infection guidelines are constantly being updated to keep abreast with the everchanging HCV infection treatment landscape and to identify the most appropriate treatments for individual patients.

The prioritization of patients who should receive early treatment for HCV infection is an important factor for consideration to appropriately balance the likelihood of optimal clinical outcomes and minimize risk for adverse treatment–related effects. However, guideline recommendations are new and not yet widely practiced. In August 2014, the AASLD and the IDSA prioritized which patients should be treated for HCV infection. They recommended that top treatment priority be given to patients at highest risk for severe complications, including those with fibrosis and stage 3 or 4 compensated cirrhosis and organ transplant recipients. Next in order of priority (labeled “high priority”) are 2 categories of patients: (1) those at high risk for complications (eg, those with stage 2 fibrosis or coinfection with HIV or hepatitis B); and (2) those with high HCV transmission risk (active injection drug users, incarcerated patients, and HIV-positive men with high-risk sexual practices).33

What is the rationale for treating patients at high risk for transmission? Recommendations by the AASLD and IDSA state: “Persons who have successfully achieved an SVR (virologic cure) no longer transmit the virus to others…successful treatment benefits public health.”33 Virologic cure rates are 90% to 100% for HCV genotype 1 infection and are high for other genotypes as well.39 The development of treatments is rapidly progressing, and shorter durations of therapy are becoming a reality. Therefore, stopping HCV before it spreads (ie, curing it early) is critical.

It is important to recognize that there are risks associated with waiting to treat HCV infection. Patients with cirrhosis and fibrosis risk progression of disease and decompensation, which are associated with other morbidities and can lead to less benefit when treatments are given at a later date. Patients with HCV-related symptoms and those with extrahepatic manifestations such as renal disease may benefit more from early treatment. In addition, waiting to treat the infection may not be prudent in patients with risk factors associated with progression of fibrosis (eg, excessive alcohol consumption, steatosis, HIV coinfection, prolonged immunosuppression).40

HCV treatments are generally more cost-effective in patients at high risk of experiencing adverse outcomes such as liver-related complications.30 For example, in a patient with advanced fibrosis and/or HIV infection, an SVR can prevent morbidity, mortality, and expenditures that would otherwise have been imminent. Other patients who should receive treatment include those at risk for accelerated fibrosis progression.30 The potential risks associated with waiting to treat include progression of these complications, resulting in poor clinical outcomes and increased expenditures.

Which patients should not receive treatment for HCV infection? According to the AASLD/IDSA guidelines, patients with limited life expectancy (ie, less than 12 months) for non-liver related comorbid conditions would likely not benefit from treatment, and palliative care strategies should be the focus.30

Treatment adherence is critical to achieving positive outcomes such as an SVR. A retrospective Veterans Affairs–based study in 5706 patients with HCV infection reported that early virologic response increased with higher levels of adherence to interferon and ribavirin therapy.41 Positive treatment outcomes are associated with adherence to therapy, which in turn is linked with reduced overall costs of care in patients with HCV infection.42 In a recent study, pharmacy and medical claims data from approximately 40 managed healthcare plans and 50 million patients between 2002 and 2006 were searched for a diagnosis of HCV infection.42 Patients were required to have a prescription claim for at least 1 HCV infection medication within 6 months prior to or any time after diagnosis. Treatment cost, prescribing patterns, and duration of treatment were assessed over the therapy period. Treatment adherence rates were lower for patients with more severe disease (50%, compared with 65% and 62% for those with mild or moderate disease, respectively). Patients who were adherent to treatment had greater total HCV-related costs compared with nonadherent patients ($20,132 vs $12,259; P <.01); this was primarily due to higher pharmacy costs from stricter refill compliance by adherent patients. When pharmacy costs were excluded, total HCV-related costs were lower for adherent patients compared with nonadherent patients ($1370 vs $2463; P <.01). Inpatient costs were also higher for nonadherent patients ($13,162 vs $8733; P <.01).42

A recent study assessed the development of an adherence monitoring and appropriateness of therapy program for patients prescribed sofosbuvir at a single healthcare center; this program involved clinical pharmacists, nurse care managers, dispensing pharmacists, and prescribers. Although only a few patients have entered the program thus far, the authors suggested that such a program is necessary to promote adherence and appropriateness of this high-cost treatment.43

Several treatment-related factors may lead patients to terminate therapy early, such as longer treatment durations, higher complexity regimens, and frequent or intolerable AEs.44 The selection of a regimen with the best chance of virologic cure, along with provision of medication adherence monitoring and overall therapy management, is critical to treatment success.

Results from a study aimed to promote cost-effective regimens for the treatment of HCV infection via telephonic prescriber outreach were presented at the 2014 AMCP Nexus meeting. The goals of the telephonic prescriber program were to promote use of a cost-effective regimen through telephonic prescriber outreach on prior authorization requests, monitor patient adherence to treatment using pharmacy claims data, and identify patients achieving virologic cure by conducting prescriber outreach. A total of 396 patients were included in the program at that time; 113 prescribers of these patients were contacted to discuss alternative regimens. Of these, 27 regimens were approved, leading to an estimated cost avoidance of $569,000 to $1,200,000. In addition, 105 prescribers were contacted for 181 members who were past due or nearly due for a medication refill. The authors concluded that telephonic interventions may assist prescribers in the management of patients who are potentially nonadherent to a prescribed drug regimen.45

Russell and colleagues46 reported on the implementation of a center of excellence model for the management of HCV infection utilizing a multidisciplinary healthcare team including pharmacists, physicians, and nurses. They noted that appropriate patients are receiving necessary treatment and care from this team approach, thereby improving correct utilization of HCV infection medications. Importantly, the authors reported that the program included strong clinical experts with a history of producing superior patient outcomes and alignment of benchmark measurement criteria with policy criteria.46

The Future Direction of HCV Infection and Managed Care

The appropriate management of HCV infection is complex and depends heavily on clear communication and collaboration between patients and members of the healthcare team to minimize adverse treatment effects, prevent drug-drug interactions, and ensure treatment adherence. New treatment options with novel mechanisms of action that have been approved by the FDA over the last few years represent groundbreaking opportunities that were historically unavailable to eradicate HCV in many patients with chronic infection. Emerging drugs offer even more choices to optimize treatment outcomes.

On October 10, 2014, the combination of ledipasvir and sofosbuvir, the first all-oral combination treatment for HCV genotype 1 infection, was approved by the FDA.27 Within days of this approval, Bristol-Myers Squibb announced it would no longer pursue approval for its combination of asunaprevir (an NS3/4A protease inhibitor) and daclatasvir for the treatment of HCV genotype 1b infection, citing the rapidly evolving treatment landscape for HCV treatment in the United States.47

Abbvie’s fixed-dose “3D” combination of the protease inhibitor paritaprevir and ritonavir (ABT-450/r) coformulated with the NS5A inhibitor ombitasvir (ABT-267) and the non-nucleoside polymerase inhibitor dasabuvir (ABT-333) was approved by the FDA in December 2014 for treatment of HCV genotype 1 infection. This directacting 3D combination therapy demonstrated SVR12 rates of 98.7%% and 99.3% with and without ribavirin, respectively.48,49

Of note, pricing wars between companies supplying recently approved all-oral HCV infection treatments may prove beneficial for payers and patients, as these competitions are beginning to drive drug prices down. This has resulted in the ability of drug providers to secure discounts that may make treatments accessible for more patients with HCV infection. Outside of the HCV infection treatment landscape, such competitions may result in discussions about drug pricing earlier in the development process, and more detailed evaluations of patients who are likely to benefit most from treatment.50

Several agents are in late-phase studies and are likely to be available in 2015. The combination of daclatasvir and sofosbuvir demonstrated SVR12 rates of 90% and 86% in treatment-naïve and treatment-experienced patients with genotype 3 infection, according to ALLY- 3, a phase 3 open-label trial (n = 152). These results are promising for treatment of genotype 3, which has become one of the most difficult HCV genotypes to treat and the second-most common genotype worldwide. Results from ALLY-3 indicate the possibility of eradicating HCV genotype 3 infection using an all-oral regimen administered for 12 weeks.51

Other emerging HCV infection medications include grazoprevir (MK-5172), elbasvir (MK-8742), and sofosbuvir in combination with the NS5A inhibitor GS-5816 and ribavirin.52

Achieving an SVR should be the ultimate treatment goal for patients with HCV infection, particularly for those who are at high risk for reinfection or may further spread the virus. As Bruce Bacon, MD, of Saint Louis University noted in an expert interview (May 25, 2014), “While costs are higher with newer DAAs, one must consider the fact that achieving cure more quickly with these drugs essentially removes the patient from the HCV healthcare system and its associated expenses, potentially saving significant costs in the long run.” Now that all-oral treatment regimens for HCV infection have become the standard of care, the balance between high drug costs and improvements in clinical outcomes—including eradication of the HCV–—must be considered. Individualized, targeted treatment plans based on HCV subtype, patient characteristics, and drug safety profiles are the key to optimizing outcomes with the minimum expense.

Author affiliation: Gary Owens Associates, Ocean View, DE.
Funding source: The activity is supported by educational grants from Bristol-Myers Squibb and Gilead Sciences Inc.
Author disclosure: Dr Owens has disclosed serving as a consultant for AbbVie, Janssen, and Towers Watson.
Authorship information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and administrative, technical or logistic support.
Address correspondence to: gowens99@comcast.net

References

Source

HCV cure for everyone or which challenges remain?

Journal of Virus Eradication 2015; 1: 55–58

Jürgen Kurt Rockstroh

Department of Medicine I, University Hospital Bonn, Germany; German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany

Abstract

Following the approval of the first HCV direct-acting antiviral (DAA) in 2011, an unforeseen revolution in the treatmentof chronic hepatitis C has taken place. In 2015 several all-oral DAA regimens, combining agents from different families(NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A proteaseinhibitors) are now commercially available. In clinical trials, these regimens result in an increase in sustained virologicalresponse (SVR) rates to above 90–95% and reduce the duration of treatment to 12 weeks or less. As these new all-oraltherapies are easy to take, with some already available as simple fixed-dose combinations, and are associated with minimaladverse events, increasing numbers of HCV patients appear treatable with these modern regimens. Nevertheless, thequestions remain on how far the spectacular treatment trial results can be reproduced in clinical practice and whether morechallenging patient populations, including previous non-responders and patients with advanced cirrhosis, will continue toexist even in the era of all-oral DAA therapy.

Keywords: HCV, genotype, cirrhosis, liver transplantation, DAA

Introduction

The hepatitis C virus (HCV) was discovered in 1989 and was quickly established as the major cause of non-A, non-B hepatitis(NANB) [1,2]. HCV is an RNA virus that belongs to the family Flaviviridae . Overall, seven major genotypes and 67 subtypes have been described, with genotype 1 accounting for ~70% of infections in the US and Europe [3]. HCV genotypes have been particularly important in the past with regard to probability of achieving cure following an interferon (IFN)-based HCV therapy.Although this may become less relevant in the direct-acting antiviral (DAA) era, so far not all DAAs are active against all genotypes. The prevalence of HCV is approximately 3% around the world [4]. This virus can cause chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Therefore, HCV treatment has always been a desirable goal in order to cure HCV and thereby prevent fibrosis progression and development of cirrhosis and other liver disease-related complications. Even before the discovery of the HCV virus, the first pilot studies had evaluated the efficacy and safety of IFN-α to treat patients with NANB hepatitis, following encouraging results from IFN treatment trialsi n hepatitis B [5]. Subsequently, IFN monotherapy administered thrice weekly for 24 weeks became the first HCV therapy, albeit with low sustained virological response (SVR) rates of only6%[6]. Adding ribavirin, extending treatment duration and finally introducing pegylated interferon helped to substantially increase overall HCV cure rates to above 50% (Figure 1) [6,7]. Host factors that were associated with a good response were young age,female gender, non-African-American heritage and low fibrosis levels, and, more recently, presence of the IL-28B CC genotype[8]. More challenging patient groups were cirrhotics, previous IFN non-responders, patients with HCV recurrence after liver transplantation, and patients with HIV co-infection who, in controlled clinical trials, were much less likely to achieve SVR.Also, IFN-based therapy was strongly restricted in its widespread use because of its very significant adverse-event profile and high rate of treatment-related complications. Indeed, more than 50%of a given HCV cohort appeared to have contraindications against interferon, preventing its use accordingly. Therefore, the development of DAAs that allowed all-oral IFN-free and, at best,also ribavirin-free HCV regimens, has introduced a whole new era of HCV therapy. Not only are these new therapies much better  tolerated but they also achieve cure of HCV defined as SVR12–24 weeks after stopping HCV therapy in more than 90–95%of patients, promising widespread cure for all [9–16]. Clearly, the most obvious limitation of these new therapies is their extremely high price, which has led to a considerable delay and hindrance in the uptake of these new treatment options. Indeed, there is still no access to these new therapies in many countries or their use is reserved only for patients with advanced F3–F4 fibrosis. In clinical practice the question remains, how will patients,particularly in the presence of liver cirrhosis and priornon-response or failure to a first DAA and IFN-containing HCV regimen, respond to these new drugs outside clinical trials? This review summarises the current successes and remaining challenges of modern all-oral HCV therapy.

HCV treatment data from real-life patient settings

One of the first large cohorts of HCV patients receiving DAA-based therapy was presented at AASLD in 2014 by the TRIO network [17]. The objective of the study was to evaluate outcomes with sofosbuvir- and simeprevir-containing regimens in a real-world, heterogeneous population. Data were collected

through the Trio Platform directly from electronic prescribing records. Overall, 1211 patients from 150 academic and community sites were included in this database. The main regimens examined were: sofosbuvir (SOF)/pegylated interferon(PEG)/ribavirin (RBV), SOF/RBV and SOF/simeprevir (SMV)±RBV. Of 995 participants who could be analysed, 59% were male, 16% African-American, 30% had cirrhosis, 16% had platelet counts below 100,000/µL, 43% were treatment-experienced (35% null responders, 65% partialresponders/relapsers) and 20% had already received an HCV protease inhibitor (PI) [17]. All baseline characteristics indicatedt hat this was a more difficult-to-treat patient population than normally enrolled into clinical trials. The SVR12 rates for the different regimens (SOF/PEG/RBV and SOF/SMV ±RBV) for genotype 1 patients were 72% and 82%, respectively. Clearly,these results demonstrate that overall cure rates in clinical practice remain high and appear reproducible. However, on average there is a 5–10% lower cure rate than in clinical trials.Indeed, there are a growing number of patients for whom treatment with DAA-based therapy has failed and who will require a more potent treatment option in the near future. This is particularly true for the more challenging patient populations such as the cirrhotic genotype 1 patient with a history of previous non-response to HCV treatment. Most impressively, treatment discontinuation rates were extremely low at only 5%, with 3%owing to non-adherence and 1.9% for adverse events only,underlining the good tolerability of modern all-oral HCV therapy.Similar data were presented at the same meeting from the TARGET database, which represents an ongoing longitudinal observational study at 43 academic and 13 community centres in North America (n =51) and Europe (n =5) [18]. Overall, 2330 HCV patients consented to be enrolled into this observational study:52.2% of whom were treatment experienced, 48.4% had cirrhosis at baseline and 9.4% had already received a first HCV PI-based regimen that had failed. In addition, 19.2% of recorded patients were aged over 65 years, again highlighting that the patients within this study were much closer to real-world patient populations. Virological response rates were very encouraging. In HCV non-cirrhotic genotype 1 patients receiving SOF/SMV±RBV, SVR4 was 92% (113/123) and 87% (1566/1800) inpatients with cirrhosis. Patients with genotype 1a were only a little less likely to achieve SVR4 (89%; 47/53) than patients with HCV genotype 1b (95%; 88/93).

Continue full article reading here …..

Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 HCV previously treated in clinical trials of sofosbuvir regimens

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Viral Hepatitis

David Wyles^1,*, Paul Pockros², Giuseppe Morelli³, Ziad Younes⁴, Evguenia Svarovskaia⁵, Jenny C. Yang⁵, Phillip S. Pang⁵, Yanni Zhu⁵, John G. McHutchison⁵, Steven Flamm⁶ and Eric Lawitz⁷

DOI: 10.1002/hep.27814

© 2015 by the American Association for the Study of Liver Diseases

Publication History

Accepted manuscript online: 2 APR 2015 11:45AM EST
Manuscript Accepted: 26 MAR 2015
Manuscript Revised: 16 MAR 2015
Manuscript Received: 23 FEB 2015

Keywords: direct-acting antiviral agents; HCV NS5B polymerase inhibitor; retreatment

Abstract

Patients who fail to achieve sustained virologic response (SVR) after treatment with sofosbuvir plus ribavirin with or without peginterferon do not have established retreatment options. We conducted an open-label trial to assess the efficacy and safety of ledipasvir-sofosbuvir plus ribavirin in patients with genotype 1 HCV who did not achieve SVR after treatment in phase 2 and 3 trials of sofosbuvir regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed-dose combination tablet of ledipasvir-sofosbuvir once daily plus weight-based ribavirin (1000 or 1200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received sofosbuvir plus peginterferon-ribavirin, 20 (39%) had received sofosbuvir-ribavirin, five (10%) had received sofosbuvir placebo plus peginterferon-ribavirin, and one (2%) received GS-0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non-CC IL28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received sofosbuvir in prior treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event, but most events were mild to moderate in severity. The most common adverse events were fatigue, headache, and diarrhea. One patient discontinued treatment due to an unrelated adverse event (bipolar disorder). Conclusion: Twelve weeks of ledipasvir-sofosbuvir plus ribavirin was an effective and safe treatment for patients who have not achieved SVR with prior regimens that included sofosbuvir. This article is protected by copyright. All rights reserved.

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Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

World J Hepatol. 2015 March 27; 7(3): 532-538.

Published online 2015 March 27. doi: 10.4254/wjh.v7.i3.532.

Copyright© The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

Kerstin Herzer and Guido Gerken.

Kerstin Herzer, Guido Gerken, Department of Gastroenterology and Hepatology, University Hospital Essen, 45122 Essen, Germany

Kerstin Herzer, Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, 45122 Essen, Germany

Author contributions: Herzer K wrote the manuscript; Gerken G contributed to the substantial supplementing of the manuscript.

Correspondence to: Kerstin Herzer, MD, Associate Professor, Department of Gastroenterology and Hepatology, University Hospital Essen, Hufeland str. 55, 45122 Essen, Germany. kerstin.herzer@uk-essen.de

Telephone: +49-201-7235147 Fax: +49-201-723 3393

Received August 29, 2014; Revised October 21, 2014; Accepted December 16, 2014;

Abstract

The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus (HCV). In the liver transplant (LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better response rates achieved with boceprevir-based and telaprevir-based triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.

Keywords: Hepatitis C virus, Liver transplant, Interferon, Sofosbuvir, Simeprevir, Daclatasvir

Core tip: In the liver transplant (LT) setting, graft loss due to hepatitis C virus (HCV) recurrence is a serious problem after LT. The former conventional treatment with pegylated interferon and ribavirin is unsatisfying, due to poor response rates and tolerability. With the first interferon-free regimens that are currently being approved for the treatment of patients with chronic HCV, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. This review summarizes the current experience with and the expectations of the new direct-acting antiviral agents in the setting of LT.

LIVER TRANSPLANT IN THE SETTING OF CHRONIC HCV INFECTION

Chronic hepatitis C virus (HCV)-induced end-stage liver disease, with or without hepatocellular carcinoma, is still the leading indication for liver transplant (LT), and reinfection of grafts by HCV is the main cause of allograft loss[^1,2]. Most patients experience recurrence of HCV infection after LT, and such recurrence can be associated with substantially accelerated cirrhosis of the graft in as many as 30% of patients[^3,4]. A subgroup of patients experience fibrotic cholestatic hepatitis (FCH), a severe and extremely aggressive form of HCV recurrence characterized by rapid progression to graft failure and death. Once cirrhosis develops, the annual risk of hepatic decompensation is approximately 40%, and 10% to 25% of patients will die or require retransplantation within 5 years after the first LT[⁵]. Unfortunately, the outcome of patients undergoing retransplantation is poor, and most transplant centers are reluctant to offer a second LT for patients with cirrhosis of the graft due to HCV reinfection[^6,7].

The shortage of donor organs, in conjunction with the accelerated progression of HCV in LT patients, emphasizes the need for effective clinical strategies aimed at treating or preventing HCV recurrence after transplant. Three approaches have been described, according to the timing of treatment: antiviral therapy before LT, which is appropriate only for patients with compensated cirrhosis; preemptive treatment after LT[⁸]; and treatment of an established reinfection[⁹]. Thus, after transplant, HCV patients can be treated either immediately with a preemptive approach or with a recurrence-based approach when liver damage is diagnosed. The advantages of preemptive or early treatment after transplant are low serum HCV-RNA levels and no substantial damage to the graft, as determined by histologic studies[¹⁰]. Although these factors are positive predictors of a favorable outcome, this therapeutic approach has been difficult to manage because the combination of pegylated interferon (PegIFN) and ribavirin (RBV) is associated with poor tolerability and reduced efficacy[⁵]. Therefore, the preferred approach to date has been to delay antiviral treatment until histological evidence establishes a diagnosis of HCV-related chronic hepatitis after transplant.

It has been reported that the presence of substantial portal tract fibrosis or of portal hypertension one year after LT are predictors of a higher risk of clinical decompensation and death; therefore, these characteristics help determine which patients urgently need treatment[¹¹]. For patients with FCH, meaning a severe recurrence of HCV early after transplantation, antiviral therapy would be life-saving; however, previous treatment options were unable to eradicate HCV in most cases, with the deleterious consequences of graft loss and death.

PREVIOUS THERAPEUTIC STRATEGIES

Since the discovery of the HCV in 1989[¹²], the development of effective therapeutic strategies has been hampered by the unavailability of cell-culture and small-animal models for investigating the virus. During the last decades, therapeutic approaches remained limited to unspecific IFN-based regimens with insufficient efficacy. Early trials of IFN monotherapy achieved sustained virologic response (SVR) in fewer than 10% of cases[¹³]. The introduction of combination therapy with RBV and IFN and the modification of IFN to PegIFN, which can be administered weekly and is associated with improved pharmacokinetics (PK), resulted in higher SVR rates[¹⁴]. The PegIFN and RBV dual combination treatment was the standard of care for all HCV genotypes for about 10 years. For many chronically infected patients, this treatment regimen fails to eradicate HCV and is associated with additional adverse effects, and it is even less efficacious for LT patients. The overall rates of SVR with PegIFN plus RBV are low, ranging from 30% to 40% across various reports[^5,15]. These poor virologic response rates were mainly due to a high frequency of treatment discontinuation and also dose reduction which became necessary because of poor tolerance or adverse effects[¹⁶]. Moreover, as LT recipients are susceptible to hematologic toxicities, especially anemia, RBV dose reductions and the use of erythropoietin are common. Hematologic toxicity necessitates a dose reduction for nearly 70% of patients and early discontinuation of treatment for nearly 30%[^16-18]. Moreover, some reports indicate that antiviral therapy may increase the risk of acute graft rejection[¹⁹]. The risk of rejection for LT patients ranges from 5% to 10%[²⁰]. However, the probability of survival for patients with SVR after LT is clearly better than that for patients who do not respond to therapy[²¹].

In May 2011, the first-generation protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TLV), broke this paradigm. The United States Food and Drug Administration approved these drugs for use in association with PegIFN and RBV[^16,22]. Both PIs inhibit the same viral protein (NS3/4A) that is crucial for viral replication, and both are active against GT 1 but not against other HCV genotypes. For the other HCV genotypes, PegIFN plus RBV remained the standard of care. Several studies have evaluated the feasibility of these regimens for several hundred LT patients with HCV recurrence[^23-26]. About one-third of the patients received BOC and the majority was treated with TLV. Most patients had advanced-stage fibrosis, and approximately half had received at least one previous course of antiviral treatment. The reports described rapid virologic response rates from 53% to 67%, and SVR rates 12 wk after the end of therapy from 48% to 62%[^27,28]. While these results were quite encouraging in terms of efficacy, the administration of direct-acting antiviral agents (DAAs) after LT was associated with serious concerns about tolerability and the risk of severe adverse events[^24-26]. Indeed, the bone marrow-suppressive effect of TLV and BCV could amplify the anemia, neutropenia, and thrombocytopenia induced by RBV and PegIFN[²⁹]. In addition, TLV and BCV cause severe dermatologic effects, such as generalized pruritus and anorectal disorders[³⁰].

In addition, drug-drug interactions are a serious obstacle of the new antiviral agents. First-generation PIs (TLV, BCV) are not only processed by but also inhibit the CYP3A4 isoenzyme, which is involved in the metabolism of most drugs, including the calcineurin inhibitors (CNIs) cyclosporin A (CSA) and tacrolimus (TAC). BCV has been shown to cause a 2.7-fold increase in the area under the curve (AUC) of CSA and a 17-fold increase in the AUC of TAC, whereas TLV causes a 4.6-fold increase in the AUC of CSA and a 70-fold increase in the AUC of TAC[^31,32]. Considering the narrow therapeutic range of CSA and TAC, dose adjustments are of imminent importance, and these drugs must be very closely monitored when they are combined with PIs[^27,28,33].

Although the first-generation PIs achieved a substantial improvement in terms of efficacy, their described disadvantages and the fact that IFN is still necessary limit the patient population for which this treatment strategy is appropriate. For particular groups of patients, IFN-based regimens are contraindicated or not applicable or repeatedly failed. Those patients depend on the development of IFN-free regimens.

In this respect, the recent introduction of second-generation DAAs, including PIs, polymerase inhibitors, and nonstructural protein inhibitors has initiated a new era of HCV treatment.

FUTURE THERAPEUTIC STRATEGIES: NEW DAAS AND IFN-FREE REGIMENS AFTER LT

For decades, HCV has successfully escaped from all efforts to generate more efficient drugs, although research efforts have been intense[³⁴]. Viral replication in vitro or in small-animal models could not be achieved, and functional studies were limited to chimpanzees[^35-37], what caused an important drawback to DAA development. The ultimate breakthrough for HCV drug development may be dated to establishment of the HCV replicon system, what was not earlier that 1999[^34,38]. HCV subgenomes, which compose the nonstructural proteins NS3-NS5 linked to a selectable marker, can efficiently replicate in vitro. A few years later, a full-length isolate of HCV became available which can produce infectious viral particles in vitro[^34,39]. The resulting improvement in the understanding of the viral life cycle opened the doors for the development of the first-generation DAAs. Drug development was further supported by structural biology, which has provided high-resolution images of the structures of the virus, revealing additional crucial drug targets, such as NS3, NS5A, and NS5B. These images have allowed modelling of interactions between specific replication inhibitors and their targets[^34,40,41].

With the advent of the NS5B polymerase inhibitor sofosbuvir (SFV)[⁴²], the NS3 PI simeprevir (SMV)[⁴³], and the NS5A replication inhibitor daclatasvir (DCV)[⁴⁴], three “second-wave” DAAs are now available and promise to be appropriate for LT patients, without severe adverse effects or negative interactions with immunosuppressants.

However, reports of trials of IFN-free DAA combinations in patients after LT are still scarce. The combination of SFV and RBV was the first IFN-free regimen to be tested for treating HCV recurrence in a compassionate use program[⁴⁵]. Preliminary results of the use of this combination for 24 wk with recurrent HCV hepatitis after LT report a high overall SVR rate of almost 80%. The treatment is not only well tolerated but did also achieve a significant improvement in liver function tests and encephalopathy as well as decompensation[^16,46]. Importantly, no clinically significant interactions with common immunosuppressants were observed and no episodes of rejection occurred. Overall, the preliminary analysis of experiences with patients in these programs indicate that a SFV-based regimen can inhibit HCV replication in most patients. This impairement of viral load goes in line with an improvement in clinical parameters and condition in the majority of those patients. However, although these results are already very encouraging, longer follow-up periods and a larger number of patients are needed to assess the impact on disease progression[⁴⁶]. In addition, SFV and RBV have been successfully used to treat FCH[^47,48].

In a phase 2, open-label study, 61 patients who were on the waiting list for liver transplant due to HCV cirrhosis were treated with SFV and RBV for up to 48 wk. At the time of LT, 43 patients had HCV RNA below detection levels and 30 patients (70%) had still a negative viral load 12 wk after LT. The most frequently reported adverse events were fatigue, headache and anemia[⁴⁹].

To date, only a few reports reflect experiences with the use of other IFN-free regimens other than SFV and RBV for LT patients. Fontana et al reported the first patients who were successfully treated with a combination of DCV and IFN or DCV and SFV for 24 wk combatting a severe HCV recurrence after LT[^50,51]. In the meantime, several multicentric clinical trials are ongoing to assess the safety and efficacy of several oral DAA combinations for patients with HCV recurrence: (1) ABT450/ABT267/ABT333/RBV for 24 wk (NCT01782495); (2) SMV/DCV for 24 wk (NCT01938625); (3) SFV/RBV for 24 wk (NCT01779518); and (4) SFV/LDV/RBV for 12 or 24 wk (NCT01938430).

It is expected that the approval of these combinations for the use after LT will dramatically change the management and outcome of LT patients[¹⁶]. First summary reports implement suggestions for IFN-free treatment regimens for LT patients[^52,53]. However, there remain several challenges and uncertainties for the use of IFN-free regimens to treat patients with very aggressive forms of hepatitis C (such as FCH), which occurs very early after transplantation. The pitfall may be the early setting while patients are still taking high doses of immunosuppressants[¹⁶]. Therefore, this period bears the risk of opportunistic infections[⁵⁴]. Moreover, patients are during that period are often recovering from or being treated for surgical complications.

Indeed, the potential interaction of DAAs with CSA, TAC, and other immunosuppressants is an important issue for LT patients. Fortunately, most anti-HCV therapeutics which currently in phase 3 development have been successfully tested for potential interactions with CSA and TAC, at least in healthy volunteers. Co-administration studies in healthy volunteers found no clinically significant interactions with CSA or TAC[^16,51].

Another common feature of LT patients is renal failure. Most patients exhibit a low glomerular filtration rate (GFR) because of previous renal damage that is aggravated by the long-term use of CSA or TAC[⁵⁵]. In some cases, dose adjustments may be necessary and some compounds like SFV may be excluded from application if the GFR is lower than 30 mL/min.

A further issue that requires particular attention is the usually high viral load in patients who underwent LT, most likely due to the immunosuppression[⁵⁶]. Exorbitantly high viral loads may well be a prerequisite for the selection of drug-resistant strains that may result in a virologic relapse if the appropriate combination of DAAs is not used. Therefore, after LT, resistance testing may become a necessary tool in the choice of the appropriate antiviral combination for the benefit of treatment efficacy and patient outcome[⁵⁷].

TREATMENT BEFORE OR AFTER LIVER TRANSPLANT?

Treatment of patients while before liver transplant or while they are awaiting LT, respectively, may have several advantages. From the experiences with successful therapy of Hepatitis B, improvement in liver function may also be awaited for HCV clearance, and LT may become unnecessary in some cases. However, safety data and pharmakokinetics are not available for all compounds when administered to patients with cirrhosis classified as Child-Pugh B or C. Early reports suggest that deterioration of liver function is slightly accelerated after the administration of SFV/DCV to patients with decompensated cirrhosis after LT[⁵⁸]. These observations suggest that treatment immediately after LT may be the better strategy for decompensated and severely sick patients.

Currently still a problem concerning patients awaiting LT is the uncertainty of treatment duration, because the length of time that a patient must remain on the waiting list cannot be predicted[¹⁶]. Though we can anticipate that, in the near future, all patients awaiting LT will receive successful treatment with the opportunity to receive LT after clearance of the virus, given the historical course of HBV.

Concerning treatment of HCV infection after LT, a few issues remain to be solved. Safety data as well as PK analyses are needed for this special patient population, particularly for those patients with advanced graft damage.

As well, drug-drug interaction studies are crucial because of the metabolism of CSA and TAC and a therapeutic range which is considerably narrow. This accounts not only for interactions with immunosuppressants but also with other commonly used drugs. Last but not least, a high barrier to resistance is also relevant for the use of direct-acting antivirals, particularly when high serum levels of HCV-RNA are observed[¹⁶].

CONCLUSION

Liver transplant due to HCV is a yet unmet challenge and a public health burden. Current developments predict a fundamental change of this situation: a large patient population for whom IFN-based treatment regiments are contraindicated, will now achieve access to potent antiviral therapies. While the use of novel DAA-based regimens in sufficient time before LT will prevent reinfection of the graft with HCV and avoid the need for retransplantation, the successful treatment of already recurred graft infection and damage in immunosuppressed patients after LT will pave the way to make a retransplant feasible. Most importantly, an early enough treatment of HCV patients on the waiting list will stabilize liver function with the consequence that LT will be dispensable in those individuals and HCV-related end stage liver disease can be expected to disappear from the transplant waiting list in the near future.

However, the efficacy of DAAs applied after LT in terms of SVR cannot yet be quantified, nor has their adverse-event profile been ascertained for patients who have undergone LT. In addition, the potential predictors of SVR have not yet been identified. However, the absence of drug- drug interactions between CNIs and DCV, SMV, and SOF, in combination with the so far reported significantly improved SVR rate achieved with these DAAs, offers a promising perspective. Given the potential clinical benefits, more extensive and reliable clinical data about the effects of these new potent HCV inhibitors on patients with recurrence of HCV infection after LT are urgently needed.

One of the remaining difficulties with these new regimens is the huge increase in treatment costs[⁴²]. Affordability could be the pacemaker to set up strategies for personalization of treatment in areas of the world with economic limitations and also in selected patient populations. Some old but in certain cases sufficiently effective regimens using IFN-based regimens may find a niche in those patients with a history of several failed DAA regiments or who harbor multiple resistance-associated variants. While we experience the dusk of IFNs, these substances might stay advantageous for HCV therapy in consideration of features like absence of viral resistances, comparatively low costs and avoidance of drug-drug interactions in patients who are reliant on various concomitant medications.

Footnotes

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: August 29, 2014

First decision: September 30, 2014

Article in press: December 16, 2014

P- Reviewer: Chiang T, Kapoor S, Li ZF, Narciso-Schiavon JL S- Editor: Tian YL L- Editor: A E- Editor: Wu HL

References

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Janssen Therapeutics Announces Support for Organizations Focused on Improving Care and Treatment for People Who Inject Drugs Living with HIV and/or Hepatitis C

Latest Program Extends Company's Ongoing Commitment to Supporting Underserved Populations in the United States

TITUSVILLE, N.J., April 1, 2015 /PRNewswire/ -- Janssen Therapeutics, Division of Janssen Products, LP (Janssen), today announced the recipients of funding from a special request for applications (RFA), "Improving Care and Treatment for People Who Inject Drugs Living with HIV and/or Hepatitis C."

Eight United States-based organizations each will receive a one-year charitable contribution to enhance access to healthcare and treatment for people who inject drugs living with HIV and/or hepatitis C.

Injection drug use is at the core of the HIV and hepatitis C epidemics, attributed as the third most frequently reported risk factor for HIV infection^1,2,3,4 and the primary cause of hepatitis C in the United States.⁵ Successful treatment of HIV and hepatitis C among people who inject drugs is important to reduce virus-related complications and the likelihood of transmitting the virus(es) to others.^6,7

In response to the significant unmet need among people who inject drugs living with HIV and/or hepatitis C in obtaining access to comprehensive healthcare in the face of multiple barriers, Janssen awarded charitable contributions of up to $40,000 each to recipient organizations in support of community- and peer-based models to improve care and address documented barriers to treatment.

The recipients comprise a diverse range of organizations, including:

• Atlanta Harm Reduction Coalition (Atlanta, GA)
• Boom!Health (New York, NY)
• Coastal Bend Wellness Foundation (Corpus Christi, TX)
• Mendocino County AIDS/Viral Hepatitis Network (Ukiah, CA)
• The Open Door, Inc. (Pittsburgh, PA)
• St. John's Well Child and Family Center, Inc. (Los Angeles, CA)
• Vermont Committee for AIDS Resources Education & Services (Burlington, VT)
• Washington Heights CORNER Project (New York, NY)

"We're committed to helping improve access to care and treatment by addressing significant unmet needs in at-risk populations facing multiple, persistent barriers," said Nefertiti Greene, president, Janssen Therapeutics. "As a leader in infectious diseases, we're honored to support these organizations in their efforts to enhance linkages to treatment and care for this often underserved part of the HIV and hepatitis C communities."

United States-based 501(c)(3) tax-exempt organizations were eligible to submit proposals. Submissions were assessed on their potential to improve access to and retention in care for people who inject drugs, and to link diagnosed patients to medical treatment and supportive care through a multi-disciplinary, partnership-based model.

About Janssen Therapeutics Commitment to Supporting Community Organizations
As part of its overall support of community organizations, Janssen Therapeutics funds endeavors addressing unmet needs for underserved populations in the HIV and hepatitis C communities while providing private sector funding to community-based organizations.

The company periodically issues focused RFAs to address significant unmet care or access needs among underserved populations living with HIV and/or hepatitis C to help stimulate new models of care and services and to enhance organizational capacity. This is the eighth funding initiative since 2008, contributing more than $3.2 million to community-based and national HIV/AIDS and hepatitis C service organizations.

To learn more, visit http://www.janssentherapeutics-grants.com.

About Janssen Therapeutics
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in HIV, hepatitis C and other infectious diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Headquartered in Titusville, New Jersey, Janssen Therapeutics, Division of Janssen Products, LP, is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Visit www.JanssenTherapeutics.com for more information and follow us on Twitter at @JanssenUS.

¹ National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. CDC Fact Sheet: HIV and AIDS in America: A Snapshot. 2012.

² Prejean J, Song R, Hernandez A, Ziebell R, Green T, et al. Estimated HIV Incidence in the United States, 2006–2009. PLoS ONE. 2011;6(8): e17502.doi:10.1371/journal.pone.0017502.

³ Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;4: 1–39.

⁴ Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data–United States and 6 U.S. dependent areas–2010. HIV Surveillance Supplemental Report. 2012; 17(No. 3, part A). Available at http://www.cdc.gov/hiv/library/reports/surveillance/2010/surveillance_Report_vol_17_no_3.html. Accessed March 31, 2015.

⁵ Seeff, L.B., 2009. The history of the "natural history" of hepatitis C (1968–2009). Liver Int. 29 (Suppl. 1), 89–99.

⁶ AASLD/IDSA/IAS-USA. Recommendations for testing, managing, and treating hepatitis C. Available at www.hcvguidelines.org. Accessed March 23, 2105.

⁷ Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed March 23, 2015.

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Fibroblast Growth Factor-2 Contributes to HCV Reinfection After Liver Transplant

By Will Boggs MD

April 02, 2015

NEW YORK (Reuters Health) - Fibroblast growth factor-2 (FGF-2) and other non-interferon mediators contribute to hepatitis C virus (HCV) reinfection after liver transplantation, researchers from Germany report.

"We have identified FGF-2 and the signaling cascade triggered by it as an unexpected novel driver of HCV replication," Dr. Sandra Ciesek from Medizinische Hochschule Hannover told Reuters Health by email. "Hence, it is important to be aware that modulation of host signaling cascades (e.g., certain novel anti-cancer drugs, such as brivanib, that block FGF signaling) may have unexpected effects on viral replication."

While orthotopic liver transplantation is the only treatment for end-stage liver disease due to HCV infection, it is not a cure, and nearly all patients develop graft reinfection.

Dr. Ciesek and colleagues set out to determine how the inflammatory response that occurs in the peritransplantation period modulates the HCV replication cycle and whether it contributes to the poor outcome of HCV-positive individuals after liver transplant.

All 13 transplant recipients (three of whom had HCV) showed marked rises in C-reactive protein levels between pre-transplant and post-transplant sera, but there was heterogeneity in the changes of serum chemokines and no apparent association with the etiology of liver disease.

Among 27 non-interferon inflammatory mediators examined by the researchers, FGF-2 alone enhanced HCV RNA replication and release of infectious particles, they report in Gut, online March 23.

In contrast, FGF-1, a close relative of FGF-2, did not enhance HCV RNA replication.

The effects of FGF-2 appeared to be mediated by signaling through FGF receptor 3 (FGFR3).

In 70 individuals with chronic HCV infection, serum FGF-2 levels were significantly higher in those with high viral load than in those with low viral load.

The investigators are now studying which exact downstream events triggered by FGF-2 and FGFR3 are required for HCV replication.

"Right now there is an enormous opportunity to prevent the majority of post-transplant HCV reinfection events by using direct antiviral agent combinations that have reached the market during the past 15 months," Dr. Ciesek said. "We do not anticipate that modulation of the host serum milieu (or FGF2 signaling) will play a major role here."

"There remains a minority of patients -- those with very advanced liver disease and concomitant renal failure -- that cannot be treated with the currently available regimens," she added. "Thus, new approaches may be needed for this subgroup of patients. It is conceivable that modulation of host factors or host signaling pathways might play a role here."

SOURCE: http://bit.ly/1GgGAwe

Gut 2015.

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Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial

Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11.

Lawitz E¹, Gane E², Pearlman B³, Tam E⁴, Ghesquiere W⁵, Guyader D⁶, Alric L⁷, Bronowicki JP⁸, Lester L⁹, Sievert W¹⁰, Ghalib R¹¹, Balart L¹², Sund F¹³, Lagging M¹⁴, Dutko F¹⁵, Shaughnessy M¹⁵, Hwang P¹⁵, Howe AY¹⁵, Wahl J¹⁵, Robertson M¹⁵, Barr E¹⁵, Haber B¹⁵.

Erratum in Lancet. 2015 Mar 21;385(9973):1074.

Abstract

BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response.

METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326.

FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]).

INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

FUNDING:

Merck & Co, Inc.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25467591 [PubMed - indexed for MEDLINE]

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All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study

Hepatology. 2015 Apr;61(4):1127-35. doi: 10.1002/hep.27726. Epub 2015 Mar 10

Nelson DR¹, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, Freilich BF, Younes ZH, Harlan W, Ghalib R, Oguchi G, Thuluvath PJ, Ortiz-Lasanta G, Rabinovitz M, Bernstein D, Bennett M, Hawkins T, Ravendhran N, Sheikh AM, Varunok P, Kowdley KV, Hennicken D, McPhee F, Rana K, Hughes EA; ALLY-3 Study Team.

Author information

¹University of Florida, Gainesville, FL.

Abstract

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient.

CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway. (Hepatology 2015;61:1127-1135).

© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

PMID: 25614962 [PubMed - in process]

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