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New Era of Antiviral Therapy for Chronic Hepatitis C Infection: Implications on Global Health

Joseph K. Lim, MD

Joseph K. Lim, MD
Associate Professor of Medicine
Director, Yale Viral Hepatitis Program
Yale University School of Medicine
New Haven, Connecticut, USA

ABT-333: Abbott non-nucleoside polymerase inhibitor
ABT-450: Abbott protease inhibitor
BI-201335: Boehringer-Ingelheim protease inhibitor
BI-207127: Boehringer-Ingelheim nucleoside polymerase inhibitor
BID: twice daily
BOC: boceprevir
CYP3A4: cytochrome P450 enzyme 3A4
DAA: directly acting antiviral agent
GS-7977: Gilead Sciences nucleotide polymerase inhibitor
GT: genotype
IVDU: intravenous drug use
N: number of subjects
Peg-IFN: pegylated interferon alpha
QD: once daily
R155K: arginine to lysine mutation at position 155
RBV: ribavirin
SVR: sustained virologic response
TPV: telaprevir
V36M: valine to methionine mutation at position 36

Global Burden

Chronic hepatitis C virus (HCV) infection represents a global public health burden which is associated with significant morbidity and mortality. The worldwide prevalence is estimated at 170 million individuals, with the highest concentration observed in sub-Saharan Africa, South-East Asia, and the Western Pacific 1-2. Chronic HCV infection represents one of the leading causes of chronic liver disease, and places individuals at risk for progressive liver fibrosis and cirrhosis, hepatocellular carcinoma, and liver-related death. Following initial infection, approximately 70% develop chronic infection, of whom an estimated 20% will progress to liver cirrhosis, and 5% will die from cirrhosis or liver cancer. More than 15,000 and 350,000 individuals in the United States (U.S.) and worldwide, respectively, die of  HCV-related liver disease each year, and this is expected to increase significantly over the next 10-20 years 2-3.

Based on World Health Organization (WHO) estimates, the highest prevalence of chronic HCV infection is seen in Africa (5.3% or 31.9  million individuals), the Eastern Mediterranean (4.6% or 21.3 million), and the Western Pacific (3.9% or 62.2 million), with a lower prevalence observed in South-East Asia (2.15% or 32.3 million), the Americas  (1.7% or 13.1 million), and Europe (1.03% or 8.9 million). Countries with the highest rates of chronic infection include Egypt (22%) and two of the world’s most populous nations, China and Pakistan, where >3% of the population are infected (Table 1). Globally, key risk factors for HCV transmission include blood transfusion from unscreened donors, unsafe therapeutic injections, and health care-related procedures, particularly in the developing world, whereas injection drug use has remained  the predominant source of new infections in most developed countries 1. In the U.S., the Centers for Disease Control and Prevention (CDC)  recently modified its screening recommendations for hepatitis C to expand beyond individuals with known risk factors to a broader population of “baby boomers” born between 1945-1965, a strategy that has been found to be cost-effective and may identify an additional 800,000 infected individuals 4-5.


Table 1: Global Prevalence of Hepatitis C by WHO Region.


Significant progress has been made over the past 15 years in our ability to eradicate chronic HCV infection. In 2001, the combination regimen  of pegylated interferon alfa (peg-IFN) plus ribavirin (RBV) emerged as a new global standard of care which was associated with a sustained virologic response (SVR) in approximately 40%, 50%, and 75% of genotypes 1, 4, and 2-3, respectively. However, this regimen has been limited by high complexity, financial cost, and significant adverse effects, thus limiting its uptake in resource-limited settings outside major developed countries; even in the U.S. and Europe, it is estimated than fewer than 20% have undergone antiviral therapy 6.

Directly Acting Antiviral Agents (DAAs)

Last year, two NS3/4A protease inhibitors were approved in North America, South America, Europe, and Japan. Boceprevir (Victrelis) and telaprevir (Incivek, Incivo, Telavic), used in conjunction with peg-IFN and RBV, significantly increase the rate of viral eradication, and  represent the new standard-of-care for the treatment of genotype 1 hepatitis C infection 7-8. In treatment-naïve individuals, a combination regimen consisting of 12 weeks of triple therapy (telaprevir, peg-IFN, RBV) followed by an additional 12-36 weeks of dual therapy (peg-IFN,  RBV) resulted in an SVR rate of 69-75% (versus 42% peg-IFN/RBV alone) in phase 3 registration trials; a similar combination regimen consisting of 4 weeks of dual therapy (peg-IFN, RBV) followed by an additional 24-44 weeks of triple therapy (boceprevir, peg-IFN, RBV) resulted in an SVR rate of 63-66% (versus 38% peg-IFN/RBV alone). Approximately 66% of treatment-experienced patients also achieved SVR with either boceprevir or telaprevir-based triple therapy regimens, although the likelihood of viral eradication diverged significantly based on prior response to peg-IFN plus RBV, with SVR rates of approximately 30% in prior null responders (<2 log decrease in HCV RNA within 12 weeks of peg-IFN plus RBV), 50-60% in prior partial responders (≥2 log decrease in HCV RNA within 12 weeks of peg-IFN plus RBV but still detectable at 24 weeks of therapy), and 80% in prior responder-relapsers (≥2 log decrease in HCV RNA within 12 weeks of peg-IFN plus RBV, undetectable at 24 weeks and at end-of-treatment, but detectable after end-of-treatment). Although triple therapy regimens are associated with significant improvements in efficacy in both treatment-naïve and treatment-experienced patients, this is balanced by additional challenges, including significant pill burden, challenging q8 hour dose schedule, drugdrug interactions due to inhibition of cytochrome P450 CYP3A4, potential for viral resistance mutations, and additional adverse effects beyond peg-IFN and ribavirin such as severe anemia, dysgeusia, rashes, anorectal symptoms, and rare skin reactions such as Stevens-Johnson Syndrome and DRESS syndrome.  Characteristics of these regimens are summarized in Table 2 9-13.


Table 2: Protease-Inhibitor Based Triple Therapy.


Future of Interferon-Free Regimens

Telaprevir and boceprevir represent only the first generation of a large number of oral DAA’s which have demonstrated remarkable promise in the suppression of HCV replication. It seems likely that triple therapy regimens with either telaprevir or boceprevir will be the best available therapy until at least 2014. Several second-generation agents are now entering phase 3 trials and provide hope for even greater increases in safety and efficacy in both treatmentnaïve and treatment-experienced individuals. Current triple therapy regimens with DAA remain limited by  the requirement for peg-IFN and RBV, complex and burdensome response-guided regimens, restriction to genotype 1-infected individuals, and less than optimal SVR rates in prior nonresponders to pegylated interferon-ribavirin. Phase 2 data from trials evaluating next generation protease inhibitors, nucleos(t) ide and non-nucleos(t)ide polymerase inhibitors, NS5A inhibitors, novel interferons, therapeutic vaccines, and cyclophilin inhibitors suggest that the next shift in the hepatitis C treatment paradigm is likely to be characterized by further increases in SVR,  decreased pill burden, once or twice daily oral regimens, shorter treatment duration, more favorable safety profiles, and broader genotype coverage. Although it is possible that quadruple therapy regimens combining two DAAs plus peginterferon plus ribavirin will be necessary for some patients with poor interferon sensitivity and multiple negative predictors of viral response, the ultimate goal of future HCV therapy will be interferon-free combination regimens of two or more oral DAAs with or without ribavirin which achieve high levels of SVR in both treatment-naïve and treatment-experienced individuals. In 2011, a landmark paper by Lok et al. provided the first proof-of-principle that SVR  can be achieved with two DAAs without interferon (NS5A inhibitor daclatasvir plus protease inhibitor asunaprevir), moreover, in a cohort of highly refractory patients who were prior null responders to peg-IFN and RBV 14. In 2012, additional reports from phase 2 trials provided  further confirmation that SVR can be achieved without interferon; two studies evaluating the role of a quadruple oral regimen for 12 weeks (ritonavir-boosted protease inhibitor ABT-450, non-nucleoside polymerase inhibitor ABT-333, and ribavirin) and a dual oral regimen for 24 weeks (nucleotide polymerase inhibitor GS-7977 plus NS5A inhibitor daclatasvir) demonstrated SVR rates of 95% and 100%, respectively  (Table 3) 15. These promising results unequivocally provide a foundation for further exploration of interferon-free regimens as a viable future  strategy for HCV treatment, and spur hope that such regimens may become available within the next 3-5 years.


Table 3: Phase 2 SVR Results for Interferon-Free Regimens.


Implications on Global Health

Although DAA-based antiviral therapy has been widely adopted in developed countries with access to first-generation protease inhibitors, these new antiviral drugs will unlikely benefit resource-limited settings in the short term. Logistical constraints related to peg-IFN  administration, high treatment complexity, substantial pill burden, prohibitive cost, significant adverse effects, and access to specialty providers all remain important barriers to broader utilization. It is hoped that simpler, shorter, safer, and more effective oral-only regimens eliminating peg-IFN may provide a critical step in drug development to permit global expansion of HCV treatment. In a similar manner as witnessed in the expansion of antiretroviral therapy for HIV, strategic partnerships between manufacturers, government agencies, specialty and advocacy  organizations, and non-governmental organizations (NGOs) will have a historic opportunity to provide the financial support and political will required to achieve truly worldwide access to HCV therapy, and fundamentally alter the global burden of this infection.


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