Hepatitis C Virus Therapy Update 2013
Curr Opin Gastroenterol. 2013;29(3):243-249.
Abstract and Purpose of review: We review here the recent literature regarding hepatitis C virus (HCV) therapy through January 2013. We discuss current therapies, targets for new therapies, and what might be expected in this rapidly changing field.Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.
Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.
Introduction
An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.[4]
Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al.[8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.[4,10]
Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.
Viral Structure
What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.
Figure 1.
Viral structure and genome demonstrating potential therapeutic targets. Reproduced with permission from.[12] HCV, hepatitis C virus.
Figure 1.
Viral structure and genome demonstrating potential therapeutic targets. Reproduced with permission from.[12] HCV, hepatitis C virus.
The Era of Triple Therapy
The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward.
First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir
Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.[14–17]
Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.
Limitations of First-generation Direct-acting Antiviral Therapy
Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.[22]
What is Needed: Goals for the Future
Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.
Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.
Understanding Direct-acting Antiviral Resistance is Important for the Future
Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.
Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.
New Drugs in Development
In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development ().[23–28]
Table 1. New hepatitis C drugs in development
NS3/4A protease inhibitors NS5A NS5B polymerase nucleos(t)ide NS5B NNI Host targets
| Asunaprevir | Daclatasvir | Mericitabine | Tegobuvir | Alisporovir |
| Vaniprevir | ABT-267 | Sofasbuvir | Filibuvir | Mirvirsen |
| Danoprevir | GS-5885 | IDX184 | BI-207127 |  |
| MK-5172 | PPI-461 | PSI-938 | VX-222 | lambda IFN |
| BI-201335 | BMS791325 | Setrobuvir | | |
| Simeprevir | | ABT-333 | | |
| Tibotec | INX-189 | | | |
| ABT-450 | | | | |
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