Research Article: Hepatitis C Variability, Patterns of Resistance, and Impact on Therapy

Date Published: July 19, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Cristina Simona Strahotin, Michael Babich.


Hepatitis C (HCV), a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is the most common indication for liver transplantation in the United States. Although annual incidence of infection has declined since the 1980s, aging of the currently infected population is expected to result in an increase in HCV burden. HCV is prone to develop resistance to antiviral drugs, and despite considerable efforts to understand the virus for effective treatments, our knowledge remains incomplete. This paper reviews HCV resistance mechanisms, the traditional treatment with and the new standard of care for hepatitis C treatment. Although these new treatments remain PEG-IFN-α- and ribavirin-based, they add one of the newly FDA approved direct antiviral agents, telaprevir or boceprevir. This new “triple therapy” has resulted in greater viral cure rates, although treatment failure remains a possibility. The future may belong to nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of HCV may ultimately parallel that of HIV. However, research should focus not only on effective treatments, but also on the development of a HCV vaccine, as this may prove to be the most cost-effective method of eradicating this disease.

Partial Text

Hepatitis C (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in the United States. The annual incidence of infection in the USA has declined from about 230,000 cases per year in the 1980s to an estimated 17,000 cases in 2007 [1, 2]. This decline has been largely attributed to changes in injection practices motivated by a concern for human immunodeficiency virus (HIV) risk [3]. Approximately 3.2 million persons have chronic HCV infection in the United States; however, the reservoir of chronically infected persons is still estimated at approximately 2.35%, representing approximately 160 million worldwide infected individuals [4]. Aging of the currently infected population is expected to result in an increase in the burden of hepatitis C in the next decade [5]. During that period, the number of HCV-related cirrhosis cases is estimated to increase by 31% and that of hepatocellular carcinoma (HCC) cases is estimated to increase by approximately 50% [5]. Estimates of hepatitis C prevalence range from <0.5% in very low endemic countries (e.g., northern European countries) to staggering rates of approximately 20% in highly endemic areas, including urban centers and the Nile Delta in Egypt [6]. HCV, like hepatitis B virus (HBV) and HIV, is prone to develop resistance to antiviral drugs. Viral dynamics include daily virion production of 1012 with a half-life of 2-3 hours for free virions and less for intracellular virions. It has a very rapid mutation rate, with 2 error-prone viral polymerases that lack proofreading, and no overlapping reading frames, which make it prone to developing resistance. However, given the moderate infected cell turnover and the absence of a viral reservoir, or in other words, the lack of host genome integration or episomal persistence in infected cells [7], HCV has the full potential for eradication. HCV exists as a mixture of populations of genetically distinct but closely related virions in every patient, including potentially drug-resistant variants that are present when antiviral therapy is initiated, thus conferring a quasispecies distribution. However, given its intracytoplasmatic replication and lack of intranuclear replication, there is no known potential for intracellular persistence [15, 16]. Drug-resistant variants often show reduced “replication fitness,” are undetectable with current technology, and have not gained much attention prior to development of the new direct acting antivirals (DAAs) [17, 18]. More sensitive techniques, such as ultra-deep pyrosequencing have been used to identify resistant variants prior to treatment, but these are not routinely used in current clinical practice [19–21]. Potent antiviral therapy eliminates sensitive strains, while resistant variants are uncovered and can expand. For many years, the recommended standard of care therapy for chronic HCV remained a combination of pegylated alpha-interferon (IFN-α) and ribavirin; however, neither drug exerts viral pressure. In other words, treatment failure is not due to selection of IFN-α or ribavirin-resistant variants but is more likely to occur due to inherent host factors (such as the presence of certain single nucleotide polymorphisms (SNPs) upstream of the IL-28B locus that correlate with the rate of SVR), inappropriate drug regimens and viral factors. Interferons are cellular proteins able to induce an antiviral state in their target cells, as well as cytokine secretion, recruitment of immune cells, and cell differentiation. Their metabolism and mechanisms were recently reviewed [22]. According to Tang et al., IFN-α attachment to interferon alpha receptors (IFNAR) [39] and the very rapid activation of Interferon Stimulated Genes (ISG) after interferon alpha administration [40] could explain the effect of IFN-α as a potent immunostimulant of an innate response in the first few hours and an adaptive response after the first four weeks. [41]. The degree of the ISG-induced innate response may result in a rapid decline of HCV replication (as measured by a decrease of HCV-RNA levels), which, if significant enough, causes very distinct CD4 and CD8 responses (shifting the immune response from innate to adaptive). Clinically, this phenomenon defines a group of patients known as rapid responders (HCV RNA serologic negativity achieved by week 4 of treatment) and differentiates them from patients with a less vigorous early reduction in viral load, known as slow responders. HCV is prone to the development of resistance to specific antiviral inhibitors due to the quasispecies nature of the virus, its rapid dynamic, and the double error-prone RdRp [15], all leading to the development and/or persistence of drug-resistant mutants. It has been proposed that all single nucleotide-mutant drug-resistant viruses and all combinations of double-nucleotide mutant viruses preexist before treatment in most patients [45]. Resistance is not an “all or none phenomenon.” Clinically significant resistance is usually associated with an “escape” pattern [72], where viral replication recovers quickly to pretreatment levels while amino acid substitution confers a high level of drug resistance without impairing fitness in the presence of the drug. If the virus is not very fit, the viral replication process will resume more gradually [46, 73–75]. Clinical resistance occurs if drugs levels are not sufficient to inhibit viral replication, and highly resistant viruses may need very high drug levels to inhibit their replication, which may not be achievable within acceptable safety parameters. In addition, sufficient drug trough levels must be maintained over time to achieve long-term viral suppression. Antiviral efficacy in vivo may remain stable if resistant variants replicate at low level and/or if the drug retains partial efficacy. Various patterns of HCV treatment failure have been reported, including viral nonresponse (persistent HCV RNA positivity on treatment), viral breakthrough on treatment, and viral relapse after treatment completion. In compliant patients, failure to respond to triple therapy derives mostly from lack of response to IFN-α and ribavirin, and consequent selection of preexistent viral species inherently resistant to DAAs. Conversely, treatment failure in noncompliant patients frequently results from de novo generation of viral mutants resistant to DAAs. This latter phenomenon is thought to account for most cases of viral breakthrough and relapse. A new standard of care for treating genotype 1 hepatitis C infected patients is now available, for both treatment-naïve patients and treatment-experienced patients. This treatment remains PEG-IFN-α and ribavirin-based but adds either telaprevir or boceprevir, protease inhibitors that became the first DAA drugs specifically targeting the HCV NS3/4A protease, and that were approved by the FDA in May, 2011. This new “triple therapy” has allowed patients to achieve dramatically greater rates of viral cure than previously, but treatment failure remains a possibility. Failure to achieve a viral cure with this regimen most likely results from the low viral genetic barrier to resistance to the protease inhibitors, allowing de novo formation of drug-resistant viral mutants, superimposed on a weak host response to pegylated IFN-α allowing persistence of drug-resistant viruses that were present at baseline. Treatment failure would allow continued progression of the liver disease and may affect candidacy for and/or responsiveness to the next line of DAAs in development. The future may belong to agents such as nucleoside/nucleotide analogues, nonnucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of hepatitis C may ultimately parallel that of HIV in the near future, with use of various combinations of “drug cocktails.”   Source: