Treating Hepatitis C Virus: How the Standard of Care is Evolving
Hepatitis C virus (HCV), a major epidemic affecting an estimated 150 million people worldwide, is responsible for more than 350,000 annual deaths from HCV-related liver diseases.1
Since 1982, the incidence of acute HCV infection in the United States has declined,2 due primarily to HCV screening in transfusion centers and universal health care precautions in health care settings.2 However, the number of patients with complications of chronic HCV is increasing—a trend that is expected to continue.2
HCV differs from other viral infections in that it can be cured with antiviral therapy because HCV nucleic acids are not integrated into the host genome, nor is there a viral latency phase.2 Current anti-HCV approaches seek to cure the infection, thereby preventing HCV-related complications and potential contagion to others.
The Evolving Standard of Care
In the 1990s, interferon (IFN) alpha-2a, IFN alpha-2b, and IFN alfacon-1 were the foundation of HCV treatment. A significant breakthrough occurred in 1998 when ribavirin (RBV), a synthetic guanosine analogue, was approved, used in combination with IFN, and found to significantly improve sustained virologic response (SVR).3
A further development, pegylated interferon (PegIFN), prolonged the IFN half-life, allowing for once-weekly dosing and improved pharmacokinetic profiles.3 Combination of ribavirin with once-weekly injectable PegIFN over a 24- to 48-week period yielded significant increase in genotype nonspecific SVR (approximately 55%)3—a dramatic improvement over previous regimens—and became the standard of care.2
However, this regimen was deficient in several areas. It yielded a low SVR in genotype 1 and poor response rates in certain subpopulations, and patients experienced side effects.2
In 2011, two direct-acting antivirals (DAAs)--telaprevir and boceprevir—were approved for treatment of HCV, to be used in conjunction with RVC and PegIFN-alpha. This triple therapy "ushered in a new era of HCV treatment."4 These agents target specific genomic pathways that interfere with HCV infection and replication.2
Telaprevir is a selective inhibitor of NS3/4A protease, a serine protease cofactor that plays an important role in HCV replication.5 Boceprevir is a "potent ketoamide inhibitor of HCV NS3 serine protease."5 Triple therapy has been shown to significantly raise SVR rates.5
Underuse of Triple Therapy
Despite its documented efficacy, triple therapy is underused in clinical practice.
Chen et al4 performed a retrospective cross-sectional study of 487 patients with HCV genotype 1 infection to compare features of patients treated with triple therapy to those who deferred it, over a nine-month period, shortly after the FDA's approval of boceprevir and telaprevir.
The majority of patients were 50 to 60 years old, male, non-Hispanic white, and married. About half the patients were treatment-naïve, while the other half had been previously treated. The majority had advanced fibrosis, with close to 20% displaying complications of liver disease.
Only 91 patients (18.7%) began treatment with triple therapy, and 396 patients remained untreated. The low number of patients initiating therapy remained constant throughout the study period.
The researchers suggested several provider- and patient-specific reasons for treatment deferral. Most of the patients had relative contraindications to treatments, such as complications of liver disease and medical comorbidities. A history of significant side effects during previous treatment was the third most common contraindication.
Additionally, more than 15% of patients had mild liver disease, suggesting that potent therapy might be unnecessary or premature. A tenth of patients (of whom 76% had at least moderate liver fibrosis) were recommended to wait for future treatment options.
Lastly, more than one-fifth of patients declined treatment because of concerns about side effects, limited success rates, financial issues, or inability to commit time for treatment.4
Of those who deferred and then started triple therapy, more than 30% were prior relapsers, while the majority of patients who deferred were treatment-naïve. However, the authors add, there was no difference in HCV RNA viral load, genotype 1 subtypes, or IL28B genotyping.
Twenty-one percent (19 patients) of those treated with triple therapy discontinued within 12 weeks of therapy—15% due to adverse events. Other reasons included nonadherence and nonresponse to DAA therapy.
The authors observed that the combined treatment rate of 18.8% was "nearly identical to the reported treatment rates during the dual therapy era." They commented, "The disappointingly low use of the new therapies . . . suggests that several concerns are at play: the continued requirement of IFN, the safety profile, the low predicted response rates in prior nonresponders, coupled with the suggestion of further major improvements, such as IFN-free therapies, likely colored the thinking of physicians and patients alike in this setting."
Several current agents under investigation are second-generation HCV NS3/N4A oral protease inhibitors: HCV NS5A and NS5B inhibitors, and iIFN-sparing regimens5 The authors state that they expect that these new agents, once approved, "will be applied in the treatment of HCV-infected patients and that they will have more potent efficacy and less adverse events."
1. World Health Organization. Hepatitis C: Fact sheet N°164. (July, 2013) Available at: http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed: August 7, 2013.
2. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. 2012;19(7):449-464.
3. Chan J. Treatment of chronic hepatitis C: The new standard of care for the future.
4. Chen EY, Sclair SN, Czul F, et al. A small percentage of patients with hepatitis C receive triple therapy with boceprevir or telaprevir. Clin Gastroenterol Hepatol. 2013;11(8):1014-1020.e2.
5. Kanda T, Yokosuka O, Omata M. Treatment of hepatitis C virus infection in the future. Clin Transl Med. 2013;2(1):9.
6. Formulary. August 1, 2011. Available at: http://formularyjournal.modernmedicine.com/formulary-journal/news/clinical/clinical-pharmacology/treatment-chronic-hepatitis-c-new-standard-car. Accessed: August 7, 2013.
7. Pol S, Ghalib RH, Rustgi VK, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis. 2012;12(9):671-677.