Direct-Acting Antiviral Medications for Chronic Hepatitis C Virus Infection Alison B. Jazwinski, MD, and Andrew J. Muir, MD, MHS Dr. Jazwinski is a Fellow and Dr. Muir Abstract: Treatment of hepatitis C virus has traditionally been diffi- is an Associate Professor in the Division cult because of low rates of treatment success and high rates of treat- of Gastroenterology and Duke Clinical ment discontinuation due to side effects. Current standard therapy Research Institute at Duke University consists of pegylated interferon α and ribavirin, both of which have Medical Center in Durham, North Carolina. nonspecific and largely unknown mechanisms of action. New thera- pies are in development that act directly on the hepatitis C virus at various points in the viral life cycle. Published clinical trial data on these therapies are summarized in this paper. A new era of hepatitis Address correspondence to: C virus treatment is beginning, the ultimate goals of which will be Dr. Andrew J. Muir directly targeting the virus, shortening the length of therapy, improv- P.O. Box 17969 Durham, NC 27715; ing sustained virologic response rates, and minimizing side effects. Tel: 919-668-8557; Fax: 919-668-7164; E-mail: [email protected] epatitis C virus (HCV) is a major public health problem, with an estimated 180 million people infected worldwide. Up to 25% of chronically infected patients eventually Hdevelop cirrhosis and related complications, including hepatocellular carcinoma.1 Chronic liver disease secondary to HCV thus remains the leading indication for liver transplantation in the United States.2 The goal of HCV treatment is to eradicate the virus and pre- vent the development of cirrhosis and its complications. Successful treatment of HCV has been defined in terms of sustained virologic response (SVR), which is the absence of detectable levels of viral RNA in the blood 24 weeks after completion of therapy. Currently, the standard treatment approach for HCV includes 24–48 weeks of treatment with pegylated interferon α (pegIFNα) in combination with ribavirin (RBV).3 These drugs act on a variety of nonspecific pathways that affect the immune response to infection. The best treatment response is seen in patients with genotypes 2 and 3 HCV, Keywords in whom SVR rates of approximately 80% can be achieved with 24 4 Hepatitis C virus, direct-acting antiviral agents, weeks of therapy. Patients with genotype 1 HCV remain the most specifically targeted antiviral therapy, sustained difficult to treat, with SVR rates of approximately 40% after 48 virologic response, telaprevir, boceprevir weeks of therapy.5 In addition to being ineffective in some patients, 154 Gastroenterology & Hepatology Volume 7, Issue 3 March 2011 D I r e c t - A c t I n G A n t ivi r A l M e di c A t I o n s f o r H c V Figure 1. Hepatitis C virus protein processing. HCV RNA 9,600 nucleotides 5’ UTR 3’ UTR HCV=hepatitis C virus; UTR=untranslated region. Translation Core E1 E2 NS2 NS3 NS4A NS4B NS5A NS5B Polyprotein processing NS4B NS5A NS5B Core NS2 E2 p E1 7 NS3 NS4A RNA-dependent RNA polymerase for Envelope RNA replication glycoproteins Protease Cofactor for NS3 protease cleaves site between NS2 and NS3 Protease catalyzes polyprotein cleavage at NS3/4A, NS4A/4B, NS4B/5A, NS5A/5B pegIFNα and RBV are difficult to tolerate, and many much lower quantities. However, when subjected to selec- patients treated with these drugs discontinue therapy due tion pressure such as the addition of a drug, the quantity to adverse events. of wild-type virus decreases and the mutated virus gains For these reasons, clinicians need therapeutic agents replication fitness. Some of the resulting mutations lead that result in higher rates of SVR and are more tolerable to changes in the structure of the viral enzymes on which to patients. Many new therapies in preclinical or clinical DAA drugs act, therefore causing the virus to be resistant development act on targets in the viral life cycle to directly to the DAA drug.6 In other viral diseases, resistance can inhibit viral production. These drugs, which are referred be overcome by using multiple drugs that target different to as specifically targeted antiviral therapy for hepatitis C mechanisms; as more drugs are developed, HCV therapy or direct-acting antiviral (DAA) agents, are the topic of will likely involve a multidrug approach as well. this paper. Viral Life Cycle Viral Resistance To better understand the targets of new HCV therapies, A major challenge in the development of new HCV basic knowledge of the HCV life cycle is helpful. HCV therapies has been the emergence of resistance to DAA is a single-stranded RNA molecule approximately 9,600 drugs. HCV has a high rate of replication, with 1012 nucleotides in length.7 This RNA molecule is translated virions produced daily. The viral protein responsible for into a polyprotein consisting of approximately 3,000 replication is NS5B RNA-dependent RNA polymerase amino acids, which are composed into structural and (RdRp), which lacks proofreading ability and has a high nonstructural proteins (Figure 1). The 4 structural pro- error rate. Thus, many genetically distinct but closely teins assemble new viral particles, and the 6 nonstructural related virus quasi species are circulating in the blood proteins participate in viral replication.8 at any given time. In general, mutated viruses have less The viral life cycle provides potential therapeutic replication fitness than wild-type virus and are present in targets at every step (Figure 2). As the first step in this life Gastroenterology & Hepatology Volume 7, Issue 3 March 2011 155 J A z w I n s k I A n D M u I r 1. Viral entry 8. Release of virus 2. Endocytosis, cell entry 7. Viral packaging 3. Release of positive strand RNA into cytoplasm 4. Translation of RNA into protein 6. RNA replication C E2 NS3 NS4B NS2 NS5B E1 5. Polyprotein processing P7 NS4A NS5A Figure 2. Hepatitis C viral life cycle. cycle, the virus attaches to a receptor on the hepatocyte the receptor is mediated by viral proteins RdRp (NS5) surface. The viral and cell membranes fuse, and the virus and NS3.9 enters the cell via receptor-mediated endocytosis. The Several studies have investigated the use of molecules nucleocapsid is then released into the cytoplasm and free, that prevent the attachment of viral particles to receptor positive-strand RNA is released into the cytoplasm, where molecules or that inhibit viral entry. Monoclonal and poly- it is translated into the polyprotein. Post-translational clonal antibodies are in development using this approach. pro cessing then occurs, followed by viral replication, Three monoclonal antibodies—HCV AB68, HCV assembly, and release.9 HCV infection is somewhat AB6865, and bavituximab (Peregrine Pharmaceuticals)— unique in that DNA is not generated at any point in the and 1 polyclonal antibody, Civacir (Biotest Pharmaceuti- life cycle; thus, the virus does not incorporate itself into cals), are currently being evaluated in early-phase trials.11 the host DNA. As a result, it is possible to achieve suc- cessful clearance of the virus with a sustained effect.10 Translation The specific proteins involved in the viral life cycle Translation of HCV is controlled by the internal ribo- and descriptions of drugs being developed to target those some entry site (IRES), which is located at the 5’ untrans- proteins are detailed further below. Table 1 contains a list lated region of the virus and binds to the ribosome to of drugs in various stages of development. initiate translation. The efficiency of IRES translation is thought to be affected by HCV core proteins NS4A and Viral Entry NS5B. Molecules in development that could potentially Both proteins encoded by the virus and those on the cell block this step of the viral life cycle include antisense surface are important for viral entry into cells. The viral oligonucleotides, strands of DNA or RNA that comple- structural proteins E1 and E2 interact with a variety of mentarily bind to messenger RNA and block translation. cell surface receptors, including glycosaminoglycans and Early-phase studies of these molecules are underway. low-density lipoprotein receptors. Fusion of the virus to Ribozymes and specific small molecule inhibitors of HCV 156 Gastroenterology & Hepatology Volume 7, Issue 3 March 2011 D I r e c t - A c t I n G A n t ivi r A l M e di c A t I o n s f o r H c V Table 1. Direct-Acting Antiviral Drugs by Stage of being developed to treat chronic HCV infection. Results Development from phase II studies of these agents are summarized below and in Table 2. A description of a phase III study Phase I Phase II Phase III is also summarized below, the results of which are antici- BMS- Telaprevir pated soon. Approval of these medications is expected TMC435 850032 (VX-950) within the next 1–2 years. Boceprevir Because the NS3/4A protease structure differs ACH-1625 BI 201335 (SCH- among HCV genotypes, protease inhibitors have dif- 503034) ferent antiviral efficacy for different genotypes. The best Vaniprevir antiviral effects are seen in patients with genotype 1 HCV. GS-9256 (MK-7009) Further studies are required to determine effectiveness in other genotypes, although, preliminarily, it appears that NS3A/4B Narlaprevir protease ABT-450 (SCH- protease inhibitors are less effective for genotypes 2, 3, 12,13 inhibitors 900518) and 4 HCV. Danoprevir Boceprevir IDX320 (ITMN-191, RG7227) Major Studies SPRINT-1 was a phase II, randomized, placebo-controlled study of treatment-naïve, genotype 1 GS-9451 HCV patients who were treated with boceprevir (800 mg ACH-2684 TID) and pegIFNα-2b, with or without RBV.