|Year : 2014 | Volume
| Issue : 5 | Page : 6-11
A review of the current anti-HCV therapy: Are we finally ready for interferon-free regimens
Tejus Anantharamu, Sushil Sharma, Ashok Kumar Sharma, Ajay Kumar Gupta, Navdeep Dahiya, DB Brashier
Department of Pharmacology, Armed Forces Medical College (AFMC), Pune, Maharashtra, India
|Date of Web Publication||19-Dec-2014|
Department of Pharmacology, Armed Forces Medical College (AFMC), Wanworie, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Hepatitis C virus (HCV) continues to be a global problem but with the arrival of new drugs it is expected to move towards exile. The health care community has finally woken up to the need to tackle this infection especially because HCV-induced hepatitis in combination with HIV has turned out to be a formidable foe. So far the management of HCV has concentrated mainly on interferon-based therapies. The focus is now increasingly on drugs targeting various other components of hepatitis C, which are essential for its survival in the host like HCV non-structural (NS) 3/4A serine protease inhibitors: Boceprevir, telaprevir, simeprevir; NS5A inhibitors (daclatasvir, ledipasvir); NS5B polymerase inhibitors (sofosbuvir), cyclophilin inhibitors and many others in the pipeline like the NS4B inhibitors and the micro-RNA122 inhibitors. These new drugs have shown excellent sustained virological response (SVR) compared to the presently available drugs and their combinations. Adding to this is the new HCV vaccine which although facing various hurdles is making good inroads and expected to meet its endpoints in the near future. This review gives a brief overview of epidemiology, pathogenesis, followed by the description of current regimens in the treatment of hepatitis C and the much eagerly awaited future all new oral anti-hepatitis C regimen, which can potentially eliminate the use of painful injections of interferon.
Keywords: HCV, interferon, polymerase inhibitors, serine protease inhibitors
|How to cite this article:|
Anantharamu T, Sharma S, Sharma AK, Gupta AK, Dahiya N, Brashier D B. A review of the current anti-HCV therapy: Are we finally ready for interferon-free regimens. Int J Nutr Pharmacol Neurol Dis 2014;4, Suppl S1:6-11
|How to cite this URL:|
Anantharamu T, Sharma S, Sharma AK, Gupta AK, Dahiya N, Brashier D B. A review of the current anti-HCV therapy: Are we finally ready for interferon-free regimens. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2020 Jan 28];4, Suppl S1:6-11. Available from: http://www.ijnpnd.com/text.asp?2014/4/5/6/147455
| Introduction|| |
Hepatitis C is responsible for a majority cases of non-A, non-B hepatitis.  The incidence is difficult to estimate as most of the times it produces a chronic infection. It has a highly mutable genome, often escapes immunological detection and elimination by the infected host.  The global prevalence is more than 185 million with estimated load of chronically infected 2-4 million patients in the United States; 5-10 million in Europe and around 12 million persons in Asia. Genotypes of hepatitis C virus (HCV) play a vital role in determining the severity and response to treatment. There are 11 genotypes; genotypes 1-3 have a worldwide distribution accounting for 60-70% of infections; type 3 predominantly seen in south-east Asia, type 4 restricted to Middle East and Africa. Genotypes 2 and 3 account for < 30%; whereas < 1% of total infection by genotype 5-11. , In the Indian scenario the Prevalence stands at 1% with types 1-3 predominating (type 3 (60%) > type 1, 2). ,
Common modes of transmission include blood transfusion, IV drug use and health care-related procedures. The risk of transmission through blood transfusion has been reduced from 1 in 200 units to 0.004-0.0004% per unit transfused after WHO made pre screening of HCV a universal requirement. The maternal-fetal transmission depends on the titers of HCV viremia (current risk stands at 5%). Sexual route as a mode of transmission appears to be a low risk. ,
Pathogenesis of HCV
HCV RNA genome is made of 9400 nucleotides including a 5′ and 3′ non-coding regions. Translation begins from the 5′ non-coding region, especially at IRES (Internal ribosomal entry site) and produces a polyprotein of 3000 amino acids which undergoes modification after translation by various proteases produced by host and virus and forms:
- Three structural proteins: HCV core forms nucleocapsid; envelope glycoproteins E1 and E2 play a vital role in virus entry into host
- Seven non-structural proteins: NS1/p7 codes an ion channel; NS2 forms cysteine protease; NS3 forms serine protease and RNA helicase; NS4A forms a co-factor for serine protease; NS4B alters membrane; NS5A forms a phosphoprotein and NS5B forms RdRp (RNA dependent RNA polymerase) [Figure 1] and [Figure 2]. ,
|Figure 1: Innate immune response in HCV infection (first line of defense)|
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After reaching the circulation the virus enters the liver cells by an interaction between HCV E2 envelop glycoprotein and extracellular loop of CD81 on host cells. CD81, a member of transmembrane protein family, acts as a receptor, expressed on surface of hepatocytes, B-lymphocytes, T-lymphocytes and natural killer (NK) cells. It can also bind to low-density lipoprotein (LDL) receptors and dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). ,
Current treatment regimens available for HCV
The currently available treatment modalities are briefly discussed below. The ultimate aim of therapy is the induction of sustained virological response (SVR); defined as negative HCV RNA by a sensitive qualitative test 6 months after the completion of therapy. 
These are glycoproteins of low molecular weight produced by fibroblasts, epithelial cells hepatocytes and predominantly dendritic cells in response to various pathogens like virus, tumor cells, bacteria, parasites. It is the first drug approved by FDA to treat hepatitis C ( IFN-α got FDA approval in 1991). There are several types of IFNs grouped into three types (types I, II and III), type I (α and β) and type II (gamma) exhibits significant activity and hence IFN-α2a and 2b produced by recombinant DNA technology used commercially. Pegylated (PEG) IFN-α2a is absorbed slowly and sustained twice longer in plasma compared to IFN-α2b.Dosage: PEG-IFN-α2a = 180 μg/week; PEG-IFN-α2b = 1.5 μg/kg/week. MOA: IFN receptors have JAK-STAT (Janus Kinase-signal transduction and transducer mechanism) signaling pathway. The phosphorylated STAT binds with p48 protein and forms an ISGF-3 (IFN-stimulated gene factor-3) which in turn enters into nucleus, stimulating IFN-stimulated regulatory element leading to synthesis of various proteins which interfere in viral penetration, synthesis of viral m-RNA, assembly of viral particles and its release [Figure 3]. ,
|Figure 3: Mechanism of action of IFN in HCV infection (Red arrow = inhibition, Green arrow = stimulation)|
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It is a synthetic guanosine analog with a broad spectrum of antiviral activity, administered along with IFN at a dose of 800-1200 mg/day with an oral bioavailability of 50% and an elimination half life of >10 days. The postulated mechanisms by which Ribavirin acts are as depicted in the [Figure 4]. 
|Figure 4: Mechanism of action of Ribavirin in HCV infection (Red arrow = inhibition, Green arrow = stimulation)|
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Common adverse effects with IFN and Ribavirin
(a) constitutional: Fatigue, headache, fever and myalgias; (b) gastrointestinal: Nausea, anorexia and diarrhea; (c) psychiatric: Insomnia, irritability and depression; (d) dermatological: Alopecia and skin rash; (e) hematological: Anemia, neutropenia and thrombocytopenia; (f) others: Dyspnea, chest pain, visual changes and thyroid dysfunction. 
HCV NS3/4A serine protease inhibitors
This group received FDA approval in 2011 and presently includes boceprevir, telaprevir and simeprevir. They are approved as add on therapy with IFN and Ribavirin in genotype I individuals, this triple regimen produced a SVR of 70-80%; compared to 50% with dual therapy and also helps in reduction of treatment duration (to 24/36 weeks). ,
First member to be approved by FDA in May 2011.It is dosed at 800 mg every 8 h in combination with IFN and Ribavirin, taken with food to have higher bioavailability; metabolized by CYP (cytochrome P) 450 3A and aldoketoreductase 1C2 and 1C3. Adverse effects are fatigue, anemia, headache, nausea, pyrexia and is highly teratogenic. 
Second member in this group approved by FDA in May 2011, used in combination with PEG-IFN and Ribavirin in genotype I adult patients, having compensated liver disease (cirrhosis) who are newly treated or non-responders to IFN regimen, administered at a dose of 1125 mg taken 10-14 h apart (with food) for 12 weeks. Metabolized and eliminated by CYP3A and p-glycoprotein. Adverse effects associated with its use include: Pruritis, anemia, rash, nausea, fatigue, diarrhea, anal pruritis, anorectal discomfort, hemorrhoids and is contraindicated in pregnancy. 
Simeprevir, a macro cyclic compound received approval by FDA in November 2013 as a once daily administered NS3/4A protease inhibitor for genotype I hepatitis C individuals in combination with PEG-IFN and Ribavirin. This is associated with fewer adr effects and better compliance. It is administered at a dose of 150mg once daily for 12 weeks, metabolized by CYP3A and p-glycoprotein. Observed side effects include rash, pruritis, nausea and dyspnea. 
Second generation NS3/4A protease inhibitor
These include a group of drugs which are in various stages of clinical trials with better therapeutic and pharmacokinetic profile. This includes danoprevir, vaniprevir, asunaprevir (very close to receive FDA approval), MK-5172, B1201335, GS-9256, GS-9451, ABT450, IDX320 and ACH-1625. 
The approved regimens are based on genotype of HCV:
- Genotype I infection: A triple therapy regimen including PEG-IFN and Ribavarin plus one of the available HCV NS3/4A protease inhibitors telaprevir or boceprevir for 24-48 weeks
- Genotype 2 and 3 infection (common in India): A dual therapy regimen with PEG-IFN and Ribavarin for 24-48 weeks is usually followed (as protease inhibitors are not approved for use in genotype 2 and 3 infection). ,
Recent advances in the treatment of HCV
- NS5A inhibitors: NS5A assists in viral replication possibly by phosphorylation, blocking of host immune response, binds to Cyclophilin A and assembles infectious virus particles. Various inhibitors like Daclatasvir (most promising, awaiting FDA approval) 60 mg QID for 12 weeks, Lediprasvir (phase III), ABT-267 (phase III), GS-5885, GSK2336805, and PPI-668, are under different phases of development ,
- Nucleotide/nucleoside NS5B polymerase inhibitors: These agents bind to RNA chain after conversion to their triphosphate form and lead to premature termination of chain elongation and thereby inhibiting the replication of virus. These drugs are less prone to resistance as NS5B is one of the highly conserved regions in the HCV RNA genome
Sofosbuvir: Received FDA approval in December 2013 as a combination therapy with PEG-IFN and Ribavirin for genotype 1 (12 weeks), and as a dual regimen in combination with Ribavirin for genotype 2 (12 weeks) and genotype 3 (24 weeks). It has produced SVR of around 70-80%. Once daily dose of 400 mg, is well tolerated with mild adverse effects include fatigue, nausea, insomnia and anemia. Various other NS5B inhibitors in pipeline are Mericitabine (cytidine nucleotide) and ALS-938 (uridine nucleotide) ,
- Non-nucleoside NS5B inhibitors (NNI): These bind to highly specific allosteric binding site on NS5B and ultimately inhibit initiation of RNA synthesis. NS5B structurally resembles the motif of right hand and are at least four well-recognized NNI-binding sites (thumb1, thumb2, palm1 and palm2). Various agents in clinical trials are B1207127 (thumb I inhibitor); flibuvir, VX-222 (thumb II inhibitors); ANA598, ABT-333 (palm I inhibitor) and tegobuvir, IDX-375 (palm I inhibitors) 
- Cyclophilin inhibitors: Cyclophilin A, a family of peptidyl prolyl isomerase (PPIase) which plays a crucial role in the replication of RNA. Novel anti-HCV drugs which are analogues of cyclosporine-A, but lacking its immunosuppressive action interacts with domain II of NS5B of HCV (possibly also NS5A and NS2) and indirectly prevents the replication of HCV RNA. Various drugs in advanced stages of clinical trials include Alisporivir, NIM-811 and SCY-635. They look promising but have exhibited risk of pancreatitis in trials ,
- Numerous other agents which are in conceptual stages are:
- Viral entry/assembly inhibitors
- NS4B inhibitors
- The micro-RNA-122 inhibitors: Miravirsen, Silibinin.
- HCV vaccines: Attempts are being made to eliminate HCV with the help of vaccines. There are two prophylactic vaccines in trials, one of which targets envelope glycoproteins E1 and E2, and the other targets various other surface non-structural proteins. The need of therapeutic vaccine is not felt as the newer agents are expected to effectively cure the HCV infection. 
Interferon-free regimens for HCV
The current regimens for HCV involve painful IFN injections every week and moreover are associated with SVR of just 25%, which improved to 45% with a PEG version. Addition of a protease inhibitor to the combination improved SVR to 72% among non-cirrhotic individuals but was pathetically low at just 42% among patients with cirrhosis. Overriding all these were the significant adverse effects attached with the use of this combination and many genotypes I individuals were resistant to IFN regimen. ,
The availability of newer and better drugs has made possible an anti-HCV therapy free from interferons. Various combinations of new all oral non-IFN drugs which are being evaluated are:
- Combination of NS3/4A inhibitors + nucleoside NS5B inhibitors ± Ribavirin: Danoprevir + Mericitabine with or without Ribavirin for 12-24 weeks (INFORM-1 study) = SVR of 26% in genotype 1a and 71% in genotype 1b. The most successful combination tested till date (ELECTRON study): Sofosbuvir + Ribavirin taken for 12 weeks in genotype 1, 2 and 3 individuals. It provided a SVR of 88% in genotype 1; 80% for genotypes 2 and 3 who were subjected to treatment before and 100% for individuals who were new and received no prior treatment. Sofosbuvir was tested as monotherapy, but provided a SVR of just 60%. Simeprevir + Sofosbuvir (2 COSMOS trial) for 12 weeks = awaiting FDA approval, SVR of 93% without Ribavirin and an outstanding SVR of 96% with Ribavirin
- Nucleoside NS5B + NS5A inhibitor ± Ribavirin:
- GS-7977 + Daclatasvir + Ribavirin = SVR of 100% in genotype I individuals (in trials)
- Sofosbuvir + Lediprasvir ± Ribavirin (ELECTRON study) for 12 weeks in phase III trials
- Daclatasvir (NS5A inhibitor) + Asunaprevir (NS3/4A inhibitor): NCT01573351: has received approval in Japan and awaiting FDA approval
- Combinations of NS3/4A inhibitors and non-nucleoside NS5B inhibitors ± Ribavirin: B1-2013356 + NNI (BI-207127) for 12 weeks = SOUNDC2 trial (SVR of 56-68% with Ribavirin); GS-9256 + NNI (tegobuvir) = higher SVR (38%) with Ribavirin compared to without Ribavirin (SVR = 7%) in genotype I. ABT -333 + ABT-450 + Ribavirin = SVR up to 93% in treatment naïve individuals. ,
| Conclusion|| |
The association of HCV with HIV has made the world realize the importance of the once neglected HCV infection. There is now a renewed interest in the field of HCV management. Till May 2011, the only drugs available for its treatment were IFN and Ribavirin and the anti-HCV treatment was not only invasive but was associated with treatment failures and various adverse effects. The new group of protease inhibitors has improved SVR to a great extent and various other groups of drugs nucleotide and non-nucleoside NS5B inhibitors, NS5A inhibitors and others have certainly opened the flood gates, with various drugs standing in line for approval. This has now made possible to design a IFN-free regimen therapy especially for genotype I-infected individuals, which will be a great stride in the fight against HCV for the millions of infected patients who can now lead a life free from weekly IFN injections.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]