Table of Contents  
MOLECULES OF THE MILLENNIUM
Year : 2012  |  Volume : 3  |  Issue : 2  |  Page : 213-215  

Boceprevir: A new hope against hepatitis C virus


Department of Pharmacology, Army College of Medical Sciences, Delhi Cantt, New Delhi, India

Date of Web Publication2-May-2012

Correspondence Address:
Dick B. S. Brashier
Department of Pharmacology, Army College of Medical Sciences, Delhi Cantt, New Delhi - 110 010
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-500X.95548

Rights and Permissions

How to cite this article:
Brashier DB, Sharma S, Mathur A G, Khare P, Gupta S. Boceprevir: A new hope against hepatitis C virus. J Pharmacol Pharmacother 2012;3:213-5

How to cite this URL:
Brashier DB, Sharma S, Mathur A G, Khare P, Gupta S. Boceprevir: A new hope against hepatitis C virus. J Pharmacol Pharmacother [serial online] 2012 [cited 2019 Jun 19];3:213-5. Available from: http://www.jpharmacol.com/text.asp?2012/3/2/213/95548


   Introduction Top


According to the statistics available, hepatitis C seems to affect 170 million people worldwide with varying prevalence according to the geographical distribution. [1] Out of 80% of infected population develop chronic hepatitis, 20% develop cirrhosis. [2] Chronic hepatitis C virus (HCV) infection is the most important cause for liver transplant. [3] Tragically being a major illness, many drugs have not been approved for the treatment of hepatitis C. HCV infection has been a major obstacle for the treating physicians, even after approval of pegylated interferon and ribavirin. [4] Researchers have being in advent for a new drug molecule to treat this infection. After years, boceprevir was approved by Food and Drug Administration (FDA) for the treatment of hepatitis C infection. Boceprevir has shown hope for clinicians not only to patients with treatment on interferon and ribavirin, but also shown hope to a big challenge of non-responders. However, the limitation with present treatment of a combined regimen of pegylated interferon and ribavirin given for 48 weeks is that its being poorly tolerated by the patients due to increased side effects. [5] With limited research in the field of HCV infection, a new drug getting approved as an add-on to conventional therapy came as a silver lining in the dark cloud, especially when it comes to deal with non-responders.


   Mechanism of Action Top


HCV virus has enveloped strands of RNA, belonging to flavivirus genus, which upon entering the host cells, undergoes translation in ribosomes. The non-structural (NS) chain contains NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7 components. [6] Functions of p7 are still not known, but for others, they function as polymerase, protease, and helicase. [6] These have being explored as potential drug targets against HCV. [6] Protease enzyme is responsible for proteolysis and breaking down of the NS strand to form NS protein. Protease are present in N terminal of NS3 strands. [6] It first cleaves NS3-NS4A junction, and then cleaves the strand at NS4A-NS5B, NS4B-NS5A, and NS5A-NS5B, which further reassembles to form protein molecules. [7] Research has found two new groups of drugs coming under a new class called, directly acting anti-virals. The first group is NS3/4A serine protease inhibitors, and the second group is NS5B RNA polymerase inhibitors. [7] Boceprevir is a non non-covalent competitive inhibitor of NS3/4A serine protease, hence inhibiting protein synthesis. [7]


   Pharmacokinetics Top


Boceprevir is quickly absorbed in small intestine with maximum levels reaching in 2 h. [8] Its metabolized in liver by two pathways. [8] The major pathway being the aldoketo-reductase pathway and the minor pathway is via CYP3A4/5. [8] The primary route of excretion is through faeces. [8] Boceprevir is a strong inhibitor of CYP3A4 and a mild inhibitor of P-glycoprotein. [9] Therefore, drugs which are metabolized by CYP3A4 or P-glycoprotein, given along with boceprevir, tend to show increased plasma levels. [9]


   Clinical Trials Top


Preclinical studies on boceprevir showed both time- dependent and dose- dependent inhibition of the HCV in in-vitro studies. After expression with boceprevir for 3 days, HCV lines showed 50% inhibition with a dose of 200 nmole/L and 90% inhibition with a dose of 400 nmole/L. [10] After a successful phase I and phase II trials (sprint 2 trial), [11] phase III trials were first conducted in September 2005, the RESPOND-2 trial. [12] The RESPOND-2 trial had three treatment arms. The first arm was control in which pegylated interferon and ribavirin was given for 48 weeks. The second arm was given a combination of pegylated interferon and ribavirin for initial 4 weeks, followed by boceprevir for 44 weeks, making it 48 weeks of total treatment, and the third arm was given pegylated interferon with ribavirin and boceprevir using response guided treatment. Sustained virological response (SVR) after 48 weeks was 21%, 66%, and 59% for groups 1, 2, and 3, respectively. [12] Adding boceprevir to the conventional treatment showed highly significant improvement, more ever it also showed favorable response for patients not responding to the treatment with combination of pegylated interferon and ribavarin. [12]


   Resistance Top


As with other drugs, boceprevir also showed resistance during Phase III trials. The drug became resistant due to mutation in the amino acid sequence in the NS3 attachment site. [13] This mutation leads to decreased susceptibility to boceprevir. Most common resistance associated variants found were A156S, R155K, V55A, T54A, and T54N. [13] In a comparison study with Telaprevir, a similar drug being approved for hepatitis C, long long-term analysis showed for both the presence of wild type variants of HCV in the majority of patients in phase Ib trials. [14]


   Adverse Efefcts Top


Borceprevir is a well-tolerated drug, showing few and mild adverse effects in phase III trials. Most common was fatigue (57%), followed by anemia (49%), headache (46%), nausea (43%), and pyrexia (33%), in treatment population. [11],[14] Other mild side effects were decreased appetite, myalgia, chills, insomnia, alopecia, diarrhea, neutropenia, and influenza-like reaction. [11],[15] It has the same contraindications as with pegylated interferon and ribavirin, as it is always given in combination. [11] Boceprevir is found to be highly teratogenic in animal studies. [16]


   Present Status Top


Subsequently FDA approved boceprevir in May 2011 for treatment of HCV genotype I infection as an add-on to the combination therapy with pegylated interferon and ribavirin, in patients above 18 years of age, with compensated liver disease in both previously untreated and non-responders. Its recommended dose is 800 mg (available as 200 mg capsules) three times a day. [17] It is being manufactured by Merck Sharp and Dohme and marketed under the trade name of Victrelis. [17]


   Conclusion Top


Boceprevir is a new hope in treatment of HCV, as it is the first drug made available after a decade for this disease. Being an add-on drug, it has shown good infection results, even for non-responders on previous conventional treatment. Second generation protease inhibitors are already in pipeline, derived from further modification of the chemical structure of boceprevir. As new targets are being explored, new drugs will be soon coming into the picture to set new treatment guidelines for HCV infection.

 
   References Top

1.Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31 Suppl 2:61-80.  Back to cited text no. 1
    
2.Bacchetti P, Boylan R, Astemborski J, Shen H, Mehta SH, Thomas DL, et al. Progression of biopsy-measured liver fibrosis in untreated patients with hepatitis C infection: Non-markov multistate model analysis. PLoS One 2011;6: e20104.  Back to cited text no. 2
    
3.Fink SA, Jacobson IM. Managing patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis. Nat Rev Gastroenterol Hepatol 2011;8:285-95.  Back to cited text no. 3
    
4.Testino G, Sumberaz A, Ansaldi F, Borro P, Leone S, Ancarani AO, et al. Treatment of recurrent hepatitis C (genotype 1) with pegylated interferon alfa-2b and ribavirin combination and maintenance therapy. Hepatogastroenterology 2011;58:536-8.  Back to cited text no. 4
    
5.Hansen N, Obel N, Christensen PB, Kjaer M, Laursen AL, Krarup HB, et al. Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study. BMC Infect Dis 2011;11:177.  Back to cited text no. 5
    
6.Asselah T, Marcellin P. New direct-acting antivirals' combination for the treatment of chronic hepatitis C. Liver Int 2011;31 Suppl 1:68-77.  Back to cited text no. 6
    
7.Lange CM, Sarrazin C, Zeuzem S. Future of antiviral therapy for chronic hepatitis C. Direct antiviral acting medications. Pharm Unserer Zeit 2011;40:60-7.  Back to cited text no. 7
    
8.Berman K, Kwo PY. Boceprevir, an NS3 protease inhibitor of HCV. Clin Liver Dis 2009;13:429-39.  Back to cited text no. 8
    
9.Velázquez F, Sannigrahi M, Bennett F, Lovey RG, Arasappan A, Bogen S. Cyclic sulfones as novel P3-caps for hepatitis C virus NS3/4A (HCV NS3/4A) protease inhibitors: Synthesis and evaluation of inhibitors with improved potency and pharmacokinetic profiles. J Med Chem 2010;53:3075-85.  Back to cited text no. 9
    
10.Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, et al. Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 2010;54:5288-97.  Back to cited text no. 10
    
11.Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-206.  Back to cited text no. 11
    
12.Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al.; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-17.  Back to cited text no. 12
    
13.Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology 2011;53:1742-51.  Back to cited text no. 13
    
14.Susser S, Vermehren J, Forestier N, Welker MW, Grigorian N, Füller C, et al. Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir. J Clin Virol 2011;52:321-7.  Back to cited text no. 14
    
15.Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta SK, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 2007;132:1270-8.  Back to cited text no. 15
    
16.Arshad M, El-Kamary SS, Jhaveri R. Hepatitis C virus infection during pregnancy and the newborn period-are they opportunities for treatment? J Viral Hepat 2011;18:229-36.  Back to cited text no. 16
    
17.Available from: http://www.medscape.com/viewarticle/742766. [Last accessed on 2011 June 20].  Back to cited text no. 17
    



This article has been cited by
1 Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase
Gentles, R.G., Ding, M., Bender, J.A., Meanwell, N.A., Kadow, J.F.
Journal of Medicinal Chemistry. 2014; 57(5): 1855-1879
[Pubmed]
2 Silybin/silymarin treatment in chronic hepatitis C
Barbero-Becerra, V.J. and Méndez-Sánchez, N.
Annals of Hepatology. 2012; 11(5): 731-733
[Pubmed]



 

Top
  
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Introduction
   Mechanism of Action
   Pharmacokinetics
   Clinical Trials
   Resistance
   Adverse Efefcts
   Present Status
   Conclusion
    References

 Article Access Statistics
    Viewed1366    
    Printed108    
    Emailed0    
    PDF Downloaded379    
    Comments [Add]    
    Cited by others 2    

Recommend this journal