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| DRUG REVIEW |
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| Year : 2013 | Volume
: 59
| Issue : 1 | Page : 42-47 |
Telaprevir: Changing the standard of care of chronic hepatitis C
AK Rajani, BK Ravindra, SA Dkhar
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| Date of Submission | 23-May-2012 |
| Date of Decision | 06-Oct-2012 |
| Date of Acceptance | 08-Oct-2012 |
| Date of Web Publication | 22-Mar-2013 |
Correspondence Address:
A K Rajani
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.109493
Chronic hepatitis C is a major public health problem and its burden is expected to increase in the near future. Out of six genotypes of hepatitis C virus (HCV) identified, genotype 1 is the most prevalent genotype in America and Europe. With peg-interferon alpha and ribavirin dual therapy, sustained virological response (SVR) is achieved in less than half of the patients infected with HCV genotype 1. Moreover, this dual therapy also causes many intolerable adverse effects. Telaprevir is an HCV protease inhibitor approved for chronic hepatitis C genotype 1 mono-infection. It is a type of direct acting antiviral drug acting through inhibition of viral non-structural 3/4A protease. It can be safely administered in mild hepatic dysfunction. Due to inhibition of CYP3A4 and P-glycoprotein, significant drug-drug interactions are possible with telaprevir. Trials have shown significantly higher SVR rates when telaprevir is added to peg-interferon alpha and ribavirin, particularly in patients with unfavorable prognostic factors. It is approved for use in treatment-naïve and previously treated patients. Rash and anemia are the major troublesome side-effects. Next-generation protease inhibitors may overcome the drawbacks of telaprevir and another approved HCV protease inhibitor - boceprevir. Evidence from small scale studies suggests that telaprevir may be used in conditions like HIV co-infection, post-transplantation and some HCV non-1 genotype infections also. Preliminary data show higher SVR rates with triple therapy even in patients with unfavorable interleukin-28B (IL28B) genotype. With development of other direct acting antivirals, it might be possible to treat chronic hepatitis C with interferon-free regimens in future. This article briefly reviews the properties of telaprevir and its status in the context of rapidly evolving aspects of management of chronic hepatitis C.
Keywords: Chronic hepatitis C, hepatitis C virus, interleukin-28B, telaprevir
How to cite this article:
Rajani A K, Ravindra B K, Dkhar S A. Telaprevir: Changing the standard of care of chronic hepatitis C. J Postgrad Med 2013;59:42-7 |
| :: Introduction | |  |
Chronic hepatitis C, caused by hepatitis C virus (HCV), affects 150 million people worldwide. Each year 3 to 4 million new cases are infected with HCV and death occurs in more than 350,000 of those infected. [1] According to recent epidemiological data from the United States (US), HCV is the leading cause of hepatocellular carcinoma (HCC) and the most common indication for liver transplantation. [2],[3] In the US, up to 4.1 million people have evidence of HCV infection. [4] The number of HCV-infected patients in the US is probably as high as five times the number of human immunodeficiency virus (HIV)-infected patients. [5] According to a recent study by Centers for Disease Control and Prevention (CDC), HCV now exceeds HIV as a cause of mortality in the US. [6] Although acute infection with HCV is asymptomatic, progression to chronic infection occurs in up to 80% of the patients and as many as 25% develop cirrhosis. [7],[8] In the long term, hepatocellular carcinoma occurs in 1-3% each year. [2] The projected proportion of the patients developing cirrhosis due to chronic hepatitis C is expected to rise from 25% in 2010 to 45% in 2030. [9]
Six major genotypes of HCV have been described. The most prevalent genotype in North America, South America and Europe is genotype 1. [10] Until recently, standard of care for chronic hepatitis C has been the combination of peg-interferon alpha (PEG-IFN α) and ribavirin (RBV). The duration of treatment is based on HCV genotype: 48 weeks for genotypes 1 and 4, 24 weeks for genotypes 2 and 3. Success of the treatment is measured in terms of sustained virological response (SVR) rates. SVR is defined as undetectable HCV ribonucleic acid (RNA) (<10 international unit/milliliter (IU/ml)) 24 weeks after cessation of treatment. [11] In addition to marked histological improvement, SVR has also been associated with reduced risk of long-term complications. [12],[13],[14] Reappearance of HCV RNA after SVR is also very rare (<1%). [12],[15] Furthermore, a recent study involving more than 16,000 patients with chronic hepatitis C proved the association of SVR with reduced risk of all-cause mortality. [16] Thus despite being a surrogate marker, SVR is considered equivalent of cure. Hence chronic hepatitis C can be considered as one of the very few chronic diseases for which "cure" is a possibility.
With PEG-IFN α and RBV, SVR can be achieved in 70-80% of the patients infected with HCV genotypes 2 or 3. However, those infected with HCV genotype 1 (which constitute the majority of cases) are less amenable to treatment. SVR is achieved in only 40-50% of genotype 1-infected patients despite longer duration of treatment. [17],[18],[19] Moreover, treatment with PEG-IFN α and RBV is poorly tolerated, producing side-effects like bone marrow depression, flu-like symptoms, psychiatric symptoms, autoimmune reactions and hemolytic anemia. [20] Discontinuation due to adverse effects is required in 10% of the patients. Up to 40% of the patients require dose reduction or temporary interruption of PEG-IFN α/RBV. [21] Reduction in the total cumulative dose of PEG-IFN α to less than 60% can further decrease the SVR rates. [22] Hence there is a definite need for newer drugs which offer superior SVR rates and better tolerability profiles. This review will focus on the pharmacology of one such new drug, telaprevir.
| :: Telaprevir | | |
Telaprevir belongs to the group of HCV protease inhibitors (PIs), which are the first direct acting antivirals approved for chronic hepatitis C. It was approved by Food and Drug Administration (FDA) in May 2011. [23] Later, it was approved in Canada, [24] the European Union [25] and Japan [26] also.
| :: Mechanism of Action | | |
Telaprevir is a peptidomimetic inhibitor of the HCV non-structural (NS) 3/4A serine protease. NS3 protease plays an important role in the HCV life-cycle by causing cleavage of HCV polyprotein at the NS3-NS4A and other downstream junctions. [27] In this process, NS4A peptide acts as a cofactor to anchor NS3/4A complex to intracellular membranes and to facilitate complete activation of NS3 protease domain. [28] Additionally, NS3/4A also causes cleavage of IFN-β promoter stimulator-1 (IPS-1), thereby abolishing activation of Type 1 IFNs. [29] Thus inhibiting NS3/4A protease would not only disrupt the viral life-cycle but would also restore the innate immune response.
| :: Pharmacokinetics | | |
As the absorption of telaprevir is enhanced with fatty food, it has to be taken with food containing at least moderate amounts of fat. It undergoes extensive metabolism in the liver, with CYP3A4 playing a major role in its metabolism. Elimination half-life is 4.0 to 4.7 h after a single dose of 750 mg and 9 to 11 h at steady state plasma concentration. Plasma protein binding ranges from 59-76%. It can be safely used without dose adjustments in mild hepatic impairment (Child Pugh A, score 5 to 6), but its use is not recommended in moderate to severe liver dysfunction. No dose modification is warranted in mild, moderate or severe renal disease. Telaprevir is a substrate as well as an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Hence it is subject to significant drug-drug interactions. Co-administration of telaprevir with drugs which are predominantly metabolized by CYP3A4 and have narrow therapeutic index is contraindicated. For example, statins (risk of myopathy); macrolide antibiotics, Class I and III antiarrhythmics, ketoconazole and related antifungals, salmeterol, tacrolimus (risk of QT interval prolongation); cyclosporine A; ergot alkaloids (risk of vasospasm); oral midazolam and triazolam (risk of respiratory depression); etc. The issue of drug interactions becomes particularly important in HCV-HIV co-infection (interactions with antiretrovirals) and in liver transplantation (interactions with immunosuppressants). However, presently telaprevir is not indicated for either of these conditions. Due to inhibition of CYP3A4, plasma levels of cyclosporine, tacrolimus and sirolimus can increase which may require close monitoring of drug levels. In HIV co-infected patients, bi-directional interactions between telaprevir and antiretrovirals are possible. Telaprevir belongs to pregnancy category B. Since RBV is teratogenic and telaprevir cannot be used without RBV, telaprevir also has to be avoided in pregnancy. [23]
| :: Clinical Trials | | |
Two Phase III studies of telaprevir have been reported-namely, ADVANCE [30] (a new direction in HCV care: A study of treatment-naïve hepatitis C patients with telaprevir) in 1088 treatment-naïve patients and REALIZE [31] (re-treatment of patients with telaprevir-based regimen to optimize outcomes) in 663 previously treated patients. In the ADVANCE trial, SVR rates were higher in patients receiving telaprevir for an initial 8 weeks (69%) or 12 weeks (75%); whereas SVR rates in the group receiving PEG-IFN α + RBV for 48 weeks were significantly lower (44%). In more than half of the patients assigned to the telaprevir groups, 24 weeks of total treatment was sufficient to achieve SVR. [30] Furthermore, the ILLUMINATE [32] (illustrating the effects of combination therapy with telaprevir) trial demonstrated that in patients achieving extended rapid virological response (eRVR-undetectable HCV RNA at Week 4 and Week 12), treatment for 24 weeks was non-inferior to treatment for 48 weeks. In addition to higher SVR rates, relapse rates reported in the ADVANCE trial were lower in the telaprevir groups. Importantly, adding telaprevir to PEG-IFN α + RBV (PR) markedly improved the SVR rates in the subgroups of patients with risk factors known to be associated with unfavorable response, such as bridging fibrosis/cirrhosis, diabetes, baseline HCV RNA more than 800,000 IU/ml, older age, etc. [30]
The REALIZE trial recruited prior relapser (HCV RNA became undetectable during treatment, but then reappeared after treatment ended), partial responder (two log decrease in HCV RNA at Week 12 but still HCV RNA positive at Week 24 of therapy) and null responder (failure to decrease HCV RNA by at least two logs after 12 weeks of therapy) patients. The patients were randomized into three arms: (i) telaprevir with PR for 12 weeks followed by PR for a total of 48 weeks (T12PR48); (ii) initial 4 weeks of lead-in phase with PR followed by 12 weeks of telaprevir with PR and then PR for a total of 48 weeks (lead-in T12PR48); (iii) a control group with PR for 48 weeks (PR48). SVR rates in these three arms respectively were 83%, 88%, 24% in relapsers; 59%, 54%, 15% in partial responders; 29%, 33%, 5% in null responders. Overall SVR rates were similar between the first and second arms. Subgroups with high basal viral load and bridging fibrosis/cirrhosis showed higher SVR rates with addition of telaprevir. [31]
In contrast to the ADVANCE and the ILLUMINATE trials, the REALIZE trial did not evaluate response-guided therapy (RGT) for possibility of shorter duration of treatment in previously treated patients. RGT in treatment-experienced patients was evaluated in two Phase II trials, albeit with a small number of patients. Retrospective cross-trial comparison of these Phase II trials and the REALIZE trial showed that in the prior relapser subgroup of patients achieving eRVR, SVR rates were high (>90%) irrespective of total treatment duration of 24 or 48 weeks. The use of RGT in prior relapsers is further supported by the bridging analysis between selected arms of the ADVANCE and the REALIZE trials, showing similar interferon responsiveness (log change in HCV RNA at fourth week in response to PR) in treatment-naïve and treatment-experienced patients. Based on these analyses, RGT was considered to be suitable for prior relapsers but not for prior partial or null responders. [33]
| :: Indications and Dosage Instructions | | |
Telaprevir is approved for treatment of genotype 1 chronic hepatitis C at a dose of 750 mg three times a day orally. Indication is limited to adult patients with HCV mono-infection and compensated liver disease (including cirrhosis). The drug is effective in treatment-naïve as well as previously treated patients (including prior partial responders, null responders and relapsers). It is approved to be always used in combination with PEG-IFN α and RBV for an initial 12 weeks. In treatment-naïve patients and prior relapsers, triple therapy of 12 weeks is followed by response-guided regimen with additional 12 or 36 weeks of PEG-IFN α and RBV. The total duration of 24 weeks is recommended only if HCV RNA is undetectable at Week 4 and Week 12. [23] In case of treatment-naïve patients with cirrhosis, the total duration of 48 weeks is recommended irrespective of undetectable HCV RNA at Week 4 and Week 12 as per the prescribing information for the product available in Europe, [25] while the prescribing information of the products available in the US and Canada mention that this group of patients may benefit from 48 weeks of treatment. [23],[24] For prior partial or null responders, initial 12 weeks of triple therapy is followed by full 36 weeks of PEG-IFN α and RBV. Telaprevir is discontinued if HCV RNA is more than 1000 IU/ml at Week 4 or Week 12. In prior null responder patients with cirrhosis, SVR with triple therapy is achieved only in 14% of subjects compared to 10% with PR. Although the number of patients belonging to this subpopulation were limited in the REALIZE trial, the small additional benefit should be considered in light of the risk of adverse effects associated with triple therapy for these patients. Moreover, null responders are also at higher risk of virological failure and emergence of telaprevir-resistant variants. [23]
| :: Adverse Effects | | |
Major side-effects reported with telaprevir are pruritus, rash, anemia, gastrointestinal side-effects (nausea, diarrhea) and fatigue. Rash and anemia were the most common side-effects leading to discontinuation. Rashes are seen in 56% of the patients and are typically eczematous. They improve upon discontinuation of telaprevir. Anemia is seen in 36% of the patients. [23] However, as per the protocol of the ADVANCE and the REALIZE trials, use of erythropoiesis-stimulating agents (ESAs) was not permitted. [30],[31] Dose of RBV (which is known to cause hemolysis) can be adjusted for management of anemia and this does not compromise the SVR rates. [31],[32] Other side-effects reported are mild to moderate anorectal discomfort, hemorrhoids and dysgeusia. [23]
| :: Comparison with Other Hepatitis C Virus Protease Inhibitors | | |
Boceprevir is another HCV PI approved in the US and Europe. Till date there are no head-to-head trials comparing boceprevir and telaprevir. However, telaprevir differs from boceprevir in certain aspects. Firstly, telaprevir has been evaluated in prior null responder patients. Unlike telaprevir, Phase III trials of boceprevir did not include null responders. The prescribing information of boceprevir in the US and Europe suggests that 48 weeks of therapy might be beneficial in null responders. [34],[35] However, further studies will be required to determine the optimal treatment of null responders with boceprevir. The second difference is in terms of dosage regimens. In contrast to telaprevir, boceprevir is started after an initial four weeks' lead-in phase of PEG-IFN α and RBV, following which boceprevir is added for 24 weeks (treatment-naïve patients) or 32 weeks (partial responders and relapsers) as per response-guided therapy. Treatment for 28 weeks or 36 weeks respectively is considered sufficient only if HCV RNA is negative at both Week 8 and Week 24. For patients with HCV RNA detectable at Week 8 and negative at Week 24, the triple therapy is continued till Week 36 and is further followed by 12 weeks of PEG-IFN α and RBV. The longer duration of therapy has implications concerned with patient compliance. Another issue which might affect the patient compliance is the 'tablet load'. While telaprevir is taken as two tablets (375 mg each) three times a day, boceprevir has to be taken as four capsules (200 mg each) three times a day. Regarding safety, important adverse reactions seen with boceprevir are anemia and neutropenia. Despite the fact that the use of ESAs was permitted in boceprevir trials, dose modification due to anemia was required twice as often in the boceprevir groups compared to the control group. Boceprevir is metabolized primarily by the aldo-keto reductase pathway. No dose adjustments are required even in severe hepatic impairment. [35] Among other HCV PIs currently in the pipeline, some may overcome the limitations of telaprevir. For example, protease inhibitor ABT-450 with ritonavir-boosting can be administered as a once-daily dose. It has shown high response rates in HCV genotype 1 infection with acceptable tolerability. [36] Asunaprevir, which is given once or twice daily, has shown activity against HCV genotypes 1 and 4. [37] Another once-daily PI, TMC435, provides higher SVR rates even in hard-to-treat null responders with an adverse effect profile comparable to placebo. [38] A macrocyclic HCV PI, MK-5172, has demonstrated activity against variants resistant to first-generation PIs as well as against all HCV genotypes. [39]
| :: Telaprevir in Non-1 Hepatitis C Virus Genotypes | | |
Currently telaprevir is not indicated for patients infected with HCV non-1 genotypes. Nevertheless, in vitro studies have demonstrated that telaprevir can inhibit NS3/4A protease of HCV genotype 2a and to a lesser extent genotype 3a also. Activity against genotype 6a is similar to that against genotype 1b, whereas genotypes 4a and 5a are the most resistant ones. [40] A Phase II trial of telaprevir suggests that it can improve the SVR rates in genotype 2-infected patients, but has a limited role in genotype 3 infections. [41]
| :: Telaprevir in Special Populations | | |
In HIV-positive patients co-infected with HCV genotype 1, both anti-HCV and anti-HIV drugs may have suboptimal efficacy at usual doses. According to current recommendations based on available data, anti-HCV treatment can be deferred in HIV co-infected patients with minimal HCV disease. For patients with good prognostic factors, dual regimen without HCV PI can be considered. [42] Preliminary data indicate that triple therapy can achieve higher response rates in HCV-HIV co-infected patients, with similar toxicity profiles as seen in HCV mono-infected patients. One adverse event which was seen more frequently in the telaprevir arm receiving atazanavir/ritonavir-based regimen was hyperbilirubinemia. [43] If triple therapy is planned in co-infected patients, the antiretroviral regimen may be modified. For patients receiving raltegrevir, atazanavir/ritonavir or two nucleoside reverse transcriptase inhibitors (NRTIs); telaprevir can be used at standard doses. Among NRTIs, zidovudine, stavudine and didanosine are to be avoided due to higher incidence of liver-associated side-effects. For patients on efavirenz, telaprevir is recommended at higher doses of 1125 mg three times a day. Co-administration of telaprevir with darunavir/ritonavir, fosamprenavir/ritonavir or lopinavir/ritonavir should be avoided. The guidelines also state that in patients with complex antiretroviral regimen or with documented resistance to some antiretrovirals, telaprevir is preferred to boceprevir due to shorter duration of its triple regimen. [42] Very limited data is available for use of telaprevir in post-transplant patients. A single-centre study showed that telaprevir-based triple regimen can be used in such patients with dose adjustment of tacrolimus and intensive monitoring. Although rapid clearance of HCV can be achieved, the regimen causes severe side-effects. [44]
| :: Pharmacogenomics | | |
Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) near interleukin-28B (IL28B) gene region as a strong predictor of response to PEG-IFN α and RBV. [45],[46],[47] CC genotype at rs12979860 is associated with significantly higher chances of achieving SVR than CT/TT genotypes, with odds ratio being as high as five. [48] Another SNP associated with non-response is rs8099917 (change from T to G). [46],[47] Since Phase III trials of telaprevir had already commenced before the results of these GWAS, the patients in these trials were not stratified as per IL28B genotype. Nevertheless, a post-hoc retrospective analysis was done for rs12979860. As described in previous studies, individuals with CT/TT genotypes had lower SVR rates. However, across all genotypes, SVR rates were higher with telaprevir-containing regimens compared to PEG-IFN α + RBV. [23] With respect to rs8099917, a Japanese study has reported this SNP as a predictive factor of response to telaprevir-containing triple therapy. [49] Another Japanese study also confirmed that SVR rates are significantly higher in patients with favorable IL28B genotypes (TT at rs8099917, CC at rs12979860) for telaprevir regimens. [50] Though both these studies highlighted the importance of IL28B genotype in triple therapy, they were done in a limited number of patients. Still larger prospective studies stratifying the patients according to IL28B genotype are needed to define the strength of association between this genotype and triple therapy. This might also help in selecting appropriate patients eligible for triple therapy as well as in determining the total duration of therapy. [51]
| :: IFN-free Regimens | | |
Although telaprevir has shown robust improvements in SVR rates, it cannot be used as a monotherapy owing to the risk of rapid emergence of resistant strains. [52] PEG-IFN α and RBV are still very much a part of the regimen. Thus patients are exposed to the same side-effects of PEG-IFN α and RBV in addition to those caused by telaprevir. Hence attempts are being made to replace PEG-IFN α and RBV with all direct acting antivirals. Removing IFN α from the regimen will not only avoid the adverse effects of IFN α, but will also make therapy an all-oral regimen; thereby improving compliance. The first such trial (INFORM-1 (interferon-free regimen for the management of HCV)) assessed the combination of HCV PI danoprevir and NS5B polymerase inhibitor mericitabine (RG 7128). [53] The combination was well tolerated with no viral breakthrough seen during four weeks. A recent study evaluating the combination of HCV PI asunaprevir and NS5A inhibitor daclatasvir provided the proof-of-concept that SVR can be achieved with direct acting antivirals alone. [54] Telaprevir is also being tried in combination with non-nucleoside inhibitor of NS5B polymerase VX-222, with or without PEG-IFN α and RBV in the ZENITH study. In an interim analysis, however, dual regimen (telaprevir with VX-222) arms were stopped due to viral breakthrough. [55]
| :: Conclusion | | |
Approval of telaprevir has brought a new hope of improving the cure rates in chronic hepatitis C. Despite being expensive, protease inhibitor-based triple therapy is found to be cost-effective. [56] At a community level, however, lack of strategy to identify all the patients with HCV infection still remains a major hurdle. [57] Telaprevir is currently not approved for non-1 HCV genotypes. Also, certain subgroups of chronic hepatitis C patients are not candidates for telaprevir therapy, like HIV or hepatitis B virus (HBV) co-infection, liver transplant patients, patients with decompensated liver functions, etc. Early data in some of these subpopulations look promising. Future trials will further evaluate the feasibility of using telaprevir in an IFN-free regimen. Nevertheless, newer American [58] as well as European [59] guidelines for management of HCV infection have recommended use of HCV PIs for the treatment of chronic hepatitis C. Thus telaprevir certainly represents the progress being made to fulfill unmet medical needs.
| :: Acknowledgment | | |
We are thankful to Dr. Melvin George for being an inspiration for writing this manuscript as well as providing his valuable inputs in finalizing the manuscript.
| :: References | | |
| 1. | World Health Organization [Internet]. Geneva (CH): The Organization; c2012. Hepatitis C; [about 5 screens]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/. [Last cited on 2012 Aug 22]. 
|
| 2. | El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142:1264-73.
[PUBMED] |
| 3. | Organ procurement and transplantation network and scientific registry of transplant recipients 2010 data report. Am J Transplant 2012;12(Suppl 1):1-156.
|
| 4. | Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705-14.
[PUBMED] |
| 5. | Edlin BR. Perspective: Test and treat this silent killer. Nature 2011;474(7350, Suppl):S18-9.
|
| 6. | Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-8.
[PUBMED] |
| 7. | Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000;132:296-305.
[PUBMED] |
| 8. | Freeman AJ, Dore GJ, Law MG, Thorpe M, Von Overbeck J, Lloyd AR, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001;34:809-16.
[PUBMED] |
| 9. | Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513-21.
[PUBMED] |
| 10. | Sy T, Jamal MM. Epidemiology of hepatitis C virus (HCV) infection. Int J Med Sci 2006;3:41-6.
[PUBMED] |
| 11. | Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association for the study of liver diseases. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2009;49:1335-74.
|
| 12. | Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: A cure and so much more. Clin Infect Dis 2011;52:889-900.
[PUBMED] |
| 13. | Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnù L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: A retrospective study. Hepatology 2007;45:579-87.
|
| 14. | Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677-84.
[PUBMED] |
| 15. | Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-601.
[PUBMED] |
| 16. | Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011;9:509-16.
[PUBMED] |
| 17. | Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55.
[PUBMED] |
| 18. | Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82.
|
| 19. | Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 2001;358:958-65.
[PUBMED] |
| 20. | Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: Efficacy, side effects, and complications. Gut 2006;55:1350-9.
[PUBMED] |
| 21. | Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36(Suppl 1):S237-44.
|
| 22. | Shiffman ML, Ghany MG, Morgan TR, Wright EC, Everson GT, Lindsay KL, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology 2007;132:103-12.
[PUBMED] |
| 23. | Vertex [Internet]. Cambridge (MA): Vertex Pharmaceuticals Incorporated; c2012. [Highlights of Prescribing Information. INCIVEK™ (telaprevir)]; p. 1-24. Available from: http://pi.vrtx.com/files/uspi_telaprevir.pdf. [Revised 2012 Jun; Last cited on 2012 Aug 22].
|
| 24. | Vertex [Internet]. Laval (QC): Vertex Pharmaceuticals (Canada) Incorporated; c2012. [Product Monograph. INCIVEK™ (Telaprevir)]; p. 1-55. Available from: http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf. [Revised 2012 Jun 29; Last cited on 2012 Aug 14].
|
| 25. | European Medicines Agency [Internet]. London (GB): The Agency; c1995-2012. [Summary of Product Characteristics. INCIVO (telaprevir)]; p. 1-54. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf. [Updated 2012 Apr 4; Last cited on 2012 Aug 14].
|
| 26. | Mitsubishi Tanabe Pharma [Internet]. Osaka (JP): Mitsubishi Tanabe Pharma Corp.; c2012. [Press Release. Approval for TELAVIC® 250 mg Tablet]; [p. 1]. Available from: http://www.mt-pharma.co.jp/e/release/nr/2011/pdf/eMTPC110926_TLV.pdf. [Last cited on 2012 May 9].
|
| 27. | Tomei L, Failla C, Santolini E, De Francesco R, La Monica N. NS3 is a serine protease required for processing of hepatitis C virus polyprotein. J Virol 1993;67:4017-26.
[PUBMED] |
| 28. | Brass V, Berke JM, Montserret R, Blum HE, Penin F, Moradpour D. Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex. Proc Natl Acad Sci U S A 2008;105:14545-50.
[PUBMED] |
| 29. | Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, et al. Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A 2006;103:6001-6.
[PUBMED] |
| 30. | Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16.
|
| 31. | Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417-28.
|
| 32. | Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011;365:1014-24.
|
| 33. | Liu J, Jadhav PR, Amur S, Fleischer R, Hammerstrom T, Lewis L, et al. Response guided telaprevir therapy in prior relapsers?: The role of bridging data from treatment-naïve and experienced subjects. Hepatology. Forthcoming 2012. [p. 22]. Available from: http://www.onlinelibrary.wiley.com/doi/10.1002/hep.25764/abstract. [Last cited on 2012 Oct 01].
|
| 34. | European Medicines Agency [Internet]. London (GB): The Agency; c1995-2012. [Summary of Product Characteristics. VICTRELIS (boceprevir)]; p. 1-44. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf. [Updated 2012 Apr 12; Last cited on 2012 Aug 19].
|
| 35. | Merck [Internet]. Whitehouse Station (NJ): Merck and Co., Inc.; c2009-2012. [Highlights of Prescribing Information. VICTRELIS® (boceprevir)]; p. 1-26. Available from: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf. [Revised 2012 Jul; Last cited on 2012 Aug 22].
|
| 36. | Lawitz E, Poordad F, DeJesus E, Kowdley K, Gaultier I, Cohen D, et al. ABT-450/ritonavir (ABT-450/R) combined with pegylated interferon alpha-2a/ribavirin after 3-day monotherapy in genotype 1 (gt1) HCV-infected treatment-naïve subjects: 12-week sustained virologic response (SVR12) and safety results. J Hepatol 2012;56 (Suppl 2):S470.
|
| 37. | Bronowicki JP, Pol S, Thuluvath P, Larrey D, Martorell CT, Rustgi VK, et al. Asunaprevir (ASV; BMS-650032), an NS3 protease inhibitor, in combination with peginterferon and ribavirin in treatment-naïve patients with genotype 1 chronic hepatitis C infection. J Hepatol 2012;56(Suppl 2):S431-2.
|
| 38. | Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: Final SVR24 results of the ASPIRE trial. J Hepatol 2012;56(Suppl 2):S1-2.
|
| 39. | Barnard R, Graham D, Acosta A, Guo Z, Howe J, Ogert R, et al. MK-5172, a next generation HCV NS3/4A protease inhibitor is active against common resistance-associated variants (RAVs) and exhibits cross-genotype activity. NewYork, NY: Paper presented at: 2 nd International Conference on Viral Hepatitis (ICVH); 2012.
|
| 40. | Imhof I, Simmonds P. Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors telaprevir (VX-950) and danoprevir (ITMN-191). Hepatology 2011;53:1090-9.
|
| 41. | Foster GR, Hézode C, Bronowicki JP, Carosi G, Weiland O, Verlinden L, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011;141:881-9.
|
| 42. | AIDSinfo [Internet]. Rockville, MD: Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services (US); HIV/Hepatitis C Virus (HCV) Coinfection | Adult and Adolescent ARV Guidelines; p. J5-J11. Available from: http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/26/hepatitis-c--hcv--hiv-coinfection. [Reviewed 2012 Mar 27; Updated 2012 Mar 27; Last cited on 2012 Aug 20].
|
| 43. | Dieterich D, Soriano V, Sherman K, Girard PM, Rockstroh J, Adiwijaya B, et al. Telaprevir in combination with pegylated interferon-α-2a+RBV in HCV/HIV-co-infected patients: A 24-week treatment interim analysis. Seattle, WA: Paper presented at: 19 th Conference on Retroviruses and Opportunistic Infections (CROI); 2012.
|
| 44. | Mantry P, Hassett MS, Weinstein J, Mubarak A, Madani B, Nazario H, et al. Triple therapy using telaprevir in the treatment of hepatitis C recurrence after liver transplantation: An early single center experience [abstract]. Global Antiviral Journal [Internet] 2011;7(Suppl 1):87-8. Available from: http://www.ihlpress.com/pdf%20files/FinalProgram&Abstract%20Book_HEPDART2011.pdf. [Last cited on 2012 Aug 21]. Koloa, HI: From a paper presented at HEP DART 2011: Frontiers in Drug Development for Antiretroviral Therapies; 2011.
|
| 45. | Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105-9.
|
| 46. | Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100-4.
|
| 47. | Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: A genome-wide association study. Gastroenterology 2010;138:1338-45.
|
| 48. | McCarthy JJ, Li JH, Thompson A, Suchindran S, Lao XQ, Patel K, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010;138:2307-14.
|
| 49. | Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, et al. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis 2011;204:84-93.
|
| 50. | Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010;52:421-9.
|
| 51. | Clark PJ, Thompson AJ, McHutchison JG. Genetic variation in IL28B: Impact on drug development for chronic hepatitis C infection. Clin Pharmacol Ther 2010;88:708-11.
|
| 52. | Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Müh U, Welker M, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007;132:1767-77.
|
| 53. | Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010;376:1467-75.
|
| 54. | Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012;366:216-24.
|
| 55. | Di Bisceglie AM, Nelson DR, Gane E, Alves K, Koziel MJ, De Souza C, et al. VX-222 with TVR alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: ZENITH study interim results. J Hepatol 2011;54(Suppl 1):S540.
|
| 56. | Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: A cost-effectiveness analysis. Ann Intern Med 2012;156:279-90.
|
| 57. | Clark PJ, Muir AJ. Overcoming barriers to care for hepatitis C. N Engl J Med 2012;366:2436-8.
|
| 58. | Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433-44.
|
| 59. | European Association for the Study of the Liver. EASL clinical practice guidelines: Management of hepatitis C virus infection. J Hepatol 2011;55:245-64.
|
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