Submit Paper

Article Processing Fee

Pay Online

           

Crossref logo

  DOI Prefix   10.20431


 

ARC Journal of Hepatology and Gastroenterology
Volume-1 Issue-1, 2016, Page No: 9-16

Hepatitis C Treatment: What to Expect in 2017

Andreia Gi, Ana Miguel Matos, Cristina Luxo

Research Centre on Chemical Processes Engineering and Forest Products (CIEPQF), Faculty of Pharmacy, University of Coimbra, Portugal.

Citation : Andreia G, Ana Miguel M, Cristina L. Hepatitis C Treatment: What to Expect in 2017. ARC Journal of Hepatology and Gastroenterology. 2016;1(1):9–16.

Copyright : © 2016 Andreia G. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract


Hepatitis C virus infection is a substantial health problem on a global scale [1] It is estimated that approximately 185 million people live with hepatitis C worldwide, with 350,000–500,000 patients dying each year from liver disease associated with hepatitis C[2]. However, something is about to change. In the latest years, there has been a shift in treatment paradigm due to the discovery and approval of direct-acting antiviral agents [3]. Nevertheless, these regimens still included ribavirin, which increased side effects, cost, and inconvenience of treatment. Moreover, improved treatment options for patients who did not respond to prior direct-acting antiviral agents (and may have drug-resistant virus) and for hepatitis C virus genotype 3 infection, with or without cirrhosis, were desirable. Thus, three new promising direct-acting antiviral agents were developed to fulfill these significant unmet medical needs [4,5]

In many countries, sustainability has been the buzzword across all stakeholders. Still, direct-acting antiviral agents have demonstrated a favorable cost-effectiveness profile [6] and their exceptional cure rates have already helped establish the concept that chronic hepatitis C virus infection can be cured in most, if not all, affected individuals.

This review summarizes the clinical potential of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir-pibrentasvir, discussing key results and future directions. Its aim is to highlight the significance of a future free from hepatitis C.

Keywords: Hepatitis C Virus, Direct-Acting Antiviral Agents, Sustained Virologic Response, Cure, Difficult-To- Treat Populations

Abbreviations

HCV - Hepatitis C virus
HCC - Hepatocellular carcinoma
SVR - Sustained Virologic Response
IFN - Interferon
RBV - Ribavirin
DAAs - Direct-acting antiviral agents
SOF – Sofosbuvir
VEL – Velpatasvir
VOX - Voxilaprevir

1.Introduction


The Hepatitis C virus (HCV) is a small-enveloped virus of the Flaviridae family and genus Hepacivirus, [7] with a single-stranded positive RNA molecule of approximately 9.6 kb [8]. Prior to the discovery of the viral agent, HCV was mainly transmitted via blood products. Since then, injection drug use has arisen as the major mode of transmission in developed countries [2]

The main problem is that, following exposure to HCV, only a minority of patients clears the acute infection, whereas 80% persist with life-long chronic viremia[9] Chronic HCV infection is a serious, progressive, and potentially life-threatening disease [10,11] If left untreated, over time it can cause liver damage or failure due to the development of cirrhosis. This liver complication can lead patients at substantial risk of decompensated disease and hepatocellular carcinoma (HCC), [12] which impose a considerable burden on affected people, healthcare systems and society [13,14] Early diagnosis could help prevent these consequences, but HCV infection is often undiagnosed because it is usually asymptomatic during decades and so, the majority of HCV-infected individuals are unaware of their infection [15].

The goal of treatment in all infected individuals, regardless of which of the six major genotypes are present, remains the achievement of a sustained virologic response (SVR) in which circulating HCV RNA is undetectable (with the use of a highly sensitive assay) following treatment. When a SVR is achieved, there is a 99% chance that the hepatitis C infection is cured [13,16]. Historically, SVR was defined as HCV RNA levels below a designated threshold of quantification 24 weeks after completion of treatment (SVR24)[17]. However, more recent data shows that viral clearance 12 weeks post-treatment (and sometimes, even 8 weeks) correlates closely to SVR24[18]. Therefore, an undetectable HCV RNA at 12 weeks after treatment (SVR12) is considered an appropriate primary efficacy endpoint [19] and translates into “cure” for nearly all patients[13]


2. Direct-Acting Antiviral Agents Versus Interferon-Based Therapies


The new regimens for HCV mean a breakthrough novelty in the history of anti-HCV treatment. Previous treatments for HCV were often long and difficult. Many lasted from 24 to 48 weeks and showed suboptimal efficacy in viral response with a range of commonly occurring significant side effects, which impaired therapeutic compliance[20]. Nowadays, HCV patients can benefit from a less complex administration schedule and expect interferon (IFN) and even ribavirin (RBV)-free combinations. This results in a reduction of the incidence and severity of adverse events, optimizing quality of life during therapy and improving adherence to direct-acting antiviral agents (DAAs).


3. Sofosbuvir-Velpatasvir


Sofosbuvir-velpatasvir (EPCLUSA®) is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with or without cirrhosis (compensated). In clinical studies, sofosbuvir-velpatasvir (SOF-VEL) had high overall cure rates. (Table 1) The most common side effects were headache and tiredness [21].




4. Sofosbuvir-Velpatasvir-Voxilaprevir


Four Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluated a once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1,2,3,4,5 and 6 chronic HCV infection. (Table 3)

The most common adverse events among patients who received SOF-VEL-VOX were headache, fatigue, diarrhea and nausea. The overall incidence of adverse events was similar to placebo or SOF- VEL. Among the 1,056 patients who received SOF-VEL-VOX in the four studies, only a patient receiving SOF-VEL-VOX for 12 weeks discontinued due to an adverse event[26]. These results show that this new three-drug co-formulation with different mechanisms of action and high barrier to resistance can provide high cure rates for patients who had previously failed treatment with other DAAs.


  

5. Glecaprevir-Pibrentasvir


Glecaprevir-pibrentasvir is an investigational, pan-genotypic regimen that is being evaluated (table 4) not only as a potential cure in 8 weeks for HCV patients without cirrhosis and who are new to treatment, but also in patients with specific treatment challenges, such as genotype 3, patients who were not cured with previous DAA treatment and those with chronic kidney disease, including patients on dialysis.

This investigational, pan-genotypic regimen of glecaprevir-pibrentasvir is showing to be well tolerated with a favorable safety profile in these difficult-to-treat populations. The most commonly reported adverse events included fatigue and nausea.




6. Discussion


Although the post-marketing phase always requires a careful evaluation of data from the “everyday” clinical practice experience, clinical trials have showed that these new DAA combinations have resolved most issues related to HCV treatment compared with the past regimens. Despite the approval of the first DAAs which have provided high cure rates and simplified treatment for most HCV patients, HCV genotype 3-infected patients with cirrhosis, patients with chronic kidney disease and those who have failed previous treatment with DAAs continued to represent an unmet medical need. In the era of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir- pibrentasvir, DAA therapy provides a new way to manage these difficult-to-treat HCV-infected patients, who are at a high risk of serious conditions[30]. They are now contemplated and are therefore expected to have a much better prognosis than they have had until very recently. Perhaps, soon, we may no longer have difficult-to-treat populations.

The advent of new generation oral antiviral therapy has led to major improvements in efficacy and tolerability but has also resulted in an explosion of data with increased treatment choice complexity [31].

Thus, clinicians need more detailed, accurate and timely information in order to choose the right regimen for individual patients and educate them. When they counsel and guide their patients, these ones are less likely to be anxious or resistant about taking steps toward possible cure. However, cure does not prevent reinfection and so, it is crucial to advise patients on measures that will reduce their risk (avoid alcohol intake and sexual and injection risk behaviors, eat a balanced diet and take exercise are some examples).


7. Conclusion


DAAs have shown that it is possible to minimize the spread of HCV and the morbidity and mortality associated with HCV infection[32].

Despite the financial controversy around their high costs, which have served as a major barrier for more widespread use, many stakeholders recognize now their long-term cost-benefits and the advantages of a future free from hepatitis C are manifest.

It is true that patients undergoing treatment need systematic monitoring before, during and after therapy, but these new treatment options have offered them hope and re-awakening. It is a clear evolution compared with the previous IFN-based therapies.


8. Future Directions


At a future time, treatment failure and resistance can occur and become a clinical challenge to be solved[30,33].

However, before them, there are already some questions that should concern us. First one is why is the association of RBV with DAAs, in some cases, increasing the SVR12 rate and shortening the duration of treatment? Then, at what point is it no longer worth treating a patient? Will we have the financial capacity to treat reinfected-patients? Will this simplicity of therapeutic regimen encourage risk behaviors in the future?


References


  1. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. European Association for the Study of the Liver. 2014;61(1):45–57.
  2. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis c infection. 2016.
  3. McConachie SM, Wilhelm SM, Kale-Pradhan PB. New direct-acting antivirals in hepatitis C therapy: a review of sofosbuvir, ledipasvir, daclatasvir, simeprevir, paritaprevir, ombitasvir and dasabuvir. Expert Rev ClinPharmacol. 2016;9(2):287–302.
  4. Li H-C, Lo S-Y. Hepatitis C virus: Virology, diagnosis and treatment. World J Hepatol.2015;7(10):1377–89.
  5. Chevaliez S, Pawlotsky J-M. HCV Genome and Life Cycle. Hepat C Viruses Genomes Mol Biol. 2006.
  6. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016.Journal of Hepatology. 2016.
  7. Summers BB, Beavers JWF, Klibanov OM. Sofosbuvir, a novel nucleotide analogue inhibitor used for the treatment of hepatitis C virus. J Pharm Pharmacol. 2014;66(12):1653–66.
  8. Kayali Z, Schmidt WN. Finally sofosbuvir: An oral anti-HCV drug with wide performance capability. PharmgenomicsPers Med. 2014;7:387–97.
  9. Gentile I, Maraolo AE, Buonomo AR, Zappulo E, Borgia G. The discovery of sofosbuvir: a revolution for therapy of chronic hepatitis C. Expert Opin Drug Discov. 2015;10(12):1363–77.
  10. Lawitz E, Jacobson IM, Nelson DR, Zeuzem S, Sulkowski MS, Esteban R, et al. Development of sofosbuvir for the treatment of hepatitis C virus infection. Ann N Y Acad Sci. 2015;1358(1):56–67.
  11. Gentile I, Coppola N, Pasquale G, Liuzzi R, D’Armiento M, Di Lorenzo ME, et al. A simple noninvasive score based on routine parameters can predict liver cirrhosis in patients with chronic Hepatitis C. Hepat Mon. 2013;13(5):1–8.
  12. Sadler MD, Lee SS. Revolution in hepatitis C antiviral therapy. Br Med Bull. 2015;113(1):31– 44.
  13. Dugum M, O’Shea R. Hepatitis C virus: Here comes all-oral treatment. Cleve Clin J Med.2014;81(3):159–72.
  14. Gordon SC, Yoshida EM, Lawitz EJ, Bacon BR, Sulkowski MS, Davis M, et al. Adherence to assigned dosing regimen and sustained virological response among chronic hepatitis C genotype 1 patients treated with boceprevir plus peginterferon alfa-2b/ribavirin. Aliment PharmacolTher. 2013;38(1):16–27.
  15. American Association for the Study of Liver Diseases. Recommendations for Testing, Managing, and Treating Hepatitis C. 2016.
  16. Strahotin CS, Babich M. Hepatitis C variability, patterns of resistance, and impact on therapy.AdvVirol. 2012;2012:1–10.
  17. Hagan LM, Schinazi RF. Best strategies for global HCV eradication. Liver Int. 2013;33(0 1):68–79.
  18. Yoshida EM, Sulkowski MS, Gane EJ, Herring RW, Ratziu V, Ding X, et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology. 2015;61(1):41–5.
  19. Kluck J, Flynn RMO, Kaplan DE, Chang K. Evaluation of the Significance of Pretreatment Liver Biopsy and Baseline Mental Health Disorder Diagnosis on Affairs Medical Center. Hepat Res Treat. 2013;2013:1–6.
  20. Schaefer EAK, Chung RT. Anti-hepatitis C virus drugs in development. Gastroenterology.Elsevier Inc. 2012;142(6):1340–50.
  21. European Medicines Agency. Epclusa summary of product characteristics. 2016.
  22. Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373(27):2599–607.
  23. Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015;373(27):2608–17.
  24. Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373(27):2618–28.
  25. Wyles D, Brau N, KottililS etal.Sofosbuvir/velpatasvir fixed dose combination for 12 weeks in patients co-infected with HCV and HIV-1: the phase 3 ASTRAL-5 study. 51st Annual Meeting of the European Association for the Study of the Liver, Barcelona. 2016.
  26. Gilead Sciences, Inc. SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naïve and Treatment- Experienced Genotype 1-6 Chronic HCV-Infected Patients. 2016.
  27. Abbvie. Eight Weeks of Treatment with AbbVie's Investigational, Pan-Genotypic Regimen of Glecaprevir/Pibrentasvir (G/P) Achieved High SVR Rates Across All Major Genotypes of Chronic Hepatitis C. 2016.
  28. AASLD The Liver Meeting Boston MA. SURVEYOR-II, PART 3: Efficacy and Safety of Glecaprevir/Pibrentasvir (Abt-493/Abt-530) in Patients with Hepatitis C Virus Genotype 3 Infection with Prior Treatment Experience and/or Cirrhosis. 2016
  29. AASLD The Liver Meeting Boston MA.EXPEDITION-4: Efficacy and Safety of Glecaprevir/Pibrentasvir (Abt-493/Abt-530) in Patients with Renal Impairment and Chronic Hepatitis C Virus Genotype 1 - 6 Infection. 2016.
  30. Benítez-Gutiérrez L, Barreiro P, Labarga P, de Mendoza C, Fernandez-Montero J V, Arias A, et al. Prevention and management of treatment failure to new oral hepatitis C drugs. Expert Opin Pharmacother. Taylor & Francis. 2016;17(9):1215–23.
  31. Zhang, Johnathan; Nguyen, Douglas; Hu K-Q. Chronic Hepatitis C Virus Infection: A Review of Current DirectActing Antiviral Treatment Strategies. N Am J Med Sci (Boston). 2016;9(2):47–54.
  32. McQuaid T, Savini C, Seyedkazemi S. Sofosbuvir, a Significant Paradigm Change in HCV Treatment. J Clin Transl Hepatol. 2015;3(1):27–35.
  33. Esposito I, Trinks J, Soriano V. Hepatitis C virus resistance to the new direct-acting antivirals.Expert Opin Drug Metab Toxicol. Taylor & Francis. 2016;12(10):1197–209.