+Model MEDMAL-3540; No. of Pages 6
ARTICLE IN PRESS Disponible en ligne sur
ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses xxx (2014) xxx–xxx
General review
Treatment of hepatitis C: Perspectives Traitement des hépatites C : perspectives S. Pol ∗ , M. Corouge Université Paris Descartes, AP–HP, Unité d’Hépatologie, Hôpital Cochin, INSERM U-1016, Institut Cochin, Paris, France Received 15 July 2014; received in revised form 15 July 2014; accepted 22 July 2014
Abstract The treatment of hepatitis C virus (HCV) infection has significantly improved in the last 2 decades. The association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR) for nearly 15 years i.e. a viral cure of the infection for 45% of genotype 1-, 65% of genotype 4-, 70% of genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleotide and non-nucleotide inhibitors, NS5A viral replication complex). The combination of first-generation protease inhibitors with PR demonstrated a high antiviral effectiveness (75% of SVR but restricted to genotypes 1) with substantial adverse effects for the first-generation protease inhibitors, which obtained market approval in 2011 (telaprevir and boceprevir), recommendations for use in HCV monoinfected patients in 2012, and in HCV/HIV coinfected in 2013. Then, the combination of second-generation protease inhibitors with PR increased SVR rates from 75 to 90%, while reducing treatment duration, adverse effects, and the number of pills. The next step will be using an interferon and ribavirin-free combination of DAAs; it should become the standard of care in 2015. These excellent results in “easy-to-treat” patients and in small populations in the first studies were confirmed in phase III studies and in “difficult-to-treat” patients (treatment – especially protease inhibitors – previously treated patients, cirrhotic patients, liver and renal transplant patients, HIV coinfected patients, and multi-drug treated patients, at increased risk of drug interaction). The high antiviral potency of these new combinations has changed the definition of “difficult-to-treat patients”. These unique achievements in drug history make any previous publication on hepatitis C treatment obsolete. © 2014 Published by Elsevier Masson SAS. Keywords: Hepatitis C virus; Direct-acting antiviral drugs; Protease inhibitor; Polymerase inhibitor; Replication complex inhibitor
Résumé Le traitement de l’infection chronique par le virus de l’hépatite C (VHC) a singulièrement progressé ces 2 dernières décennies. Depuis 15 ans environ, la combinaison de l’interféron alfa pégylé et de la ribavirine permettait d’obtenir un taux de réponse virologique prolongée, assimilable à une guérison, chez 45 % des patients infectés par un génotype 1, 65 % de ceux infectés par un génotype 4, 70 % des génotypes 3 et environ 85 % des génotypes 2. Une meilleure compréhension du cycle réplicatif du VHC a permis le développement d’antiviraux directs spécifiques du VHC ciblant les protéines virales (la protéase NS3/4A, la polymérase NS5B avec des inhibiteurs nucléosidiques et non nucléosidiques, la protéine multifonctionnelle NS5A du complexe de réplication). La combinaison d’inhibiteurs de première génération en association avec l’interféron pégylé et la ribavirine a montré une efficacité antivirale élevée (75 % de guérison des génotypes 1) avec une tolérance difficile pour les inhibiteurs de protéases de première génération qui ont fait l’objet d’une autorisation de mise sur le marché en 2011 (telaprevir et boceprevir) et de recommandations d’utilisation chez les patients mono-infectés par le VHC en 2012 et chez les co-infectés VIH/VHC en 2013. Puis des combinaisons d’antiviraux directs de deuxième génération avec l’interféron pégylé et la ribavirine ont permis d’augmenter les taux de guérison de 75 à 90 % et de réduire la durée des traitements, les effets secondaires et le nombre de comprimés. La prochaine étape sera la combinaison d’antiviraux directs qui deviendra le standard de traitement en 2015. Ces excellents résultats obtenus chez des patients « faciles à traiter » et en petit nombre ont été confirmés dans les études de phase III et dans les « populations difficiles à traiter » (en échec de traitements antérieurs, notamment des inhibiteurs de protéases,
∗
Corresponding author at: Unité d’Hépatologie, Hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France. E-mail address: [email protected] (S. Pol).
http://dx.doi.org/10.1016/j.medmal.2014.07.015 0399-077X/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 2
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
cirrhotiques, transplantés hépatiques ou rénaux, sujets infectés par le VIH ou chez des patients polymédicamentés avec les risques d’interactions médicamenteuses). Ces progrès uniques dans l’histoire du médicament rendent obsolète tout écrit sur le traitement de l’hépatite C. © 2014 Publi´e par Elsevier Masson SAS. Mots clés : Virus de l’hépatite C ; VHC ; Antiviraux directs ; Inhibiteurs de protéase du VHC ; Inhibiteurs de polymérase du VHC ; Inhibiteurs NS5A
Hepatitis C virus (HCV), an ARN virus, was discovered in 1988, and induces acute hepatitis with spontaneous recovery in 1 out of 3 patients: this high rate of chronicity (70%) accounts for 170 billion patients with chronic HCV infection worldwide [1]. HCV infection is one of the main causes of liver transplantation and hepatocellular carcinoma, at least as documented in industrialized countries, and should increase until 2030 [2,3]. The currently observed genuine therapeutic revolution is unique both because of the speed at which new treatments have been developed (with a constant improvement of their effectiveness and safety) and because of the approval of regulatory agencies to put on the market drugs tested without randomized trials and control groups. This is clearly due to 2 facts: on one hand, HCV infection is the only chronic infection which may be cured and on the other hand, liver has a unique ability to regenerate; fibrosis is continuously remodeled by liver enzymes, allowing its regression in case of moderate or non-necrotic-inflammatory activity. This encourages an extensive screening for a broader access to more effective treatments.
Fig. 1. Natural history of hepatitis C virus infection and when to treat (indicated by arrows). The recommendation to treat chronic hepatitis is usually a “significant” fibrosis as defined by a fibrosis grade greater than 1 by the Metavir scoring system, with usually a significant necrotic-inflammation as defined by an activity stage greater than 1 by the Metavir scoring system. Histoire naturelle de l’infection virale C et moments où traiter (indiqués par une flèche). La recommandation pour traiter l’hépatite chronique est habituellement une fibrose « significative » définie par un score de fibrose par Metavir > 1.
1. Chronic HCV infection: a systemic disease
2. Treatment of hepatitis C virus
HCV infection results in 3 kinds of damage: hepatic, vascular through cryoglobulinemic vasculitis and systemic. Liver injury, mostly immune-mediated, is responsible for chronic hepatitis [4], possibly resulting (in 1 case out of 3) in extensive fibrosis or cirrhosis which promotes the occurrence of hepatocellular carcinoma (HCC) (the transforming capacity of some viral proteins is discussed) (Fig. 1). Cryoglobulinemia is due to HCV lymphotropism, most frequently type II mixed (polyclonal IgG and monoclonal kappa IgM components) in 40% of infected patients. In 5 to 10% of the cases, deposits of antigenHCV antibody complex and rheumatoid factor in medium-sized arteries cause skin (purpura), rheumatologic (polyarthritis), nephrologic (membranoproliferative glomerulonephritis), or neurological (peripheral polyneuropathy) manifestations. There is also a risk of clonal selection with the development of lymphoma (particularly splenic lymphoma with villous lymphocytes) [5]. Finally, other extrahepatic manifestations could be related to chronic inflammation as a consequence of chronic C viral infection (lymphocytic activation as observed in HIV infection): an increased risk of adult-onset diabetes (from 1.5 to 1.8), cardiovascular diseases (from 2.0 to 2.5), cerebrovascular diseases (from 2.5 to 3.0), and also cancer (hepatic and extrahepatic) (Fig. 1). Hepatic and extrahepatic presentations (among which asthenia and psychophysical impact of chronic infection, often the major complaint) are an indication for treatment.
2.1. Why treat the infection? HCV infection is the only chronic viral infection that may be cured: there is no viral reservoir and a sustained virologic response (SVR) corresponds to a viral cure of the infection. Viral RNA becomes and remains undetectable in the liver or in blood mononuclear cells [6]. There is no late relapse without reinfection, even when a strong immunosuppressive therapy is used after chemotherapy or transplantation. The treatment of hepatitis C virus infection has evolved over the last 2 decades, with a 10-fold increase in SVR rates. Beginning in 1997, a weekly subcutaneous injection of pegylated interferon associated with fixed (800 mg per day for genotype 2 or 3) or weight-adjusted (13–15 mg/kg per day for genotype 1 or 4) dosing of ribavirin (Fig. 2) had increased therapeutic effectiveness and allowed to cure the infection in 45%, 85%, 70%, and 65% of respectively genotypes 1, 2, 3, and 4 infected patients [7]. However, many interferon-related adverse events (flulike syndrome, neurocognitive disorders, immunostimulation of asymptomatic preexisting issues – tuberculosis, sarcoidosis, thyroid dysfunction, diabetes, bone marrow hypoplasia, etc.) or to ribavirin (rash, pruritus, cough, skin dryness, anemia, etc.), have limited the feasibility and safety of treatments lasting between 24 (genotype 2 or 3) or 48 (genotype 1, 4, or 5) and up to 72 weeks (genotype 1 infected slow responders).
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
3
carcinomatous related complications of cirrhosis) and significant decrease of HCC incidence (or its relapse), in case of SVR [8]. Hepatic remodeling and regeneration could lead to cirrhosis reversal (only biopsy-proven), and a complete resolution of hepatic disorders [9]. The results of large cohort studies of monoinfected HCV (viremic or not) patients [10] or coinfected HIV-HCV patients [11] with SVR or not, showed a decrease of global, hepatic and extrahepatic (cardiovascular, cerebrovascular, or extrahepatic cancer related) mortality rates in case of SVR. 2.2. A therapeutic revolution
Fig. 2. History of the rate of sustained virologic response corresponding to a complete cure over the last 2 decades (the rates correspond to the treatment of genotype 1). IFN corresponds to interferon and riba to ribavirin; PI are first-generation protease inhibitors (telaprevir or boceprevir and direct-acting antiviral drugs). Histoire des progrès thérapeutiques au cours de l’infection virale C (les chiffres donnés de guérison virologique correspondent au traitement des génotypes 1). IFN correspond à l’interféron, riba à ribavirine et PI aux inhibiteurs de protéases de première génération (telaprevir et boceprevir).
Hepatic and extrahepatic benefits are proven in case of virologic cure: resolution of preexisting asthenia in 2 cases out of 3, normalization of hypertransaminasemia, resolution of hepatic pedicle lymph node involvement and of extrahepatic manifestations (cutaneous, rheumatic, neurological, or renal) related to cryoglobulinemic vasculitis [4]. SVR allows remodeling hepatic fibrosis when there is no hepatic comorbidity (overweight, excessive alcohol consumption). This is best illustrated by the significant decrease of liver related mortality, particularly in case of preexisting cirrhosis (almost total resolution of non
A better understanding of the mechanisms of HCV entry and release (during the 2000s) and the characterization of viral proteins involved in HCV replication [12,13] has led to the development of HCV specific antiviral drugs [14] (Fig. 3). 2.2.1. First stage: first-generation protease inhibitors Protease inhibitors, especially telaprevir and boceprevir, first obtained their market approval in 2011. They showed a higher antiviral effectiveness in genotype 1 infected patients in combination with PR (pegylated interferon alfa and ribavirin): SVR rates of 75% in naive patients, 85% in relapsers, nearly 50% in partial responders, and only 30% in non-responders to prior PR treatment. These results were also obtained with a reduction of treatment duration from 48 to 24 weeks in half of the patients with a rapid virologic response (RVR), i.e. undetectable viral load at week 4, and still undetectable after 12 weeks of treatment [15–20]. The main limitation of these treatments was additional adverse events besides those related to PR: skin effects for telaprevir with serious rashes in 5 to 10% out of the cases [21] and anemia for telaprevir and boceprevir [22–24]. Cost is a
Fig. 3. Specific hepatitis C virus (HCV) viral proteins and cyclophilin (host target) which are involved in HCV replication, and which are the targets of specific inhibitors, including oral antiviral agents in development. Cibles virales spécifiques du virus de l’hépatite C (protéines virales essentielles à la réplication) dont les antiviraux oraux, inhibiteurs spécifiques de ces cibles, sont en cours de développement et la cyclophilline, cible de l’hôte.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 4
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
limitation of treatment, at least in less wealthy countries than Northern Europe or the United States (around 35,000 euros for direct costs only) and the number of pills: 6 for telaprevir and 12 for boceprevir, to be taken every 8 or 12 hours during a high-fat meal, in addition to the 4 or 6 pills of ribavirin. These 2 oral antiviral agents were the first stage of the therapeutic revolution and remained the standard of care for genotype 1 (mainly 1a and 1b) infections in 2013. They were particularly necessary for patients presenting with cirrhosis, extensive fibrosis or intermediate fibrosis, and with hepatic comorbidities (excessive alcohol consumption, overweight) promoting a rapid progression of fibrosis [4]. Progress has been made so rapidly that these triple therapies were no longer recommended as of January 2014, in American or German guidelines; whereas in Italy reimbursement was accepted only in spring 2013, and in Portugal it was accepted only in the first trimester 2014. 2.2.2. French recommendations for the use of first-generation protease inhibitors An expert meeting was held by the French association for the study of the liver (French acronym AFEF) in spring 2011, at the same time as availability of the early access program (French acronym ATU, temporary authorization for use TAU) of first protease inhibitors, to better define the indication of triple therapy with telaprevir or boceprevir. The objective was to provide recommendations for the prescription of these new agents reserved for genotype 1 infections. These recommendations are available on the AFEF website and published in international journals [22]. Briefly, the combination of pegylated interferon, ribavirin, and a protease inhibitor (telaprevir or boceprevir) allowed obtaining viral eradication in 70% of naive patients, 75 to 85% of relapsers, 52 to 57% of partial responders, and 31% of non-responders [16–20,25–27]. The treatment duration could be shortened for some patients, particularly those with RVR and without extensive fibrosis. These “new” treatments were responsible for an increase of adverse effects: anemia, skin effects, and dysgeusia [21–23]. But they should decrease hepatitis C related mortality [8,9,28–31]. One year later, the AFEF and the societies of internal medicine and infectious diseases held an expert meeting similar to the previous one, to define the relevance of recommendations for triple therapy in genotype 1 HCV monoinfected and HCV HIV coinfected patients [32]. The recommendations for coinfected patients were quite similar to those for monoinfected patients, not to mention drug interactions, especially because of interactions between HCV inhibitors and antiretroviral agents [33]. 2.2.3. Data from the ANRS CO20-Cupic cohort (National agency for the research on AIDS and hepatitis) concerning the TAU of first-generation protease inhibitors in previously treated cirrhotic patients The TAU data in cirrhotic patients having failed pegylated bitherapy, and treated by 48 weeks of triple therapy with telaprevir (n = 299) or boceprevir (n = 212) was compiled [34,35]. Viral cure (SVR 12) was obtained with telaprevir in 74.2% of relapsers or patients having experienced a virological breakthrough,
Fig. 4. Recent and planned history of hepatitis C virus treatments. Histoire récente et prévue des progrès thérapeutiques dans le traitement du virus de l’hépatite C.
40.0% of partial responders, and 19.4% of null responders; the rates with boceprevir were respectively 53.9%, 38.3%, and 0% (2-fold higher in genotype 1b than in genotype 1a infected patients). Serious adverse effects were observed in 49.9% of patients: hepatic decompensation or severe infections in 10.4%, and deaths in 2.2% of patients (in multivariate analysis, baseline albuminemia and platelet count were 2 risk factors of death). Briefly, a high rate of viral cure in previously treated patients was obtained in half of cirrhotic patients with triple therapy [35] but common adverse effects, already reported in cirrhotic patients treated with interferon [36]. This real-life observational study changed the indications of triple therapy and it is now clear that cirrhotic patients with predictors of severe adverse effect (albuminemia < 35 g/L and platelet count < 100,000/mm3 ) must not be treated by interferon but should wait for new treatments.
2.3. Second-stage and second-generation specific inhibitors Many other antiviral agents have been developed: nucleotide [37,38] and non-nucleotide [39] NS5B polymerase inhibitors, NS5A viral replication complex inhibitors [40], or secondgeneration protease inhibitors [41,42]. These new antiviral agents were initially used in combination with PR, allowing viral cure in 75 to 95% of patients (Fig. 4). This secondstage in treatment progress was not only characterized by a wide range of new therapeutic alternatives but also by the decrease of treatment duration (12 to 24 weeks) and in pill burden. The real revolution has come from the development of therapeutic strategies combining direct antiviral agents without interferon (and without its adverse effects), or even without PR [43–52]. These oral multiple therapies are better tolerated, have a lower pill burden, and shorter treatment duration from 24 to 12 weeks. Above all, these oral combinations should cure more than 90% of naive patients but also previously treated patients, and even those who did not respond to triple therapy with a first-generation protease inhibitor, pegylated interferon, and ribavirin.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
5
It is currently impossible to summarize all the on-going trials and their effectiveness, but these oral 12–24-week multiple therapies should allow curing all patients in the mid term because:
GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and MSD. Dr M. Corouge has no conflict to disclose.
• they have a pan-genotypic activity; • there is no cross-resistance among the various classes of direct antiviral agents; • new agents (third generation) and even new targets (entry inhibitors, release inhibitors) are being studied.
References
Other antiviral agents (such as cyclophilin inhibitors, antisense RNA) or vaccine therapy should provide answers to unresolved issues such as overcoming an initial non-response to a first-line treatment. The development of these antiviral agents, specific of HCV or of the host, will decrease the role of interferon, including lambda interferon (which has a better hematologic safety than alpha interferon) that will no longer be used. Nevertheless, interferon could still be used as rescue therapy in case of treatment failure after 1 or 2 lines of antiviral agents. Thus, 25 years after its discovery, HCV history seems to end with the promise of a cure for almost all identified patients. However, many challenges remain. The first is HCV testing: France is world champion of HCV management (including for screening since an estimated 60% of infected patients have been diagnosed), but a lot of work must be done worldwide and especially in Southern hemisphere countries, both for testing and access to specific care. The second is improving health care access, limited by many issues that need to be solved. The most vulnerable people, major targets of HCV infection (drug users, people in difficult socio-economic situations, migrants, prisoners) still do not have an easy access to diagnosis or treatment, because of patients themselves, physicians, or health policy. Nevertheless, the development of rapid diagnostic tests and of new treatments with better safety, effectiveness, and an easier formulation will hopefully improve HCV care. The third challenge is economic, treatment is expensive, and we will have to demonstrate that HCV cure is cost-effective by reducing hepatic and extrahepatic morbidity and mortality. The last challenge is prevention: the development of a prophylactic vaccine is crucial but remains difficult due to the high variability of HCV. Thus, if theoretically a complete eradication of HCV infection should be achieved in rich countries [less than 10% of infected patients were treated and cured in the United Kingdom or in the United States, where HCV systematic screening was recommended for baby boomers in 2012 by the Centers for Disease Control and Prevention (CDC)], a lot remains to be done concerning the screening, management, and cure of patients. There are great differences in screening, access to care, or even to treatment worldwide but also within Europe. Disclosure of interest Dr S. Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, MSD, Novartis, Abbvie, Sanofi and
[1] Muhlberger N, Schwarzer R, Lettmeier B, Sroczynski G, Zeuzem S, Siebert U. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality. BMC Public Health 2009;9:34. [2] Omland LH, Krarup H, Jepsen P, Georgsen J, Harritshoj LH, Riisom K, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010;53(1):36–42. [3] Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol 2008;48(1): 148–62. [4] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis C virus infection. J Hepatol 2011;55(2):245–64. [5] Hermine O, Lefrère F, Bronowicki JP, et al. Regression of splenic lymphoma with lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347(2):89–94. [6] Fontaine H, Chaix ML, Lagneau JL, et al. Recovery from chronic hepatitis C in long-term responders to ribavirin plus interferon alfa. Lancet 2000;356:41. [7] Mchutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–93. [8] Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147(10):677–84. [9] Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine F, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008;149(6):399–403. [10] Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012;206(4): 469–77. [11] Berenguer J, Rodríguez E, Miralles P, Von Wichmann MA, López-Aldeguer J, Mallolas J, et al. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and hepatitis C virus. Clin Infect Dis 2012;55(5):728–36. [12] Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5(6):453–63. [13] Buhler S, Bartenschlager R. New targets for antiviral therapy of chronic hepatitis C. Liver Int 2012;32(suppl.):16–9. [14] Yang PL, Gao M, Lin K, Liu Q, Villareal VA. Anti-HCV drugs in the pipeline. Curr Opin Virol 2011;1(6):607–16. [15] Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–50. [16] Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentric phase 2 trial. Lancet 2011;376:705–16. [17] McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–303. [18] 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. [19] Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
[20] 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. [21] Cacoub P, Bourlière M, Lübbe J, Dupin N, Buggish P, Dusheiko G, et al. Dermatological adverse effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 2012;56(2):455–63. [22] Leroy V, Serfaty L, Bourlière M, Bronowicki J-P, Delasalles P, Pariente A, et al. Protease inhibitor-based triple therapy in chronic hepatitis C: guideline by the French association for the study of the Liver. Liver Int 2012;32:1477–92. [23] Poordad F, Lawitz E, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, et al. Effects of ribavirin dose reduction vs. erythropoietin for boceprevir-related anemia in patients with chronic HCV genotype 1 infection—a randomized trial. Gastroenterology 2013;145(5):1035–44, http://dx.doi.org/10.1053/j.gastro.2013.07.051 [e5. Epub 2013 Aug 4]. [24] Pol S. HCV, Ribavirin, and anemia: a new dawn. Gastroenterology 2013;145(5):930–3, http://dx.doi.org/10.1053/j.gastro.2013.09.036 [Epub 2013 Sep 20]. [25] Bruno S, Vierling JM, Esteban R, Nyberg LM, Tanno H, Goodman Z, et al. Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis. J Hepatol 2013;58:479–87. [26] Bronowicki JP, Davis M, Flamm S, Gordon S, Lawitz E, Yoshida E, et al. Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: the PROVIDE study interim results. J Hepatol 2012;56(Suppl. 2):S6. [27] Vierling JM, Zeuzem S, Poordad F, et al. Safety and efficacy of boceprevir/peginterferon/ribavirin (BOC/P/R) combination therapy for chronic HCV G1 patients with compensated cirrhosis: a meta-analysis of five phase 3 clinical trials. J Hepatol 2013;58:S576. [28] Gomez EV, Rodriguez YS, Bertot LC, Gonzalez AT, Perez YM, Soler EA, et al. The natural history of compensated HCV-related cirrhosis: a prospective long-term study. J Hepatol 2013;58:434–44. [29] Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010;32:344–55. [30] Sangiovanni A, Prati GM, Fasani P, Ronchi G, Romeo R, Manini M, et al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 2006;43:1303–10. [31] Bruno S, Zuin M, Crosignani A, Rossi S, Zadra F, Roffi L, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a longterm prospective study. Am J Gastroenterol 2009;104:1147–58. [32] Salmon D, Arvieux C, Bourlière M, Cacoub M, Halfon P, Lacome K, et al. Use of first-generation HCV protease inhibitors in patients coinfected by HIV and HCV genotype 1. Liver Int 2014;34(6):869–89. [33] Hézode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCVcirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013;59(3):434–41, http://dx.doi.org/10.1016/j.jhep.2013.04.035 [Epub 2013 May 10]. [34] Burger D, Back D, Buggish P, Buti M, Craxi A, Foster G, et al. Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 2013;58(4):792–800. [35] Hezode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterol 2014;147(1):132–42. [36] Roomer R, Hansen BE, Janssen HLA, de Knegt RJ. Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. Hepatology 2010;52:1225–31.
[37] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, Demicco M, et al. Sofosbuvir, an NS5 nucleotide polymerase inhibitor, with peginterferon alfa-2a and ribavirin intreatment-naïve patients with hepatitis C genotypes 1, 4, and 6 infection (ATOMIC): an open-label, randomised, multicentre, phase 2 trial. Lancet 2013 [doi:pii: S0140-6736(13)60247-0. 10.1016/S0140-6736(13)60247-0]. [38] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368(20):1878–87. [39] 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, doseescalation trial. Lancet 2010;376:1467–75. [40] Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebocontrolled, dose-finding, phase 2a trial. Lancet Infect Dis 2012: 12671–7. [41] Zeuzem S, Asselah T, Angus PW, Zarski JP, Larrey D, Mullhaupt B, et al. Efficacy of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C. Gastroenterology 2011;141(6):2047–55. [42] Lenz O, Vijgen L, Berke JM, Cummings MD, Fevery B, Peeters M, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol 2013;58(3):445–51, http://dx.doi.org/10.1016/j.jhep.2012.10.028 [Epub 2012]. [43] 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 Eng J Med 2012;366(3):216–24. [44] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor Sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368(1):34–45. [45] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 2013;368(1):45–55. [46] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370(3):211–21, http://dx.doi.org/10.1056/NEJMoa1306218 [16]. [47] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014;370(3):222–32, http://dx.doi.org/10.1056/NEJMoa1306227 [16]. [48] Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973–82. [49] Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Copper C, et al. ABT450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370(21):1983–92. [50] Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Eng J Med 2014;370(20):1889–98. [51] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Eng J Med 2014;370(16):1483–93. [52] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Eng J Med 2014;370(20):1879–88.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
ARTICLE IN PRESS Disponible en ligne sur
ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses xxx (2014) xxx–xxx
General review
Treatment of hepatitis C: Perspectives Traitement des hépatites C : perspectives S. Pol ∗ , M. Corouge Université Paris Descartes, AP–HP, Unité d’Hépatologie, Hôpital Cochin, INSERM U-1016, Institut Cochin, Paris, France Received 15 July 2014; received in revised form 15 July 2014; accepted 22 July 2014
Abstract The treatment of hepatitis C virus (HCV) infection has significantly improved in the last 2 decades. The association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR) for nearly 15 years i.e. a viral cure of the infection for 45% of genotype 1-, 65% of genotype 4-, 70% of genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleotide and non-nucleotide inhibitors, NS5A viral replication complex). The combination of first-generation protease inhibitors with PR demonstrated a high antiviral effectiveness (75% of SVR but restricted to genotypes 1) with substantial adverse effects for the first-generation protease inhibitors, which obtained market approval in 2011 (telaprevir and boceprevir), recommendations for use in HCV monoinfected patients in 2012, and in HCV/HIV coinfected in 2013. Then, the combination of second-generation protease inhibitors with PR increased SVR rates from 75 to 90%, while reducing treatment duration, adverse effects, and the number of pills. The next step will be using an interferon and ribavirin-free combination of DAAs; it should become the standard of care in 2015. These excellent results in “easy-to-treat” patients and in small populations in the first studies were confirmed in phase III studies and in “difficult-to-treat” patients (treatment – especially protease inhibitors – previously treated patients, cirrhotic patients, liver and renal transplant patients, HIV coinfected patients, and multi-drug treated patients, at increased risk of drug interaction). The high antiviral potency of these new combinations has changed the definition of “difficult-to-treat patients”. These unique achievements in drug history make any previous publication on hepatitis C treatment obsolete. © 2014 Published by Elsevier Masson SAS. Keywords: Hepatitis C virus; Direct-acting antiviral drugs; Protease inhibitor; Polymerase inhibitor; Replication complex inhibitor
Résumé Le traitement de l’infection chronique par le virus de l’hépatite C (VHC) a singulièrement progressé ces 2 dernières décennies. Depuis 15 ans environ, la combinaison de l’interféron alfa pégylé et de la ribavirine permettait d’obtenir un taux de réponse virologique prolongée, assimilable à une guérison, chez 45 % des patients infectés par un génotype 1, 65 % de ceux infectés par un génotype 4, 70 % des génotypes 3 et environ 85 % des génotypes 2. Une meilleure compréhension du cycle réplicatif du VHC a permis le développement d’antiviraux directs spécifiques du VHC ciblant les protéines virales (la protéase NS3/4A, la polymérase NS5B avec des inhibiteurs nucléosidiques et non nucléosidiques, la protéine multifonctionnelle NS5A du complexe de réplication). La combinaison d’inhibiteurs de première génération en association avec l’interféron pégylé et la ribavirine a montré une efficacité antivirale élevée (75 % de guérison des génotypes 1) avec une tolérance difficile pour les inhibiteurs de protéases de première génération qui ont fait l’objet d’une autorisation de mise sur le marché en 2011 (telaprevir et boceprevir) et de recommandations d’utilisation chez les patients mono-infectés par le VHC en 2012 et chez les co-infectés VIH/VHC en 2013. Puis des combinaisons d’antiviraux directs de deuxième génération avec l’interféron pégylé et la ribavirine ont permis d’augmenter les taux de guérison de 75 à 90 % et de réduire la durée des traitements, les effets secondaires et le nombre de comprimés. La prochaine étape sera la combinaison d’antiviraux directs qui deviendra le standard de traitement en 2015. Ces excellents résultats obtenus chez des patients « faciles à traiter » et en petit nombre ont été confirmés dans les études de phase III et dans les « populations difficiles à traiter » (en échec de traitements antérieurs, notamment des inhibiteurs de protéases,
∗
Corresponding author at: Unité d’Hépatologie, Hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France. E-mail address: [email protected] (S. Pol).
http://dx.doi.org/10.1016/j.medmal.2014.07.015 0399-077X/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 2
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
cirrhotiques, transplantés hépatiques ou rénaux, sujets infectés par le VIH ou chez des patients polymédicamentés avec les risques d’interactions médicamenteuses). Ces progrès uniques dans l’histoire du médicament rendent obsolète tout écrit sur le traitement de l’hépatite C. © 2014 Publi´e par Elsevier Masson SAS. Mots clés : Virus de l’hépatite C ; VHC ; Antiviraux directs ; Inhibiteurs de protéase du VHC ; Inhibiteurs de polymérase du VHC ; Inhibiteurs NS5A
Hepatitis C virus (HCV), an ARN virus, was discovered in 1988, and induces acute hepatitis with spontaneous recovery in 1 out of 3 patients: this high rate of chronicity (70%) accounts for 170 billion patients with chronic HCV infection worldwide [1]. HCV infection is one of the main causes of liver transplantation and hepatocellular carcinoma, at least as documented in industrialized countries, and should increase until 2030 [2,3]. The currently observed genuine therapeutic revolution is unique both because of the speed at which new treatments have been developed (with a constant improvement of their effectiveness and safety) and because of the approval of regulatory agencies to put on the market drugs tested without randomized trials and control groups. This is clearly due to 2 facts: on one hand, HCV infection is the only chronic infection which may be cured and on the other hand, liver has a unique ability to regenerate; fibrosis is continuously remodeled by liver enzymes, allowing its regression in case of moderate or non-necrotic-inflammatory activity. This encourages an extensive screening for a broader access to more effective treatments.
Fig. 1. Natural history of hepatitis C virus infection and when to treat (indicated by arrows). The recommendation to treat chronic hepatitis is usually a “significant” fibrosis as defined by a fibrosis grade greater than 1 by the Metavir scoring system, with usually a significant necrotic-inflammation as defined by an activity stage greater than 1 by the Metavir scoring system. Histoire naturelle de l’infection virale C et moments où traiter (indiqués par une flèche). La recommandation pour traiter l’hépatite chronique est habituellement une fibrose « significative » définie par un score de fibrose par Metavir > 1.
1. Chronic HCV infection: a systemic disease
2. Treatment of hepatitis C virus
HCV infection results in 3 kinds of damage: hepatic, vascular through cryoglobulinemic vasculitis and systemic. Liver injury, mostly immune-mediated, is responsible for chronic hepatitis [4], possibly resulting (in 1 case out of 3) in extensive fibrosis or cirrhosis which promotes the occurrence of hepatocellular carcinoma (HCC) (the transforming capacity of some viral proteins is discussed) (Fig. 1). Cryoglobulinemia is due to HCV lymphotropism, most frequently type II mixed (polyclonal IgG and monoclonal kappa IgM components) in 40% of infected patients. In 5 to 10% of the cases, deposits of antigenHCV antibody complex and rheumatoid factor in medium-sized arteries cause skin (purpura), rheumatologic (polyarthritis), nephrologic (membranoproliferative glomerulonephritis), or neurological (peripheral polyneuropathy) manifestations. There is also a risk of clonal selection with the development of lymphoma (particularly splenic lymphoma with villous lymphocytes) [5]. Finally, other extrahepatic manifestations could be related to chronic inflammation as a consequence of chronic C viral infection (lymphocytic activation as observed in HIV infection): an increased risk of adult-onset diabetes (from 1.5 to 1.8), cardiovascular diseases (from 2.0 to 2.5), cerebrovascular diseases (from 2.5 to 3.0), and also cancer (hepatic and extrahepatic) (Fig. 1). Hepatic and extrahepatic presentations (among which asthenia and psychophysical impact of chronic infection, often the major complaint) are an indication for treatment.
2.1. Why treat the infection? HCV infection is the only chronic viral infection that may be cured: there is no viral reservoir and a sustained virologic response (SVR) corresponds to a viral cure of the infection. Viral RNA becomes and remains undetectable in the liver or in blood mononuclear cells [6]. There is no late relapse without reinfection, even when a strong immunosuppressive therapy is used after chemotherapy or transplantation. The treatment of hepatitis C virus infection has evolved over the last 2 decades, with a 10-fold increase in SVR rates. Beginning in 1997, a weekly subcutaneous injection of pegylated interferon associated with fixed (800 mg per day for genotype 2 or 3) or weight-adjusted (13–15 mg/kg per day for genotype 1 or 4) dosing of ribavirin (Fig. 2) had increased therapeutic effectiveness and allowed to cure the infection in 45%, 85%, 70%, and 65% of respectively genotypes 1, 2, 3, and 4 infected patients [7]. However, many interferon-related adverse events (flulike syndrome, neurocognitive disorders, immunostimulation of asymptomatic preexisting issues – tuberculosis, sarcoidosis, thyroid dysfunction, diabetes, bone marrow hypoplasia, etc.) or to ribavirin (rash, pruritus, cough, skin dryness, anemia, etc.), have limited the feasibility and safety of treatments lasting between 24 (genotype 2 or 3) or 48 (genotype 1, 4, or 5) and up to 72 weeks (genotype 1 infected slow responders).
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
3
carcinomatous related complications of cirrhosis) and significant decrease of HCC incidence (or its relapse), in case of SVR [8]. Hepatic remodeling and regeneration could lead to cirrhosis reversal (only biopsy-proven), and a complete resolution of hepatic disorders [9]. The results of large cohort studies of monoinfected HCV (viremic or not) patients [10] or coinfected HIV-HCV patients [11] with SVR or not, showed a decrease of global, hepatic and extrahepatic (cardiovascular, cerebrovascular, or extrahepatic cancer related) mortality rates in case of SVR. 2.2. A therapeutic revolution
Fig. 2. History of the rate of sustained virologic response corresponding to a complete cure over the last 2 decades (the rates correspond to the treatment of genotype 1). IFN corresponds to interferon and riba to ribavirin; PI are first-generation protease inhibitors (telaprevir or boceprevir and direct-acting antiviral drugs). Histoire des progrès thérapeutiques au cours de l’infection virale C (les chiffres donnés de guérison virologique correspondent au traitement des génotypes 1). IFN correspond à l’interféron, riba à ribavirine et PI aux inhibiteurs de protéases de première génération (telaprevir et boceprevir).
Hepatic and extrahepatic benefits are proven in case of virologic cure: resolution of preexisting asthenia in 2 cases out of 3, normalization of hypertransaminasemia, resolution of hepatic pedicle lymph node involvement and of extrahepatic manifestations (cutaneous, rheumatic, neurological, or renal) related to cryoglobulinemic vasculitis [4]. SVR allows remodeling hepatic fibrosis when there is no hepatic comorbidity (overweight, excessive alcohol consumption). This is best illustrated by the significant decrease of liver related mortality, particularly in case of preexisting cirrhosis (almost total resolution of non
A better understanding of the mechanisms of HCV entry and release (during the 2000s) and the characterization of viral proteins involved in HCV replication [12,13] has led to the development of HCV specific antiviral drugs [14] (Fig. 3). 2.2.1. First stage: first-generation protease inhibitors Protease inhibitors, especially telaprevir and boceprevir, first obtained their market approval in 2011. They showed a higher antiviral effectiveness in genotype 1 infected patients in combination with PR (pegylated interferon alfa and ribavirin): SVR rates of 75% in naive patients, 85% in relapsers, nearly 50% in partial responders, and only 30% in non-responders to prior PR treatment. These results were also obtained with a reduction of treatment duration from 48 to 24 weeks in half of the patients with a rapid virologic response (RVR), i.e. undetectable viral load at week 4, and still undetectable after 12 weeks of treatment [15–20]. The main limitation of these treatments was additional adverse events besides those related to PR: skin effects for telaprevir with serious rashes in 5 to 10% out of the cases [21] and anemia for telaprevir and boceprevir [22–24]. Cost is a
Fig. 3. Specific hepatitis C virus (HCV) viral proteins and cyclophilin (host target) which are involved in HCV replication, and which are the targets of specific inhibitors, including oral antiviral agents in development. Cibles virales spécifiques du virus de l’hépatite C (protéines virales essentielles à la réplication) dont les antiviraux oraux, inhibiteurs spécifiques de ces cibles, sont en cours de développement et la cyclophilline, cible de l’hôte.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 4
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
limitation of treatment, at least in less wealthy countries than Northern Europe or the United States (around 35,000 euros for direct costs only) and the number of pills: 6 for telaprevir and 12 for boceprevir, to be taken every 8 or 12 hours during a high-fat meal, in addition to the 4 or 6 pills of ribavirin. These 2 oral antiviral agents were the first stage of the therapeutic revolution and remained the standard of care for genotype 1 (mainly 1a and 1b) infections in 2013. They were particularly necessary for patients presenting with cirrhosis, extensive fibrosis or intermediate fibrosis, and with hepatic comorbidities (excessive alcohol consumption, overweight) promoting a rapid progression of fibrosis [4]. Progress has been made so rapidly that these triple therapies were no longer recommended as of January 2014, in American or German guidelines; whereas in Italy reimbursement was accepted only in spring 2013, and in Portugal it was accepted only in the first trimester 2014. 2.2.2. French recommendations for the use of first-generation protease inhibitors An expert meeting was held by the French association for the study of the liver (French acronym AFEF) in spring 2011, at the same time as availability of the early access program (French acronym ATU, temporary authorization for use TAU) of first protease inhibitors, to better define the indication of triple therapy with telaprevir or boceprevir. The objective was to provide recommendations for the prescription of these new agents reserved for genotype 1 infections. These recommendations are available on the AFEF website and published in international journals [22]. Briefly, the combination of pegylated interferon, ribavirin, and a protease inhibitor (telaprevir or boceprevir) allowed obtaining viral eradication in 70% of naive patients, 75 to 85% of relapsers, 52 to 57% of partial responders, and 31% of non-responders [16–20,25–27]. The treatment duration could be shortened for some patients, particularly those with RVR and without extensive fibrosis. These “new” treatments were responsible for an increase of adverse effects: anemia, skin effects, and dysgeusia [21–23]. But they should decrease hepatitis C related mortality [8,9,28–31]. One year later, the AFEF and the societies of internal medicine and infectious diseases held an expert meeting similar to the previous one, to define the relevance of recommendations for triple therapy in genotype 1 HCV monoinfected and HCV HIV coinfected patients [32]. The recommendations for coinfected patients were quite similar to those for monoinfected patients, not to mention drug interactions, especially because of interactions between HCV inhibitors and antiretroviral agents [33]. 2.2.3. Data from the ANRS CO20-Cupic cohort (National agency for the research on AIDS and hepatitis) concerning the TAU of first-generation protease inhibitors in previously treated cirrhotic patients The TAU data in cirrhotic patients having failed pegylated bitherapy, and treated by 48 weeks of triple therapy with telaprevir (n = 299) or boceprevir (n = 212) was compiled [34,35]. Viral cure (SVR 12) was obtained with telaprevir in 74.2% of relapsers or patients having experienced a virological breakthrough,
Fig. 4. Recent and planned history of hepatitis C virus treatments. Histoire récente et prévue des progrès thérapeutiques dans le traitement du virus de l’hépatite C.
40.0% of partial responders, and 19.4% of null responders; the rates with boceprevir were respectively 53.9%, 38.3%, and 0% (2-fold higher in genotype 1b than in genotype 1a infected patients). Serious adverse effects were observed in 49.9% of patients: hepatic decompensation or severe infections in 10.4%, and deaths in 2.2% of patients (in multivariate analysis, baseline albuminemia and platelet count were 2 risk factors of death). Briefly, a high rate of viral cure in previously treated patients was obtained in half of cirrhotic patients with triple therapy [35] but common adverse effects, already reported in cirrhotic patients treated with interferon [36]. This real-life observational study changed the indications of triple therapy and it is now clear that cirrhotic patients with predictors of severe adverse effect (albuminemia < 35 g/L and platelet count < 100,000/mm3 ) must not be treated by interferon but should wait for new treatments.
2.3. Second-stage and second-generation specific inhibitors Many other antiviral agents have been developed: nucleotide [37,38] and non-nucleotide [39] NS5B polymerase inhibitors, NS5A viral replication complex inhibitors [40], or secondgeneration protease inhibitors [41,42]. These new antiviral agents were initially used in combination with PR, allowing viral cure in 75 to 95% of patients (Fig. 4). This secondstage in treatment progress was not only characterized by a wide range of new therapeutic alternatives but also by the decrease of treatment duration (12 to 24 weeks) and in pill burden. The real revolution has come from the development of therapeutic strategies combining direct antiviral agents without interferon (and without its adverse effects), or even without PR [43–52]. These oral multiple therapies are better tolerated, have a lower pill burden, and shorter treatment duration from 24 to 12 weeks. Above all, these oral combinations should cure more than 90% of naive patients but also previously treated patients, and even those who did not respond to triple therapy with a first-generation protease inhibitor, pegylated interferon, and ribavirin.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
5
It is currently impossible to summarize all the on-going trials and their effectiveness, but these oral 12–24-week multiple therapies should allow curing all patients in the mid term because:
GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and MSD. Dr M. Corouge has no conflict to disclose.
• they have a pan-genotypic activity; • there is no cross-resistance among the various classes of direct antiviral agents; • new agents (third generation) and even new targets (entry inhibitors, release inhibitors) are being studied.
References
Other antiviral agents (such as cyclophilin inhibitors, antisense RNA) or vaccine therapy should provide answers to unresolved issues such as overcoming an initial non-response to a first-line treatment. The development of these antiviral agents, specific of HCV or of the host, will decrease the role of interferon, including lambda interferon (which has a better hematologic safety than alpha interferon) that will no longer be used. Nevertheless, interferon could still be used as rescue therapy in case of treatment failure after 1 or 2 lines of antiviral agents. Thus, 25 years after its discovery, HCV history seems to end with the promise of a cure for almost all identified patients. However, many challenges remain. The first is HCV testing: France is world champion of HCV management (including for screening since an estimated 60% of infected patients have been diagnosed), but a lot of work must be done worldwide and especially in Southern hemisphere countries, both for testing and access to specific care. The second is improving health care access, limited by many issues that need to be solved. The most vulnerable people, major targets of HCV infection (drug users, people in difficult socio-economic situations, migrants, prisoners) still do not have an easy access to diagnosis or treatment, because of patients themselves, physicians, or health policy. Nevertheless, the development of rapid diagnostic tests and of new treatments with better safety, effectiveness, and an easier formulation will hopefully improve HCV care. The third challenge is economic, treatment is expensive, and we will have to demonstrate that HCV cure is cost-effective by reducing hepatic and extrahepatic morbidity and mortality. The last challenge is prevention: the development of a prophylactic vaccine is crucial but remains difficult due to the high variability of HCV. Thus, if theoretically a complete eradication of HCV infection should be achieved in rich countries [less than 10% of infected patients were treated and cured in the United Kingdom or in the United States, where HCV systematic screening was recommended for baby boomers in 2012 by the Centers for Disease Control and Prevention (CDC)], a lot remains to be done concerning the screening, management, and cure of patients. There are great differences in screening, access to care, or even to treatment worldwide but also within Europe. Disclosure of interest Dr S. Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, MSD, Novartis, Abbvie, Sanofi and
[1] Muhlberger N, Schwarzer R, Lettmeier B, Sroczynski G, Zeuzem S, Siebert U. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality. BMC Public Health 2009;9:34. [2] Omland LH, Krarup H, Jepsen P, Georgsen J, Harritshoj LH, Riisom K, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010;53(1):36–42. [3] Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol 2008;48(1): 148–62. [4] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis C virus infection. J Hepatol 2011;55(2):245–64. [5] Hermine O, Lefrère F, Bronowicki JP, et al. Regression of splenic lymphoma with lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347(2):89–94. [6] Fontaine H, Chaix ML, Lagneau JL, et al. Recovery from chronic hepatitis C in long-term responders to ribavirin plus interferon alfa. Lancet 2000;356:41. [7] Mchutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–93. [8] Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147(10):677–84. [9] Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine F, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008;149(6):399–403. [10] Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012;206(4): 469–77. [11] Berenguer J, Rodríguez E, Miralles P, Von Wichmann MA, López-Aldeguer J, Mallolas J, et al. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and hepatitis C virus. Clin Infect Dis 2012;55(5):728–36. [12] Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5(6):453–63. [13] Buhler S, Bartenschlager R. New targets for antiviral therapy of chronic hepatitis C. Liver Int 2012;32(suppl.):16–9. [14] Yang PL, Gao M, Lin K, Liu Q, Villareal VA. Anti-HCV drugs in the pipeline. Curr Opin Virol 2011;1(6):607–16. [15] Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–50. [16] Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentric phase 2 trial. Lancet 2011;376:705–16. [17] McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–303. [18] 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. [19] Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
+Model MEDMAL-3540; No. of Pages 6 6
ARTICLE IN PRESS S. Pol, M. Corouge / Médecine et maladies infectieuses xxx (2014) xxx–xxx
[20] 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. [21] Cacoub P, Bourlière M, Lübbe J, Dupin N, Buggish P, Dusheiko G, et al. Dermatological adverse effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 2012;56(2):455–63. [22] Leroy V, Serfaty L, Bourlière M, Bronowicki J-P, Delasalles P, Pariente A, et al. Protease inhibitor-based triple therapy in chronic hepatitis C: guideline by the French association for the study of the Liver. Liver Int 2012;32:1477–92. [23] Poordad F, Lawitz E, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, et al. Effects of ribavirin dose reduction vs. erythropoietin for boceprevir-related anemia in patients with chronic HCV genotype 1 infection—a randomized trial. Gastroenterology 2013;145(5):1035–44, http://dx.doi.org/10.1053/j.gastro.2013.07.051 [e5. Epub 2013 Aug 4]. [24] Pol S. HCV, Ribavirin, and anemia: a new dawn. Gastroenterology 2013;145(5):930–3, http://dx.doi.org/10.1053/j.gastro.2013.09.036 [Epub 2013 Sep 20]. [25] Bruno S, Vierling JM, Esteban R, Nyberg LM, Tanno H, Goodman Z, et al. Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis. J Hepatol 2013;58:479–87. [26] Bronowicki JP, Davis M, Flamm S, Gordon S, Lawitz E, Yoshida E, et al. Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: the PROVIDE study interim results. J Hepatol 2012;56(Suppl. 2):S6. [27] Vierling JM, Zeuzem S, Poordad F, et al. Safety and efficacy of boceprevir/peginterferon/ribavirin (BOC/P/R) combination therapy for chronic HCV G1 patients with compensated cirrhosis: a meta-analysis of five phase 3 clinical trials. J Hepatol 2013;58:S576. [28] Gomez EV, Rodriguez YS, Bertot LC, Gonzalez AT, Perez YM, Soler EA, et al. The natural history of compensated HCV-related cirrhosis: a prospective long-term study. J Hepatol 2013;58:434–44. [29] Alazawi W, Cunningham M, Dearden J, Foster GR. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010;32:344–55. [30] Sangiovanni A, Prati GM, Fasani P, Ronchi G, Romeo R, Manini M, et al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 2006;43:1303–10. [31] Bruno S, Zuin M, Crosignani A, Rossi S, Zadra F, Roffi L, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a longterm prospective study. Am J Gastroenterol 2009;104:1147–58. [32] Salmon D, Arvieux C, Bourlière M, Cacoub M, Halfon P, Lacome K, et al. Use of first-generation HCV protease inhibitors in patients coinfected by HIV and HCV genotype 1. Liver Int 2014;34(6):869–89. [33] Hézode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCVcirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013;59(3):434–41, http://dx.doi.org/10.1016/j.jhep.2013.04.035 [Epub 2013 May 10]. [34] Burger D, Back D, Buggish P, Buti M, Craxi A, Foster G, et al. Clinical management of drug-drug interactions in HCV therapy: challenges and solutions. J Hepatol 2013;58(4):792–800. [35] Hezode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterol 2014;147(1):132–42. [36] Roomer R, Hansen BE, Janssen HLA, de Knegt RJ. Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. Hepatology 2010;52:1225–31.
[37] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, Demicco M, et al. Sofosbuvir, an NS5 nucleotide polymerase inhibitor, with peginterferon alfa-2a and ribavirin intreatment-naïve patients with hepatitis C genotypes 1, 4, and 6 infection (ATOMIC): an open-label, randomised, multicentre, phase 2 trial. Lancet 2013 [doi:pii: S0140-6736(13)60247-0. 10.1016/S0140-6736(13)60247-0]. [38] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368(20):1878–87. [39] 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, doseescalation trial. Lancet 2010;376:1467–75. [40] Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebocontrolled, dose-finding, phase 2a trial. Lancet Infect Dis 2012: 12671–7. [41] Zeuzem S, Asselah T, Angus PW, Zarski JP, Larrey D, Mullhaupt B, et al. Efficacy of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C. Gastroenterology 2011;141(6):2047–55. [42] Lenz O, Vijgen L, Berke JM, Cummings MD, Fevery B, Peeters M, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol 2013;58(3):445–51, http://dx.doi.org/10.1016/j.jhep.2012.10.028 [Epub 2012]. [43] 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 Eng J Med 2012;366(3):216–24. [44] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor Sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368(1):34–45. [45] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med 2013;368(1):45–55. [46] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370(3):211–21, http://dx.doi.org/10.1056/NEJMoa1306218 [16]. [47] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014;370(3):222–32, http://dx.doi.org/10.1056/NEJMoa1306227 [16]. [48] Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973–82. [49] Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Copper C, et al. ABT450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;370(21):1983–92. [50] Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Eng J Med 2014;370(20):1889–98. [51] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Eng J Med 2014;370(16):1483–93. [52] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Eng J Med 2014;370(20):1879–88.
Please cite this article in press as: Pol S, Corouge M. Treatment of hepatitis C: Perspectives. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.07.015
