G Model
ARTICLE IN PRESS
ANTAGE-4399; No. of Pages 2
International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Discussion
Is hepatitis C virus eradication around the corner only 25 years after its discovery? Giuseppe Ippolito a , Maria Rosaria Capobianchi a , Simone Lanini a , Guido Antonelli b,∗ a b
National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, Via Portuense 292, 00149 Rome, Italy Department of Molecular Medicine, ‘Sapienza’ University, Viale di Porta Tiburtina 28, 00185 Rome, Italy
a r t i c l e
i n f o
Article history: Received 1 August 2014 Accepted 4 August 2014 Keywords: Hepatitis C virus HCV Antiviral therapy
a b s t r a c t Hepatitis C virus (HCV), identified approximately 25 years ago, is recognised as the cause of several clinical conditions besides chronic hepatitis. New compounds with direct antiviral activity have recently been introduced. These drugs promise to outdo old therapies based on interferon and ribavirin both in terms of improved safety and virological response. In fact, these drugs may pave the way to complete eradication of the disease. However, their actual price is exceedingly high and a strategy is necessary to guarantee wide and sustainable access to new therapies. © 2014 Published by Elsevier B.V.
Hepatitis C virus (HCV), identified approximately 25 years ago [1], is now recognised as the cause of different clinical conditions besides chronic hepatitis [2,3]. Until recently, anti-HCV therapy consisted of a combination of interferon and ribavirin, which achieves a global success rate of ca. 50%. These compounds, whose action is mainly mediated by indirect antiviral mechanisms, have significant collateral effects and several contraindications [4]. This scenario has been suddenly transformed by the recent introduction of new compounds directly inhibiting viral replication, known as direct-acting antivirals (DAAs), which exhibit outstanding efficacy (80–100% sustained response) and improved safety profiles [5]. Besides excellent clinical performance, DAAs promise to pave the way to an ambitious public health programme as, with their introduction, all three indicators of eradicability have been met for HCV, i.e. effective interventions, practical diagnostic tools, and essential need for humans in the life-cycle of the agent [6]. Nevertheless, infection eradication (permanent absence of incident cases worldwide) and infection extinction (elimination of all prevalent cases worldwide) are complex tasks that will necessarily need international co-ordination to provide full and global access to drugs. Although desirable, this goal will be hardly achieved in the imminent future owing to the high cost and significant
∗ Corresponding author. E-mail address: [email protected] (G. Antonelli).
differences in national healthcare systems. Reduction to zero of the incidence of HCV in settings with high healthcare standards may represent a feasible long-term objective in countries with adequate resources and healthcare strategies. However, the availability of highly active antivirals, although being a prerequisite, is not sufficient, by itself, for elimination programmes. In fact, these programmes also include intervention for primary prevention, reduction of nosocomial/occupational risks, and definition of a model to address special groups that currently sustain HCV transmission, such as drug users [7], convicts [8] and recipients of frequent invasive procedures [9]. Identification of special groups at the greatest need of prioritisation for DAAs, such as transplant recipients [10] and human immunodeficiency virus (HIV) co-infected subjects [11], is also relevant for the issue of sustainability of care delivery. In fact, unrestricted DAA access would create a financial burden that might be unsustainable for national healthcare systems providing free universal access to care. The increasing cost of patient management owing to the high market price of DAAs has ignited a vibrant debate on affordability and prioritisation issues versus ethical obligation to treat. Indeed, the treatment costs are expected to further increase with association of different DAA classes; nevertheless, companies are expected to be reluctant to cut their profit. There are concerns that, even in industrialised countries such as in the European Union (EU) and the USA, new drugs will be limited only to the sickest patients with endstage hepatitis. Likely, local national healthcare systems’ structure will significantly influence policies for access to care. In fact, these
http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001 0924-8579/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Ippolito G, et al. Is hepatitis C virus eradication around the corner only 25 years after its discovery? Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001
G Model ANTAGE-4399; No. of Pages 2 2
ARTICLE IN PRESS G. Ippolito et al. / International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
diverse attitudes are already mirrored by guidelines produced in different settings. Settings where national healthcare systems are mainly privately funded are on one extreme. In the USA, scientific societies have endorsed a network of excellence aimed at implementing an innovative system to produce ‘living guidelines’, able to ‘provide recommendations based on evidence and rapidly updated’. These recommendations reflect the best possible management of any individual subject, but pay little attention to sustainability issues [12]. On the other hand, national healthcare systems in the EU, mainly oriented to free and universal access to care, have delayed DAA implementation. For example, earlier DAAs (telaprevir and boceprevir) have been authorised 12 months later than in the USA. As well, similar delay has been reported for sofosbuvir, the only NS5B inhibitor, and as jet the most versatile drug, currently authorized for clinical use [12,13]. European Association for the Study of the Liver guidelines reflects this approach: it acknowledges that all patients willing to be treated should be considered for therapy, but also states that therapy can be delayed until moderate liver disease is present [13]. The World Health Organization guidance document reflects a further different approach, oriented to promote access to the best ‘possible’ therapy. This document, rather than providing guidance on which drug combination should (or should not) be used, proposes a compelling revision that compares potential advantages and disadvantages of different protocols [14]. On top of these issues, until now the debate has addressed mainly the market price of the drugs, which represents only a component of the overall cost. Yet the outstanding efficacy of DAA combinations will translate into shorter treatment and fewer additional medications, hospital visits and liver decompensation events. Hence, the cost of a treatment course cannot be simply calculated with reference to percentage of retail mark-up, or to the cost of the prior standard of care, without considering global patient management costs. In conclusion, DAAs can render HCV elimination an affordable (long-term) goal. However, outstanding issues remain, such as: (a) availability of effective antivirals does not directly translate into elimination/eradication; (b) DAA cost may be troublesome for national healthcare systems also in industrialised settings; and (c) special groups with enhanced risk of progression need rapid access to new drugs.
Prioritisation frameworks may be a short-term strategy for improving disease control and providing rapid access to DAAs to all subjects who urgently need therapy. Funding: This study has been funded by independent research grant from the Italian Ministry of Health – Ricerca Corrente INMI Lazzaro Spallanzani. Competing interests: None declared. Ethical approval: Not required.
References [1] Houghton M. The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 2009;51:939–48. [2] Ali A, Zein NN. Hepatitis C infection: a systemic disease with extrahepatic manifestations. Cleve Clin J Med 2005;72, 1005–8, 1010–4, 1016. [3] Samuel DG, Rees IW. Extrahepatic manifestations of hepatitis C virus (HCV). Frontline Gastroenterol 2013;4:249–54. ˇ [4] Hauser G, Awad T, Brok J, Thorlund K, Stimac D, Mabrouk M, et al. Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C. Cochrane Database Syst Rev 2014;2:CD005441. [5] Ippolito G, Antonelli G, Capobianchi MR, Lanini S. HCV treatment revolution: needs for close monitoring. Clin Microbiol Infect 2014, http://dx.doi.org/10.1111/1469-0691.12693. May 28 [Epub ahead of print]. [6] Dowdle WR. The principles of disease elimination and eradication. Bull World Health Organ 1998;76(Suppl. 2):22–5. [7] Valdiserri R, Khalsa J, Dan C, Holmberg S, Zibbell J, Holtzman D, et al. Confronting the emerging epidemic of HCV infection among young injection drug users. Am J Public Health 2014;104:816–21. [8] Boutwell AE, Allen SA, Rich JD. Opportunities to address the hepatitis C epidemic in the correctional setting. Clin Infect Dis 2005;40(Suppl. 5):S367–72. [9] Lanini S, Abbate I, Puro V, Soscia F, Albertoni F, Battisti W, et al. Molecular epidemiology of a hepatitis C virus epidemic in a haemodialysis unit: outbreak investigation and infection outcome. BMC Infect Dis 2010;10:257. [10] Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2014;16:1–16. [11] Antonucci G, Goletti D, Lanini S, Girardi E, Loiacono O. HIV/HCV co-infection: putting the pieces of the puzzle together. Cell Death Differ 2003;10(Suppl. 1):S25–6. [12] American Association for the Study of the Liver Diseases (AASLD); Infectious Diseases Society of America (IDSA). Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ [accessed 18.06.14]. [13] European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2014. http://www.easl.eu/ newsroom/ latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014 [accessed 18.06.14]. [14] World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. WHO; April 2014. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ [accessed 18.06.14].
Please cite this article in press as: Ippolito G, et al. Is hepatitis C virus eradication around the corner only 25 years after its discovery? Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001
ARTICLE IN PRESS
ANTAGE-4399; No. of Pages 2
International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Discussion
Is hepatitis C virus eradication around the corner only 25 years after its discovery? Giuseppe Ippolito a , Maria Rosaria Capobianchi a , Simone Lanini a , Guido Antonelli b,∗ a b
National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, Via Portuense 292, 00149 Rome, Italy Department of Molecular Medicine, ‘Sapienza’ University, Viale di Porta Tiburtina 28, 00185 Rome, Italy
a r t i c l e
i n f o
Article history: Received 1 August 2014 Accepted 4 August 2014 Keywords: Hepatitis C virus HCV Antiviral therapy
a b s t r a c t Hepatitis C virus (HCV), identified approximately 25 years ago, is recognised as the cause of several clinical conditions besides chronic hepatitis. New compounds with direct antiviral activity have recently been introduced. These drugs promise to outdo old therapies based on interferon and ribavirin both in terms of improved safety and virological response. In fact, these drugs may pave the way to complete eradication of the disease. However, their actual price is exceedingly high and a strategy is necessary to guarantee wide and sustainable access to new therapies. © 2014 Published by Elsevier B.V.
Hepatitis C virus (HCV), identified approximately 25 years ago [1], is now recognised as the cause of different clinical conditions besides chronic hepatitis [2,3]. Until recently, anti-HCV therapy consisted of a combination of interferon and ribavirin, which achieves a global success rate of ca. 50%. These compounds, whose action is mainly mediated by indirect antiviral mechanisms, have significant collateral effects and several contraindications [4]. This scenario has been suddenly transformed by the recent introduction of new compounds directly inhibiting viral replication, known as direct-acting antivirals (DAAs), which exhibit outstanding efficacy (80–100% sustained response) and improved safety profiles [5]. Besides excellent clinical performance, DAAs promise to pave the way to an ambitious public health programme as, with their introduction, all three indicators of eradicability have been met for HCV, i.e. effective interventions, practical diagnostic tools, and essential need for humans in the life-cycle of the agent [6]. Nevertheless, infection eradication (permanent absence of incident cases worldwide) and infection extinction (elimination of all prevalent cases worldwide) are complex tasks that will necessarily need international co-ordination to provide full and global access to drugs. Although desirable, this goal will be hardly achieved in the imminent future owing to the high cost and significant
∗ Corresponding author. E-mail address: [email protected] (G. Antonelli).
differences in national healthcare systems. Reduction to zero of the incidence of HCV in settings with high healthcare standards may represent a feasible long-term objective in countries with adequate resources and healthcare strategies. However, the availability of highly active antivirals, although being a prerequisite, is not sufficient, by itself, for elimination programmes. In fact, these programmes also include intervention for primary prevention, reduction of nosocomial/occupational risks, and definition of a model to address special groups that currently sustain HCV transmission, such as drug users [7], convicts [8] and recipients of frequent invasive procedures [9]. Identification of special groups at the greatest need of prioritisation for DAAs, such as transplant recipients [10] and human immunodeficiency virus (HIV) co-infected subjects [11], is also relevant for the issue of sustainability of care delivery. In fact, unrestricted DAA access would create a financial burden that might be unsustainable for national healthcare systems providing free universal access to care. The increasing cost of patient management owing to the high market price of DAAs has ignited a vibrant debate on affordability and prioritisation issues versus ethical obligation to treat. Indeed, the treatment costs are expected to further increase with association of different DAA classes; nevertheless, companies are expected to be reluctant to cut their profit. There are concerns that, even in industrialised countries such as in the European Union (EU) and the USA, new drugs will be limited only to the sickest patients with endstage hepatitis. Likely, local national healthcare systems’ structure will significantly influence policies for access to care. In fact, these
http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001 0924-8579/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Ippolito G, et al. Is hepatitis C virus eradication around the corner only 25 years after its discovery? Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001
G Model ANTAGE-4399; No. of Pages 2 2
ARTICLE IN PRESS G. Ippolito et al. / International Journal of Antimicrobial Agents xxx (2014) xxx–xxx
diverse attitudes are already mirrored by guidelines produced in different settings. Settings where national healthcare systems are mainly privately funded are on one extreme. In the USA, scientific societies have endorsed a network of excellence aimed at implementing an innovative system to produce ‘living guidelines’, able to ‘provide recommendations based on evidence and rapidly updated’. These recommendations reflect the best possible management of any individual subject, but pay little attention to sustainability issues [12]. On the other hand, national healthcare systems in the EU, mainly oriented to free and universal access to care, have delayed DAA implementation. For example, earlier DAAs (telaprevir and boceprevir) have been authorised 12 months later than in the USA. As well, similar delay has been reported for sofosbuvir, the only NS5B inhibitor, and as jet the most versatile drug, currently authorized for clinical use [12,13]. European Association for the Study of the Liver guidelines reflects this approach: it acknowledges that all patients willing to be treated should be considered for therapy, but also states that therapy can be delayed until moderate liver disease is present [13]. The World Health Organization guidance document reflects a further different approach, oriented to promote access to the best ‘possible’ therapy. This document, rather than providing guidance on which drug combination should (or should not) be used, proposes a compelling revision that compares potential advantages and disadvantages of different protocols [14]. On top of these issues, until now the debate has addressed mainly the market price of the drugs, which represents only a component of the overall cost. Yet the outstanding efficacy of DAA combinations will translate into shorter treatment and fewer additional medications, hospital visits and liver decompensation events. Hence, the cost of a treatment course cannot be simply calculated with reference to percentage of retail mark-up, or to the cost of the prior standard of care, without considering global patient management costs. In conclusion, DAAs can render HCV elimination an affordable (long-term) goal. However, outstanding issues remain, such as: (a) availability of effective antivirals does not directly translate into elimination/eradication; (b) DAA cost may be troublesome for national healthcare systems also in industrialised settings; and (c) special groups with enhanced risk of progression need rapid access to new drugs.
Prioritisation frameworks may be a short-term strategy for improving disease control and providing rapid access to DAAs to all subjects who urgently need therapy. Funding: This study has been funded by independent research grant from the Italian Ministry of Health – Ricerca Corrente INMI Lazzaro Spallanzani. Competing interests: None declared. Ethical approval: Not required.
References [1] Houghton M. The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 2009;51:939–48. [2] Ali A, Zein NN. Hepatitis C infection: a systemic disease with extrahepatic manifestations. Cleve Clin J Med 2005;72, 1005–8, 1010–4, 1016. [3] Samuel DG, Rees IW. Extrahepatic manifestations of hepatitis C virus (HCV). Frontline Gastroenterol 2013;4:249–54. ˇ [4] Hauser G, Awad T, Brok J, Thorlund K, Stimac D, Mabrouk M, et al. Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C. Cochrane Database Syst Rev 2014;2:CD005441. [5] Ippolito G, Antonelli G, Capobianchi MR, Lanini S. HCV treatment revolution: needs for close monitoring. Clin Microbiol Infect 2014, http://dx.doi.org/10.1111/1469-0691.12693. May 28 [Epub ahead of print]. [6] Dowdle WR. The principles of disease elimination and eradication. Bull World Health Organ 1998;76(Suppl. 2):22–5. [7] Valdiserri R, Khalsa J, Dan C, Holmberg S, Zibbell J, Holtzman D, et al. Confronting the emerging epidemic of HCV infection among young injection drug users. Am J Public Health 2014;104:816–21. [8] Boutwell AE, Allen SA, Rich JD. Opportunities to address the hepatitis C epidemic in the correctional setting. Clin Infect Dis 2005;40(Suppl. 5):S367–72. [9] Lanini S, Abbate I, Puro V, Soscia F, Albertoni F, Battisti W, et al. Molecular epidemiology of a hepatitis C virus epidemic in a haemodialysis unit: outbreak investigation and infection outcome. BMC Infect Dis 2010;10:257. [10] Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2014;16:1–16. [11] Antonucci G, Goletti D, Lanini S, Girardi E, Loiacono O. HIV/HCV co-infection: putting the pieces of the puzzle together. Cell Death Differ 2003;10(Suppl. 1):S25–6. [12] American Association for the Study of the Liver Diseases (AASLD); Infectious Diseases Society of America (IDSA). Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ [accessed 18.06.14]. [13] European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2014. http://www.easl.eu/ newsroom/ latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014 [accessed 18.06.14]. [14] World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. WHO; April 2014. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ [accessed 18.06.14].
Please cite this article in press as: Ippolito G, et al. Is hepatitis C virus eradication around the corner only 25 years after its discovery? Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.09.001
![[Hepatitis C virus: 25 years-old, the end?].](/assets/img/hold.png)
