25 years of Hepatitis C

25 anos de Hepatite C

Edison Roberto PARISE About the author

Hepacivirus; Liver cirrhosis

Hepacivirus; Cirrose hepática

During the decade of 60 and even 70 medical literature recognized only two types of hepatitis: type A, mainly affecting children, spread often at epidemic levels via food or water contaminated with infected feces and never chronic and type B, with parenteral transmission that could eventually evolve into chronicity, leading to the (then called) post-necrotic cirrhosis( 1515. Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J. 2013;10:239. ). After the identification of the Australia antigen (later called surface antigen of hepatitis B, HBsAg) by Blumberg et al.( 77. Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA. 1965;252:252-7. ) it seemed that the causative agent of parenteral transmission of hepatitis had been found, but it soon became clear that this virus could not be responsible for all cases of post-transfusion hepatitis. When hepatitis A virus was recognized and an antigenic system was developed, it could be associated with the infectious hepatitis. After analysis of many cases of transfusion hepatitis which could not be attributed to the hepatitis virus A or B, cytomegalovirus or Epstein Bar, Alter et al. denominated this disease as non-A non-B hepatitis, and a series of unique epidemiological characteristics were being identified for this hepatitis and its clinical outcomes( 33. Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Am J Med Sci. 1975;270:329-34. , 44. Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Lancet. 1978;1(8062):463-6. ). Finally in 1989, researchers were able to identify an antibody (Anti-HCV) as a marker for hepatitis C and related to different aspects of the disease( 55. Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, Kuo G. Detection of Antibody to Hepatitis C Virus in Prospectively Followed Transfusion Recipients with Acute and Chronic Non-A, Non-B Hepatitis. N Engl J Med. 1989;321:1494-1500. , 1717. Holland PV. Post-transfusion hepatitis: current risks and causes.Vox Sang. 1998;74(Suppl 2):135-41. ). The identification of this antibody and its rapid implementation for blood and derivatives screening by blood banks, associated with the determination of hepatitis B antigenic system determine dramatic reduction in post-transfusion-transmitted disease in the world( 1717. Holland PV. Post-transfusion hepatitis: current risks and causes.Vox Sang. 1998;74(Suppl 2):135-41. ). However, the damage was already done during the previous years leading up to the discovery of the marker for hepatitis C, millions of people were infected by blood transfusion, use of non-disposable needles and syringes or cutting pierce materials contaminated with hepatitis C.

According to a national study, the prevalence of hepatitis C in Brazil is 1.54% in the adult population (age 20-69 years) and 0.70% in the 10-to-20-year age range( 88. Brasil. Ministério da Saúde. Estudo de Prevalência de base populacional das infecções pelos vírus das hepatites A, B e C nas capitais do Brasil. 2010. ). Based on the age distribution data of this survey, the current population infected with the hepatitis C virus (HCV) would be in the order of 2 million of people( 1919. Kershenobich D, Razavi HA, Sánchez-Avila JF, Bessone F, Coelho HS, Dagher L, et al. Trends and projections of hepatitis C virus epidemiology in Latin America. Liver Int. 2011;31(Suppl 2):18-29. ). Chronic HCV infection follows an asymptomatic or oligosymptomatic course over decades and because of that most infected patients are unaware of their condition and do not look for medical attention. According to DataFolha and Brazilian Society of Hepatology survey performed in 2012 in the main metropolitan areas of the country, only 1/4 of the population of Brazil had already performed the test for hepatitis C( 3232. Sociedade Brasileira de Hepatologia. Pesquisa sobre Hepatite C. 2012. Available from: http://release.ketchumdigital.com/pesquisa-hepatite
http://release.ketchumdigital.com/pesqui...
). As the majority of patients is not identified and treated of the disease, the hepatitis slowly continues to progress and as late the diagnosis of the infection is made, the more likely the patients will be in advanced stages of the disease( 2424. Oliveira AC, Bortotti AC, Nunes NN, El Bacha IA, Parise ER. Association between age at diagnosis and degree of liver injury in hepatitis C.Braz J Infect Dis. 2014;18:507-11. ). Hepatitis C is now the second leading cause of chronic liver disease in public hospitals and outpatient care facilities only supplanted by alcohol abuse( 2323. Oliveira AC, PariseER, El Bacha IAH - Esteatose na doença hepática alcoólica e na hepatite pelo vírus C. In Parise ER & Mendonça Filho HTF. Esteatose Hepática. Ed. MTS. São Paulo. 2013:59-72. ) and the leading cause of hepatocellular carcinoma in Brazil( 99. Carrilho FJ, Kikuchi L, Branco F, Goncalves CS, Mattos AA, Brazilian HCC Study Group. Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil. Clinics (Sao Paulo). 2010;65:1285-90. ), accounting for nearly 40% of all cases diagnosed in the country. As an obvious consequence of these facts hepatitis C is now the main cause of liver transplantation, accounting for over half of all cases of cirrhosis and hepatocellular carcinoma leading to transplantation( 3030. Salvalaggio P, Afonso R, Pereira L, Ferraz-Neto B. The Meld system and liver transplant wating-list mortality in developing countries: lessons from São Paulo, Brasil. Revista Einstein. 2012;3:278-285. ).

Official data from Ministry of Health of Brazil, state that 8,216 patients received treatment within the framework of the National Viral Hepatitis Program in 2004, the year of its creation. This number grew from 2009 to 2011, plateauing in the region of 11,000 patients per year in the last years( 1111. Coordenação de Cuidado e Qualidade de Vida Departamento de DST, Aids e Hepatites Virais/SVS/MS. “38ª Reunião da Comissão de Articulação com Movimentos Sociais em HIV/AIDS E Hepatites Virais - CAMS”. ). Even taken in account that 5% to 10% of these cases constitute retreatment of patients that do not responded to previous antiviral therapy, in total, no more than 100,000 patients have already received treatment for hepatitis C in the country. As sustained virological response (SVR) rate could be calculated as no more than 50%, it can be realized that mere 2.5% of the infected population has been cured in Brazil (Figure 1). It bears stressing that, unlike therapy of other viral illnesses, successful treatment of hepatitis C cures the infection, halts disease progression, significantly reduces the risk of developing hepatocellular carcinoma (even in advanced cases) and even reduces non-liver-related mortality, both in patients with HCV infection alone and in the presence of HIV-HCV co-infection( 11. Alberti A. Impact of a sustained virological response on the long-term outcome of hepatitis C. Liver Int. 2011;31(Suppl 1):18-22. , 66. Berenguer J, Rodriguez E, Miralles P, Von Wichmann MA, Lopez-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: 728-6. , 1818. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315:1575-8. , 3535. Velosa J, Serejo F, Marinho R, Nunes J, Gloria H. Eradication of hepatitis C virus reduces the risk of hepatocellular carcinoma in patients with compensated cirrhosis. Dig Dis Sci. 2011;56:1853-61. ).

FIGURE 1.
Efectvity of hepatitis C diagnosis and treatment in Brazil.

Hepatitis C treatment with interferon was first applied at the time that the disease was called “non A non B hepatitis”( 1818. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315:1575-8. ), and has evolved since them. The incorporation of ribavirin and, in the last years, of first generation protease inhibitors (telaprevir and boceprevir) have increased significantly the numbers of responders to such antiviral therapy at same time that increased the number and the gravity of the adverse events as demonstrated by Almeida et al. in this issue of ARQA( 22. Almeida PRL, Fonseca CB, Koch VW, Souza AM, Feltrin AA, Tovo CV. Triple therapy in chronic hepatitis C: initial series in a public health program in the South of Brazil. Arq Gastroenterol. 2015;52(1):14-7. ). Despite the limited number of patients studied, which prevents any consideration about the virological response rate, it portrays the higher rate of complications seen with this therapy, with almost 60% of patients with anemia and early discontinuation of treatment in more than 30 % of patients. These numbers were much higher than the observed with dual therapy (peg-interferon and ribavirin), and are in accordance with data from the most important real-life study with triple therapy, the French Cupic Study( 1616. Hézode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, De Ledinghen V, et al. CUPIC Study Group Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology. 2014;147:132-42. ). The DAA second generation (sofosbuvir, simeprevir and daclatasvir), in the opposite direction, with the possibility of combining themselves and avoiding peguilated interferon are able to significantly reduce the extension and the complexity of the treatment and the incidence of side effects, in parallel with a rate of SVR near 80%-90% for all genotypes( 2727. Petta S, Craxi A. Current and future HCV therapy; do we still need other anti-HCV drugs ? Liver Internat. 2015;35(Suppl 1):4-10. ). Although extremely important, this achievement is not enough. If the number of patients receiving antiviral therapy stays the same, the expectation for the coming years is of an important increase in the number of chronic hepatitis C complications as cirrhosis and hepatocellular carcinoma, with increase in medical costs for the public and private sector( 2828. Razavi H, Waked I, Sarrazin C, Myers RP, Idilman R, Calinas F, Vogel W, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. J Viral Hepat. 2014;21(Suppl 1):34-59. ). In order to have a great impact on hepatitis C burden it will be necessary to increase both diagnosis and access to treatment. In the detection of carriers of this virus, it is important to modify the standard used so far to their identification by prioritizing those with parenteral risk factors (blood transfusion, hemodialysis, etc.). About 70% -75% of patients infected by hepatitis C virus in our country is aged more than 40-45 years( 1313. Focaccia R, da Conceicao OJ, Sette H, Jr., Sabino E, Bassit L, Nitrini DR, Lomar AV, et al. Estimated Prevalence of Viral Hepatitis in the General Population of the Municipality of Sao Paulo, Measured by a Serologic Survey of a Stratified, Randomized and Residence-Based Population. Braz J Infect Dis. 1998;2:269-84. , 2424. Oliveira AC, Bortotti AC, Nunes NN, El Bacha IA, Parise ER. Association between age at diagnosis and degree of liver injury in hepatitis C.Braz J Infect Dis. 2014;18:507-11. , 3131. SINAM. Boletim de Hepatites - casos notificados. In: www.aids.gov.br/sites/defaut/boletim hepatitis; 2011.
www.aids.gov.br/sites/defaut/boletim hep...
). Individuals in this age group must be consider at risk and tested for hepatitis C, regardless of whether they have a history of blood transfusions, have made use of disposable syringes and needles, or exposed to other forms of contamination. This strategy proved to be superior to conventional methods in the detection of hepatitis C( 1010. Centers for Disease Control and Prevention. Recommendations for the identification of Chronic Hepatitis C Virus Infection among persons born during 1945-1965. Morbidity and Mortality Weekly Report. 2012;61:1-18. , 2929. Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, Patel N, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med; 2012;156(4):263-70. ). In this issue of the Archives of Gastroenterology, Oliveira et al. assessed the prevalence of hepatitis C in Paulista University (UNESP) employee in total more than 3000 people( 2525. Oliveira CV, Barbosa WF, Silveira LVA, Menezes J, Machado FS, Silva GF. Prevalence of the hepatitis C virus among university employees in São Paulo, Southeastern Brazil: predictive factors and geoprocessing spatial analysis. Arq Gastroenterol. 2015;52(1):9-13. ). Despite the low prevalence observed (0.7%) for hepatitis C in such population, they were able to confirm that those older than 40 years of age are at more risk to be contaminated with HCV virus. Additionally the authors call attention to factor overlooked by younger doctors in epidemiological studies, which is the use of non-disposable syringes and needles in the past. It is specially mentioned the application of energetic stimulant (Glucoenergan®) often formerly used by revelers at Carnival or by athletes that is responsible for several cases of hepatitis C in these populations( 3333. Souto FJ, da Silva AG, Yonamine F. Risk of hepatitis C among Brazilian ex-soccer players. Mem Inst Oswaldo Cruz. 2003;98:1025-6. ). Increase access to treatment is another important task getting rid of the barriers that prevent the patient to have their treatment( 3434. Strauss E. Barriers to care of chronic hepatitis patients in Latin America. Arch Med Res. 2007;38:711-5. ). Expedite the diagnosis with rapid serological tests and staging of disease with noninvasive tests in place of liver biopsies, use of more effective drugs with safer treatments, with lower rates of adverse events are important part of this equation. But doctors from other areas beyond the hepatologists and infectious disease specialists will be needed in this fight against hepatitis, and the gastroenterologists are among them. Therapeutic simplicity in the use of new coming drugs (as those to be approved by ANVISA in 2015) in antiviral therapy will allow the gastroenterologist not affect the treatment of hepatitis to join the efforts against hepatitis C.

In this special issue of the Archives of Gastroenterology, we have another interesting article on hepatitis C addressing the beneficial effects of caffeine in the evolution of this liver disease( 2626. Oliveira KS, Buss C, Tovo CV. Association of caffeine intake and liver fibrosis in patients with chronic hepatitis C. Arq Gastroenterol. 2015;52(1): ). It has long been aware of the beneficial effects of coffee on serum liver enzymes and the alcoholic liver disease, but since 2009 several studies have shown that caffeine intake, especially in the form of coffee, has a protective effect on the development of hepatitis C virus( 1212. Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hezode C: Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol. 2011,54(6):1123-9. , 1414. Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, et al. HALT-C Trial Group. Coffee Intake Is Associated with Lower Rates of Liver Disease Progression in Chronic Hepatitis C. Hepatology. 2009;50:1360-9. , 2121. Machado SR, Parise ER, Carvalho L.Coffee has hepatoprotective benefits in Brazilian patients with chronic hepatitis C even in lower daily consumption than in American and European populations. Braz J Infect Dis. 2014;18:170-6. , 2222. Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, Hoofnagle JH. Increased Caffeine Consumption Is Associated with Reduced Hepatic Fibrosis. Hepatology. 2010;51:201-9. ). In our previously published study( 2121. Machado SR, Parise ER, Carvalho L.Coffee has hepatoprotective benefits in Brazilian patients with chronic hepatitis C even in lower daily consumption than in American and European populations. Braz J Infect Dis. 2014;18:170-6. ), we observed a reduction in liver fibrosis in patients taking higher doses of caffeine in univariate and multivariate analysis when compared to patients with lower daily intake of caffeine, but did not observe a relationship between caffeine with inflammatory activity in liver biopsy. We drew attention fact that the amount of caffeine necessary to reduce the degree of fibrosis was significantly lower than in English literature (125 mg or only 4 Brazilian cups of coffee versus 250 mg or 308 mg daily). This difference can be attributed to several factors but interestingly, in our population coffee represented more than 90% of the daily caffeine intake, while in other studies a large contingent of caffeine derived from soft drinks and processed juices( 1212. Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hezode C: Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol. 2011,54(6):1123-9. , 1414. Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, et al. HALT-C Trial Group. Coffee Intake Is Associated with Lower Rates of Liver Disease Progression in Chronic Hepatitis C. Hepatology. 2009;50:1360-9. , 2222. Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, Hoofnagle JH. Increased Caffeine Consumption Is Associated with Reduced Hepatic Fibrosis. Hepatology. 2010;51:201-9. ). The study of Oliveira et al. confirms our findings of the relationship between lower grade of fibrosis and the ingestion of higher doses of caffeine, although this association was not find in multivariate analysis. The cutoff value for caffeine used was the traditional (250 mg) and although certainly researched, it was not report in the article the origin of calculated amount of caffeine. It should be remembered that in the South of Brazil there is another form of caffeinated beverage that is the use of mate infusion (“chimarrão”), and it would be interesting to know whether this had any impact in caffeine ingestion in this study. Also like in our study, there was no association between the amount of caffeine and the inflammatory activity in the tissue, suggesting that this protective effect could be relate to the fibrogenic activity of the tissue, but this would be a speculation far beyond the purpose of the studies presented.

Thus, when we complete 25 years of hepatitis C, witnessing one of the fastest and unprecedented advances in the history of medicine in the diagnosis and effective treatment of a disease, is important not to lose focus if we are to make a difference to health policies in this country no impact will be achieve only with excellent medicines. Even with drugs that reach 95% SVR we only effectively will reduce the future impact of the disease if we treat at least 70% of infected patients. It is not yet time to celebrate it’s time to roll up our sleeves and go to fight.

Edison Roberto PARISE*

REFERENCES

  • 1
    Alberti A. Impact of a sustained virological response on the long-term outcome of hepatitis C. Liver Int. 2011;31(Suppl 1):18-22.
  • 2
    Almeida PRL, Fonseca CB, Koch VW, Souza AM, Feltrin AA, Tovo CV. Triple therapy in chronic hepatitis C: initial series in a public health program in the South of Brazil. Arq Gastroenterol. 2015;52(1):14-7.
  • 3
    Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Am J Med Sci. 1975;270:329-34.
  • 4
    Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Lancet. 1978;1(8062):463-6.
  • 5
    Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, Kuo G. Detection of Antibody to Hepatitis C Virus in Prospectively Followed Transfusion Recipients with Acute and Chronic Non-A, Non-B Hepatitis. N Engl J Med. 1989;321:1494-1500.
  • 6
    Berenguer J, Rodriguez E, Miralles P, Von Wichmann MA, Lopez-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: 728-6.
  • 7
    Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA. 1965;252:252-7.
  • 8
    Brasil. Ministério da Saúde. Estudo de Prevalência de base populacional das infecções pelos vírus das hepatites A, B e C nas capitais do Brasil. 2010.
  • 9
    Carrilho FJ, Kikuchi L, Branco F, Goncalves CS, Mattos AA, Brazilian HCC Study Group. Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil. Clinics (Sao Paulo). 2010;65:1285-90.
  • 10
    Centers for Disease Control and Prevention. Recommendations for the identification of Chronic Hepatitis C Virus Infection among persons born during 1945-1965. Morbidity and Mortality Weekly Report. 2012;61:1-18.
  • 11
    Coordenação de Cuidado e Qualidade de Vida Departamento de DST, Aids e Hepatites Virais/SVS/MS. “38ª Reunião da Comissão de Articulação com Movimentos Sociais em HIV/AIDS E Hepatites Virais - CAMS”.
  • 12
    Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hezode C: Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol. 2011,54(6):1123-9.
  • 13
    Focaccia R, da Conceicao OJ, Sette H, Jr., Sabino E, Bassit L, Nitrini DR, Lomar AV, et al. Estimated Prevalence of Viral Hepatitis in the General Population of the Municipality of Sao Paulo, Measured by a Serologic Survey of a Stratified, Randomized and Residence-Based Population. Braz J Infect Dis. 1998;2:269-84.
  • 14
    Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, et al. HALT-C Trial Group. Coffee Intake Is Associated with Lower Rates of Liver Disease Progression in Chronic Hepatitis C. Hepatology. 2009;50:1360-9.
  • 15
    Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J. 2013;10:239.
  • 16
    Hézode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, De Ledinghen V, et al. CUPIC Study Group Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology. 2014;147:132-42.
  • 17
    Holland PV. Post-transfusion hepatitis: current risks and causes.Vox Sang. 1998;74(Suppl 2):135-41.
  • 18
    Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315:1575-8.
  • 19
    Kershenobich D, Razavi HA, Sánchez-Avila JF, Bessone F, Coelho HS, Dagher L, et al. Trends and projections of hepatitis C virus epidemiology in Latin America. Liver Int. 2011;31(Suppl 2):18-29.
  • 20
    Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989;244(4902):362-4.
  • 21
    Machado SR, Parise ER, Carvalho L.Coffee has hepatoprotective benefits in Brazilian patients with chronic hepatitis C even in lower daily consumption than in American and European populations. Braz J Infect Dis. 2014;18:170-6.
  • 22
    Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, Hoofnagle JH. Increased Caffeine Consumption Is Associated with Reduced Hepatic Fibrosis. Hepatology. 2010;51:201-9.
  • 23
    Oliveira AC, PariseER, El Bacha IAH - Esteatose na doença hepática alcoólica e na hepatite pelo vírus C. In Parise ER & Mendonça Filho HTF. Esteatose Hepática. Ed. MTS. São Paulo. 2013:59-72.
  • 24
    Oliveira AC, Bortotti AC, Nunes NN, El Bacha IA, Parise ER. Association between age at diagnosis and degree of liver injury in hepatitis C.Braz J Infect Dis. 2014;18:507-11.
  • 25
    Oliveira CV, Barbosa WF, Silveira LVA, Menezes J, Machado FS, Silva GF. Prevalence of the hepatitis C virus among university employees in São Paulo, Southeastern Brazil: predictive factors and geoprocessing spatial analysis. Arq Gastroenterol. 2015;52(1):9-13.
  • 26
    Oliveira KS, Buss C, Tovo CV. Association of caffeine intake and liver fibrosis in patients with chronic hepatitis C. Arq Gastroenterol. 2015;52(1):
  • 27
    Petta S, Craxi A. Current and future HCV therapy; do we still need other anti-HCV drugs ? Liver Internat. 2015;35(Suppl 1):4-10.
  • 28
    Razavi H, Waked I, Sarrazin C, Myers RP, Idilman R, Calinas F, Vogel W, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. J Viral Hepat. 2014;21(Suppl 1):34-59.
  • 29
    Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, Patel N, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med; 2012;156(4):263-70.
  • 30
    Salvalaggio P, Afonso R, Pereira L, Ferraz-Neto B. The Meld system and liver transplant wating-list mortality in developing countries: lessons from São Paulo, Brasil. Revista Einstein. 2012;3:278-285.
  • 31
    SINAM. Boletim de Hepatites - casos notificados. In: www.aids.gov.br/sites/defaut/boletim hepatitis; 2011.
    » www.aids.gov.br/sites/defaut/boletim hepatitis
  • 32
    Sociedade Brasileira de Hepatologia. Pesquisa sobre Hepatite C. 2012. Available from: http://release.ketchumdigital.com/pesquisa-hepatite
    » http://release.ketchumdigital.com/pesquisa-hepatite
  • 33
    Souto FJ, da Silva AG, Yonamine F. Risk of hepatitis C among Brazilian ex-soccer players. Mem Inst Oswaldo Cruz. 2003;98:1025-6.
  • 34
    Strauss E. Barriers to care of chronic hepatitis patients in Latin America. Arch Med Res. 2007;38:711-5.
  • 35
    Velosa J, Serejo F, Marinho R, Nunes J, Gloria H. Eradication of hepatitis C virus reduces the risk of hepatocellular carcinoma in patients with compensated cirrhosis. Dig Dis Sci. 2011;56:1853-61.

Publication Dates

  • Publication in this collection
    Jan-Mar 2015
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