Advances in Treatment of Hepatitis C and B by Naglaa Allam


62596aab662f3d6-261x361.jpg Author Naglaa Allam
Isbn 9789535129936
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Year 2017
Pages 397
Language English
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Advances in Treatment of Hepatitis C and B Edited by Naglaa Allam Advances in Treatment of Hepatitis C and B Edited by Naglaa Allam Stole src from http://avxhome.se/blogs/exLib/ Published by ExLi4EvA Copyright © 2017 All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Technical Editor Cover Designer AvE4EvA MuViMix Records Спизжено у ExLib: avxhome.se/blogs/exLib ISBN-10: 953-51-2994-5 Спизжено у ExLib: ISBN-13: 978-953-51-2994-3 Print ISBN-10: 953-51-2993-7 ISBN-13: 978-953-51-2993-6 Stole src from http://avxhome.se/blogs/exLib: avxhome.se/blogs/exLib Contents Preface Chapter 1 Introductory Chapter: Treatment of Viral Hepatitis Current Challenges and Future Perspectives by Naglaa Allam and Imam Waked Chapter 2 Advances in Treatment of Hepatitis C by Sanaa M. Kamal Chapter 3 Comparative Study of IFN-Based Versus IFN-Free Regimens and Their Efficacy in Treatment of Chronic Hepatitis C Infections by Ramesh Rana, Yizhong Chang, Jing Li, ShengLan Wang, Li Yang and ChangQing Yang Chapter 4 Management of Hepatitis C Virus Infection in Patients with Cirrhosis by Aziza Ajlan and Hussien Elsiesy Chapter 5 Management of Hepaitits C Virus Genotype 4 in the Liver Transplant Setting by Waleed K. Al-Hamoudi Chapter 6 HCV Treatment Failure in the Era of DAAs by Mohamed Hassany and Aisha Elsharkawy Chapter 7 Treatment of Chronic Hepatitis B: An Update and Prospect for Cure by Andrew Dargan and Hie-Won Hann Chapter 8 Recent Advancement in Hepatitis B Virus, Epigenetics Alterations and Related Complications by Mankgopo Magdeline Kgatle VI Contents Chapter 9 Response-Guided Therapy Based on the Combination of Quantitative HBsAg and HBV DNA Kinetics in Chronic Hepatitis B Patients by Valeriu Gheorghiță and Florin Alexandru Căruntu Chapter 10 Current Management Strategies in Hepatitis B During Pregnancy by Letiția Adela Maria Streba, Anca Pătrașcu, Aurelia Enescu and Costin Teodor Streba Chapter 11 Treatment and Prognosis of Hepatitis B Virus Concomitant with Alcoholism by Chih-Wen Lin, Chih-Che Lin and Sien-Sing Yang Chapter 12 Hepatitis B and C in Kidney Transplantation by Smaragdi Marinaki, Konstantinos Drouzas, Chrysanthi Skalioti and John N. Boletis Chapter 13 Strategies to Preclude Hepatitis C Virus Entry by Thierry Burnouf, Ching-Hsuan Liu and Liang-Tzung Lin Chapter 14 Hepatitis C Virus Infection Treatment: Recent Advances and New Paradigms in the Treatment Strategies by Imran Shahid, Waleed H. AlMalki, Mohammed W. AlRabia, Muhammad H. Hafeez and Muhammad Ahmed Chapter 15 Importance of MicroRNAs in Hepatitis B and C Diagnostics and Treatment by Mateja M. Jelen and Damjan Glavač Chapter 16 Can Proteomic Profiling Identify Biomarkers and/or Therapeutic Targets for Liver Fibrosis? by Seyma Katrinli, H. Levent Doganay, Kamil Ozdil and Gizem DinlerDoganay Chapter 17 New Strategy Treating Hepatitis B Virus (HBV) Infection: A Review of HBV Infection Biology by Yong-Yuan Zhang Preface As in many areas of medicine, treatment of viral hepatitis has seen an acceleration of change driven by new therapies and evolving technology. Thanks to the direct-acting antiviral agents (DAAs), the era of HCV eradication and cure has begun. As regards to hepatitis B therapy, potent antiviral drugs for suppression of viral replication are available, new research activities to enhance eradication are visible, and these may influence clinical practice in the coming years. This book covers the latest advances in hepatitis C and hepatitis B therapeutics as well as the emerging and investigational treatment strategies. This book is an up-to-date source of information for physicians, residents, and advanced medical students seeking a broader understanding of treatment of viral hepatitis. The authors of the chapters come from many eminent centers around the world and are experts in their respective fields. Chapter 1 Provisional chapter Provisional chapter Introductory Chapter: Treatment of Viral Hepatitis Current Challenges and Future Perspectives Introductory Chapter: Treatment of Viral Hepatitis Current Challenges and Future Perspectives Naglaa Allam and Imam Waked Additional information is available at the end of the chapter Naglaa Allam and Imam Waked http://dx.doi.org/10.5772/67420 Additional information is available at the end of the chapter 1. Hepatitis C therapy Cure of hepatitis C has come true! Clinical care for patients with hepatitis C (HCV) has advanced remarkably during the last two decades, as a result of better understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention. With the introduction of genotype 1 effective directly acting antiviral agents (DAAs) in 2011, the manage‐ ment of HCV infection started to change. By 2013, second-generation pangenotypic DAAs became available, and the biggest problem was solved: interferon (IFN) became no longer necessary. Unlike IFN regimens, which rely on upregulating the patients’ own immune system, these DAAs block different stages of viral replication. There are four major groups of DAAs namely: NS5B nucleotide inhibitors, NS5B nonnucleoside inhibitors, NS5A replication complex inhibi‐ tors, and NS3/4A protease inhibitors [1]. Specific treatment regimens vary, depending on fac‐ tors such as HCV genotype, and may include multiple drugs [2]. Multiple regimens have been approved and several new regimens with high potencies, less resistance, and better safety pro‐ file are in the process of approval. Prof. Kamal elegantly describes them in detail in Chapter 2. Sustained virological response (SVR) rates achieved in phase III clinical trials generally exceeded 90% (although real‐world rates may be lower) along with reduction in treatment duration to 12 weeks or less and with fewer adverse events. An SVR is generally associated with normalization of liver enzymes and amelioration or disappearance of liver necroinflam‐ mation and fibrosis in noncirrhotic patients [3]. The use of DAAs in patients with cirrhosis, as discussed in Chapter 4, has also shown excellent results with good safety profile. SVR also improves HCV‐induced portal hypertension [4]. DAAs have also begun to change the land‐ scape of management of the HCV transplant candidate on the waiting list. Prof. Al‐Hamoudi provides an update on this in Chapter 5. Even patients with HCV infection and advanced kidney disease now have alternative treatment options. 4 Advances in Treatment of Hepatitis C and B Thus, the era of HCV eradication and cure has begun. And in 2017, hepatologists can treat all patients irrespective of fibrosis score—but the job is not over yet. Real‐world experience has revealed several challenges and unmet needs! 1.1. Challenges: (a) Limited or absent access to therapy in the majority of infected patients Unfortunately, the very high cost of the new DAA drugs is creating a barrier for introduc‐ tion of treatment in most limited resource settings and may prove an obstacle on the path for elimination of HCV infection worldwide. Of course, successful treatment should prevent many late HCV complications, but even if treatment actually proves cost saving in the long run, it is too expensive and infeasible to treat all patients immediately [5]. Hence hepatitis C treatment prioritization, as the European Association for the Study of the Liver states, is necessary when resources are limited [6]. However, new data suggest that this approach may be suboptimal, if not carefully executed. Treatment prioritization is complex and may not be fair. Treating first those with the most need makes sense. But, those who need it most may also be those who benefit the least because of issues as extensive liver damage, comorbid illness, older age, or have already developed hepatocellular carcinoma? Targeting populations with high HCV prevalence like drug users, prisoners, and migrants also makes sense since they are most likely to spread infection to others. But, those most likely to transmit to others often have low disease stage. Besides they are most likely to abrogate the personal benefits of treatment by being reinfected. Treating those who have the most symptoms also makes sense, but unfortunately symptoms do not always improve with cure. And there is another major issue: who should decide whom to prioritize? [7]. Health care providers often impose socioeconomic and racial biases when prioritizing treatments [8]. Moreover, health care providers prefer not to be the barrier between patients and life‐saving therapies. While not all patients require immediate treatment, an ideal strategy should treat patients before they progress toward end‐stage liver disease when even highly effective treatments can confer only marginal benefit. In response, many countries have instituted coverage policies that autho‐ rize treatment only for the advanced patients, putting off therapy for less severely ill patients [5]. Aggressive action is warranted to see progress toward HCV elimination. Only if we use efficacious therapy in a significant proportion of patients will we significantly decrease the burden of the disease. So efforts should be made to make DAAs cost effective in all clinical scenarios and accessible to all patients. In places like Egypt and India, generic versions of the DAAs sofosbuvir and daclatasvir are being mass produced for <1% of the current US retail price and are available for a higher proportion of patients. Another solution to reduce treatment cost is by shortening the duration of treatment without affecting efficacy. A study in China demonstrated 100% SVR with triple DAAs for only 3 weeks if the patient without cirrhosis achieved ultra‐rapid virological response (HCV‐RNA < 500 IU 48 hours after starting treatment) [9]. By shortening the duration of therapy from the currently Introductory Chapter: Treatment of Viral Hepatitis - Current Challenges and Future Perspectives http://dx.doi.org/10.5772/67420 r­ ecommended 12 to 3 weeks, the cost of therapy could be markedly reduced as well as the rate of adverse events. Large clinical trials should further study the application of this response‐ guided treatment approach in patients with different ethnic backgrounds and with different genotypes. (b) Emergence of drug resistance and DAA failure Despite improved SVR rates with DAA‐based combination regimens, treatment fails to erad‐ icate HCV infection in 5–15%, dependening on the treatment regimen and treated popula‐ tion. Treatment failure is generally associated with the selection of HCV resistant‐associated substitution (RAS) (or resistant‐associated variant (RAV)), that is, viral molecular substitu‐ tions or variants that have reduced susceptibility to the DAA(s) administered. NS5A inhib‐ itors have a low barrier to resistance, and the variants they select confer cross‐resistance across all members of the drug class. Thus, NS5A resistance currently appears as the prin‐ cipal challenge of IFN‐free, DAA‐based therapy and they tend to persist for several years after treatment failure. In contrast, RASs selected by NS3/4A protease inhibitors persist for a much shorter time and are progressively replaced by wild‐type virus within a few months posttherapy. Additionally, RASs selected by the NS5B polymerase inhibitor sofosbuvir have poor viral fitness; thus, they rarely emerge in the presence of the drug and tend to rapidly disappear if selected [10]. The utility of HCV resistance testing, i.e., the determination of the sequence of the DAA target region prior to retreatment in patients who failed on any of the DAA‐containing regimens is unknown. Chapter 6 summarizes the retreatment in case of drug failures. (c) HCV eradication and the risk of hepatocellular carcinoma (HCC): issues with direct acting antiviral (DAA) therapy? Several recent publications raise concerns about unexpected high rate of HCC recurrence after undergoing direct‐acting antiviral therapy. Reig et al. showed early tumor “recurrence” in patients with HCV‐related hepatocellular carcinoma (HCC) [11]. Conti et al. showed that in patients with HCV‐related cirrhosis, DAA‐induced resolution of HCV infection does not reduce recurrence of HCC, and patients previously treated for HCC have still a high risk of tumor recurrence, in the short term [12]. Kozbial et al. showed an unexpected high “occur‐ rence” in patients with advanced liver diseases after SVR [13]. In contrast, Cheung et al. found that DAA therapy in patients with decompensated cirrhosis led to sustained improvement in liver function, with no evidence of increase in HCC development in Chinese patients [14]. Also, the French ANRS study analyzed more than 6000 DAA‐treated patients who underwent curative therapies for HCC and they found no increased risk of HCC [15]. Altogether these studies convey a strong message that great attention is needed to address the issue of HCC recurrence/occurrence. There is an urgent need for large prospective stud‐ ies evaluating the impact of DAA therapy on the risk of HCC in patients with HCV‐related cirrhosis. For the time being, the risk of HCC development justifies HCC screening after viral clearance in patients with HCV‐related cirrhosis. 5 6 Advances in Treatment of Hepatitis C and B (d) There is no vaccine yet. Is a prophylactic vaccine still necessary? Obviously, therapy is not enough to surmount the burden of HCV. Is it technically possible to have vaccine? If HCV vaccines are available in the future, then vaccination program in high‐risk populations would probably have a great impact on preventing and eradicating HCV infection. An experimental protective vaccine, as shown in Chapter 14, demonstrated promise in preliminary human safety trials, and a phase II clinical trial is under way to further determine the efficacy of the vaccine. 1.2. Future perspectives: Therefore, although the DAAs have opened up new horizons for HCV cure, challenges per‐ sist in the real‐world setting. It is becoming clear that developing therapeutic strategies with different modes of action would be necessary to address the various limitations of current DAAs. Third generation pangenotypic antivirals are currently in final phases of development: voxilaprevir [16], glecaprevir [17] (both NS3/NS4 protease inhibitors) and pibrentasvir (NS5A inhibitor) [17]. Antivirals with alternate mechanism of action, such as by restricting viral entry or cell‐to‐cell spread could help expand the scope of antiviral strategies for the management of hepatitis C. Chapters 14 and 15 describe some of the new paradigms in antiviral strategies to preclude HCV entry, such as through monoclonal antibodies and small molecules. With these strategies, it is foreseeable, in a not too distant future, that they will help provide a better management of hepatitis C. 2. Hepatitis B therapy An overview of the six currently approved treatments is presented in Chapter 7. The advent of anti‐HBV treatment drugs has made significant progress in improving the health and life expectancy of patients with HBV. But there is no cure for Hepatitis B till now! Chronic hepatitis B remains a difficult to treat disease because at this time no treatment pro‐ vides both an optimal virological and immunological control. There is a high rate of relapse following any antiviral therapy. In addition, there are no approved therapy stopping rules, especially in HBeAg negative patients treated with nucleoside and nucleotide analogs. An early stopping rule using the combination of serum HBsAg and HBV DNA was proposed and is discussed in Chapter 9. While there have been significant advances in the management of hepatitis B with available nucleos(t)ide analogues, there remains much work to be done to prevent HCC. Viral suppres‐ sion alone has proven not effective for the absolute prevention of HCC. Additionally, the required long‐term therapy imposes not only financial burden but also may put patients at risk for potential drug resistance and unknown toxicity. Therefore, more effec‐ tive treatment regimens aiming for HBV cure are urgently needed. New investigational thera‐ pies are in the pipeline as discussed in Chapter 17. With multiple new therapies in the pipeline, Introductory Chapter: Treatment of Viral Hepatitis - Current Challenges and Future Perspectives http://dx.doi.org/10.5772/67420 the future of treating hepatitis B is an exciting one, and there is hope that it will become a disease of the past but this will not be too soon! The new therapy will not be available soon. Another challenge is a demand for screening pregnant females and newborns for HBV. Pregnancy screening for HBV is very defective in most countries; it is not practiced except on individual basis. Chapter 10 reviews current management strategies for hepatitis B in the pregnancy and the postpartum. Conclusion So, in conclusion, the highly effective and well‐tolerated direct‐acting antiviral drugs (DAAs) for the treatment of the hepatitis C virus have revolutionized therapy for HCV. Several novel therapeutic strategies for each of HBV and HCV are under development. But until the devel‐ oping antiviral strategies are available, there is much more that can be done. The public health burden posed by viral hepatitis should be recognized as a priority. The leading professional organizations in liver disease, the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) urge governments, health care organizations, and nongovernmental organizations to adopt recommendations for immuni‐ zation, screening, diagnosis and treatment and to make them available and affordable for public health programs [18]. Overall, the achievements and improvements in the field of HCV and HBV care predict that the future of HCV and HBV therapeutics is becoming brighter every day. Author details Naglaa Allam* and Imam Waked *Address all correspondence to: [email protected] Hepatology, National Liver Institute, Menoufeya University, Egypt References [1] Rupp D, Bartenschlager R. Targets for antiviral therapy of hepatitis C. Semin Liver Dis 2014;34:9–21. [2] Chung Raymond T et al. Hepatitis C guidance: AASLD‐IDSA recommendationsfor testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015;62:932–54. [3] Pinzani M. Liver fibrosis in the Post‐HCV Era. Semin Liver Dis 2015;35:157–65. 7 8 Advances in Treatment of Hepatitis C and B [4] Mandorfer M, Kozbial K, Schwabl P, Clarissa Freissmuth C, Schwarzer R, Stern R, Chromy D Stättermayer AF, Reiberger T, Beinhardt S, Sieghart W, Trauner M, Hofer H, Ferlitsch A, Ferenci P, Markus Peck‐Radosavljevic M. Sustained virologic response to interferon‐free therapies ameliorates HCV‐induced portal hypertension. J Hepatol 2016;65:692–99. [5] Fox S, McCombs J. Optimizing HCV treatment – Moving beyond the cost conundrum. J Hepatol 2016;65:222–25. [6] World Health Organization guidelines for the screening care and treatment of chronic hepatitis C infection; 2016. Update. http://www.who.int/hiv/pub/hepatitis/hepatitis‐ cguidelines/en/ [7] Mehta SH, David L, Thomas DL. Doing the math on hepatitis C virus treatmentJ Hepatol 2016;65:5–6. [8] Institute of Medicine Committee on U, Eliminating R, Ethnic Disparities in Health C. In: Smedley BD, Stith AY, Nelson AR, editors. Unequal treatment: confronting racial and ethnic disparities in health care. Washington (DC): National Academies Press (US); 2003. [9] Lau G, Benhamou Y, Chen G, Li J, Shao Q, Ji D, Li F, Li B, Liu J, Hou J, Jian Sun J, Wang C, Chen J, Wu V, Wong A, Wong C, Tsang S, Wang Y, Bassit L, Tao S, Jiang Y, Hsiao H, Ke R, Perelson A, Schinazi R. Efficacy and safety of 3‐week response‐guided triple direct‐acting antiviral therapy for chronic hepatitis Cinfection: a phase 2, open‐label, proof‐of‐concept study. Lancet Gastroenterol Hepatol 2016;1(2):97–104. [10] Pawlotsky JM. Hepatitis C virus resistance to direct‐acting antiviral drugs in interferon‐ free regimens. Gastroenterology 2016;151(1):70–86. [11] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCV‐related HCC undergoing interferon‐free therapy. J Hepatol 2016;65:719–26. [12] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, Lenzi M, Mazzella G, Verucchi G, Andreone P, Brillanti S. Early occurrence and recurrence of hepatocellular carcinoma in HCV‐related cirrhosis treated with direct acting antivirals. J Hepatol 2016;65:727–33. [13] Kozbial K, Moser S, Schwarzer R, Laferl H, Al‐Zoairy R, Stauber R, Stättermayer AF, Beinhardt S, Graziadei I, Freissmuth C, Maieron A, Gschwantler M, Strasser M, Peck‐ Radosalvjevic M, Trauner M, Hofer H, Ferenci P. Unexpected high incidence of hepato‐ cellular carcinoma in cirrhotic patients with SVR following IFN‐free DAA treatment. J Hepatol 2016;65:856–8. [14] Cheung MC, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, Brown A, Gelson WT, MacDonald DC, Agarwal K, Foster GR, Irving WL; HCV Research UK. Outcomes after successful direct‐acting antiviral therapy for patients with chronic hepa‐ titis C and decompensated cirrhosis. J Hepatol 2016;65(4):741–7. Introductory Chapter: Treatment of Viral Hepatitis - Current Challenges and Future Perspectives http://dx.doi.org/10.5772/67420 [15] ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Lack of evidence of an effect of direct‐acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J Hepatol 2016;65(4):734–40. [16] Jacobson IM, Asselah T, Nahass R, Bhandari BR, Tran A, Hyland RH, Stamm LH, Dvory‐ Sobol H, Zhu Y, Brainard DM, Subramanian M, McHutchison JG, Shafran S, Davis M, Stedman CA, Lawitz E, Gane J. POLARIS‐2: A Randomized Phase 3 Trial of Sofosbuvir/ Velpatasvir/Voxilaprevir for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in DAA‐Naïve Genotype 1‐6 HCV‐Infected Patients: The POLARIS‐2 Study. Abstract LB‐12. Presented at: The Liver Meeting; Nov. 11–15, 2016; Boston. [17] Gane E, Poordad F, Wang S, Asatryan A, Kwo PY, Lalezari J, Wyles DL, Hassanein T, Aguilar H, Maliakkal B, Liu R, Lin CW, Ng TI, Kort J, Mensa FJ. High Efficacy of ABT‐493 and ABT‐530 treatment in patients with HCV Genotype 1 or 3 infection and compensated cirrhosis. Gastroenterology 2016;151(4):651–659.e1. Epub 2016 Jul 25. [18] Brahm J, Castera L, Hou J, Lindor K. Joint society statement for the elimination of viral hepatitis. J Hepatol 2016;65;661–2. 9 Provisional chapter Chapter 2 Advances Advances in in Treatment Treatment of of Hepatitis Hepatitis C C Sanaa M. Kamal Sanaa M. Kamal Additional information is available at the end of the chapter Additional information is available at the end of the chapter http://dx.doi.org/10.5772/66719 Abstract Hepatitis C infection (HCV) is a major cause of chronic hepatitis and cirrhosis worldwide. Interferon-based regimen has been the sole therapy to eradicate HCV infection for decades. However, this interferon and ribavirin combination is associated with several serious adverse events and the sustained virologic response rate was suboptimal. The recent discovery of oral direct-acting antiviral agents (DAAs) heralded a revolution in the treatment of chronic HCV. This breakthrough in HCV resulted in high rates of HCV eradication with sustained virologic response rates ranging between 90 and 100% across different genotypes. New therapies were administered orally for 12 or 24 months and this resulted in better compliance and few adverse events. DAAs are categorized into four major groups namely: NS5B nucleotide inhibitors, NS5B nonnucleoside inhibitors, NS5A replication complex inhibitors, and NS3/4A protease inhibitors (PI). Several interferonfree regimens have been approved and adequately assessed and several new regimens with high potencies, less cross-resistance, and better safety profile are in the process of approval. Thus, the era of HCV eradication and cure has begun. Keywords: hepatitis C, direct-acting antivirals, interferon-free regimen 1. Introduction Hepatitis C virus (HCV) is a major cause of liver cirrhosis, end-stage liver disease, and liver transplantation throughout the world [1]. Approximately 170–200 million people equating to 3% of the world’s population are infected with HCV [2]. The prevalence of HCV varies in different geographic regions. The prevalence of HCV infection is greater in Africa and Asia, with infection rates exceeding 5% [3–5]. Egypt has the highest prevalence of hepatitis C in the world, with 15% of the population affected [6–8]. In the USA, nearly 2% of the population is infected [9, 10]. In Europe, the prevalence ranges from 0.1% in northern European countries and 1% in 14 Advances in Treatment of Hepatitis C and B countries on the Mediterranean [10, 11]. The immigration crisis may increase HCV prevalence in Europe given that immigrants originate from countries with high rates of HCV [12]. 2. Natural history and outcome of HCV infection Acute HCV infection is mostly asymptomatic and rarely recognized clinically. Spontaneous viral clearance (SVC) occurs in approximately 25% of patients [13, 14]. The striking feature of HCV infection is its tendency to persist and evolve to chronic hepatitis. In some patients, chronic HCV progresses to liver cirrhosis and hepatocellular carcinoma (HCC) [14, 15]. The outcome of HCV infection depends largely on several host, viral and environmental factors. During an early stage, HCV infection triggers viral-associated molecular pattern (PAMP) receptors resulting in induction of an antiviral state through several pathways such as limiting cellular, modifying and degrading viral RNA, altering cellular vesicle trafficking and probably other not yet discovered antiviral mechanisms [15–17]. Clearance of HCV is associated with the development of robust and multispecific CD4+ and CD8+T-cell responses in blood and liver that can be maintained for years after recovery from acute disease [18–20]. In contrast, individuals who progress to chronic infection fail to mount such a response or may have inadequate production of the cytokines essential to control viral replication. Incomplete control of viral replication by CD8+ T cells in the absence of sufficient memory CD4+T cells leads to viral persistence and emergence of CTL escape mutants [21–24]. Acute resolving hepatitis has been shown to be associated with HCV homogeneity, whereas progressing hepatitis correlated with genetic diversity, presumably reflecting greater immune pressure during acute spontaneous clearance [25]. Polymorphisms of genes involved in innate immunity as well as those in genes encoding cytokines and other immunologic mediators may explain spontaneous recovery from acute HCV and influence the strength and nature of immune defense. Genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand influenced spontaneous resolution of HCV infection suggesting that inhibitory NK cell interactions are critical for antiviral immunity [26, 27]. To date, there are no reliable methods to predict who will resolve acute HCV spontaneously and who will develop chronic HCV. Similarly, no reliable indicators exist for distinguishing chronic hepatitis C patients who may develop cirrhosis or HCC. Thus, early effective treatment of patients with HCV is necessary for prevention of progression of liver disease to cirrhosis, hepatocellular carcinoma. In the absence of a vaccine against HCV, efficient treatment is important for prevention of transmission along with adoption of infection control measures. 3. Evolution of HCV therapy The ultimate goal of hepatitis C treatment is to reduce the occurrence of end-stage liver disease and its complications including decompensated cirrhosis, liver transplantation, and Advances in Treatment of Hepatitis C http://dx.doi.org/10.5772/66719 HCC. Treatment success is assessed by sustained virologic response (SVR), defined undetectable HCV RNA in blood several months after completing a course of treatment [28]. For two decades, the standard of care (SOC) for hepatitis C infection was interferon based. IFNα has potent antiviral activity due to its ability to induce IFN-stimulated genes (ISGs) that encode proteins which inhibit various stages of viral replication [29]. Type I IFNs bind a unique ubiquitous heterodimeric receptor consisting of interferon-alpha receptor 1/2 (IFNAR1/IFNAR2), resulting in the activation of signaling pathways and induction of a large number of IFN-stimulated genes (ISGs). ISG-encoded proteins mediate the antiviral and other effects of interferons [29]. IFNAR1 and IFNAR2 are associated with the Janus-activated kinases (JAKs) tyrosine kinase 2 (TYK2) and JAK1, respectively. Binding of type I IFNs to their heterodimeric receptors leads to activation of JAKs, which results in tyrosine phosphorylation of signal transducer and activator of transcription 2 (STAT2) and STAT1; STAT1/ STAT2 migrates into the nucleus and associates with the IFN regulatory factor 9 (IRF9) to form the STAT1-STAT2-IRF9 complex. This complex then binds IFN-stimulated response elements (ISREs) inside DNA to initiate the transcription of hundreds of different ISGs [30, 31]. IFN regulatory genes (IRGs) facilitate both clearance of virus from infected cells and protection of neighboring uninfected cells from incoming viral progeny. The antiviral-associated protein kinase R (PKR) plays an important role in restricting HCV 1a replication through regulating the NF-κB pathway [32, 33]. Initially, chronic hepatitis C was treated by conventional interferon (IFN) monotherapy which yielded very poor response rates. Addition of the guano sine analog, ribavirin, to conventional interferon was associated with slight improvement in sustained virologic response (SVR) although the improvement was far from satisfactory particularly in HCV genotypes 1 and 4. Pegylation of the interferon molecule resulted in modification of the pharmacokinetic profile of IFN-α-2. Both PEG-IFN-α-2a and PEG-IFN-α-2b have slower absorption, more reduced distribution and lower elimination rate than the nonpegylated IFN-α. The maintained concentrations of PEG-IFNα allowed longer periods of viral inhibition with once a week dosing. Pegylated interferon and ribavirin therapy resulted in improved sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks after completion of treatment. With pegylated interferon alpha-2 and ribavirin (RBV) combination, response rates in genotypes 2 and 3 range between 70 and 80%. However, SVR rates in chronic HCV genotypes 1 and 4 infection are suboptimal. Adverse events are common with interferon-based regimen and include fatigue, flu-like symptoms, anxiety, skin rash, and gastrointestinal symptoms such as nausea and diarrhea. Hemolytic anemia is frequent due to the use of ribavirin. Some patients treated with PEG-IFN and RBV may develop cardiac arrhythmias or severe neuropsychiatric adverse events depression and suicidal tendency. The various adverse effects, the long duration of therapy and the need to inject interferon reduce compliance and treatment adherence. These factors have driven the urgent need to develop new treatments that are safer and more effective (Figure 1). The discovery of direct-acting antiviral agents (DAAs) heralded the dawn of a new era of HCV cure which was a dream. 15

Author Naglaa Allam Isbn 9789535129936 File size 17MB Year 2017 Pages 397 Language English File format PDF Category Fitness Book Description: FacebookTwitterGoogle+TumblrDiggMySpaceShare This book covers the latest advances in hepatitis C and hepatitis B therapeutics as well as the emerging and investigational treatment strategies. This book is an up-to-date source of information for physicians, residents, and advanced medical students seeking a broader understanding of treatment of viral hepatitis. The authors of the chapters come from many eminent centers around the world and are experts in their respective fields. As in many areas of medicine, treatment of viral hepatitis has seen an acceleration of change driven by new therapies and evolving technology. Thanks to the direct-acting antiviral agents (DAAs), the era of HCV eradication and cure has begun. As regards to hepatitis B therapy, potent antiviral drugs for suppression of viral replication are available, new research activities to enhance eradication are visible, and these may influence clinical practice in the coming years.     Download (17MB) Neuroblastoma Macular Edema: A Practical Approach The Encyclopedia of Hepatitis and Other Liver Diseases Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis The Cure for Alcoholism: Drink Your Way Sober Without Willpower, Abstinence or Discomfort Load more posts

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