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Hepatitis c
Hepatitis C is a major global public health problem, infecting around 180 million people worldwide. It is a leading cause of liver disease and liver transplants. The hepatitis C virus is a RNA virus that primarily infects liver cells. Around 70-85% of infections become chronic, and 20-40% of chronic infections can lead to severe liver disease like cirrhosis or liver cancer over time. The most common modes of transmission are through blood exposure, though sexual transmission risk is low. There is no vaccine, but effective antiviral treatment exists.
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Hepatitis c
- 1. Lali Sharvadze Associated Professor ViralHepatitis Hepatitis C Infectious Diseases, AIDS & Clinical Immunology Research Center 2016
- 2. Viral Hepatitis AlphabetViralHepatitis Alphabet Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis F Hepatitis GHepatitis G Hepatitis TTVHepatitis TTV
- 3. Viral hepatitisViral hepatitis HepatitisAHepatitis A Hepatitis BHepatitis B Hepatitis CHepatitis C Hepatitis DHepatitis D Enteral rout of transmission Parenteral rout of transmission By ways of transmission Hepatitis EHepatitis E
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- 5. Hepatitis C Is aViral infection of the liver caused by the hepatitis C virus. Definition
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- 7. Global Burden ofHepatitis C Hepatitis C is major public health problem worldwide. About 180 million people are infected with hepatitis C virus It account for 3 percent of global population 3-4 million people become infected with HCV annually About 25 million people are infected in Europe HCV prevalence 5 times exceeds HIV prevalence
- 8. Global Burden ofHepatitis C More then 350 000-500 000 people die every year from Hepatitis C related end-stage liver disease (cirrhoses, HCC, liver failure) Hepatitis C infection is top priority problem for Georgia as well.
- 9. • Infection withthe hepatitis C virus (HCV) remains chronic in 70-85% of infected individuals. • In 20-40% cases of chronic hepatitis C infection leads to end-stage liver diseases: cirrhoses, hepatocellular carcinoma and liver failure after 20-30 years of HCV infection. • Liver failure from chronic hepatitis C is one of the most common reasons for liver transplantation. • Infection with the hepatitis C virus (HCV) remains chronic in 70-85% of infected individuals. • In 20-40% cases of chronic hepatitis C infection leads to end-stage liver diseases: cirrhoses, hepatocellular carcinoma and liver failure after 20-30 years of HCV infection. • Liver failure from chronic hepatitis C is one of the most common reasons for liver transplantation.
- 10. There is noprophylactic vaccine and/or specific immunoglobulin against hepatitis C But effective antiviral treatment exist, which is disease prophylaxis as well
- 12. Epidemiology of hepatitis Cin Georgia Epidemiology of hepatitis C in Georgia
- 13. 6.7% (≈150, 000adults) − General population (age: 18-65) − Patients with HCV Prevalence of HCVPrevalence of HCV in General Population of Georgiain General Population of Georgia Data of 2001-2002Data of 2001-2002 population-based cross-sectional survey of the adult population of Tbilisi.
- 14. 14 Primary Objectives 1.Estimate HCV prevalence in Georgia • Nation-wide • In 6 major cities (including Tbilisi) • Several specific geographical regions • Urban vs. rural 2. Determine HCV genotype distribution and risk factors of HCV transmission Anti-HCV positive 7.1% HCV RNA positive 5.16% HCV prevalence and Genotype distributions According new survey-2015 30.9%30.9% 23.8%23.8%
- 15. HCV Infection inKey Populations Tsertsvadze T. In: Frontiers in Research. Humana Press. 2008:257-261. Shapatava et al. Drug Alcohol Depend. 2006 Apr;82 Suppl 1:S35-8. Richards et al. Int J Tuberc Lung Dis. 2006;10:396-401. CIF, Tanadgoma. BSS Survey among MSM in Tbilisi, 2010.
- 16. Study of Prevalenceof Hepatitis C among HIV infected patients Badridze et al. Prevalence of hepatitis B and C among HIV positive patients in Georgia and it's associated risk factors. Georgian Med News. 2008;(165):54-60. 49% of patients were HIV/HCV co-infected. 49% of patients were HIV/HCV co-infected. 2008 73.4
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- 18. RNA virus Family- Flaviviridae Genus- Hepacivirus Hepatitis C virus is a linear, single-strand, 9600-nucleotide RNA virus.
- 19. Electron micrograph ofhepatitis C virus
- 20. The hepatitisC virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further covered in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteins, E1 and E2, are surrounded in the lipid envelope.
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- 24. At least sixdistinct major genotypes, as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing. At least six distinct major genotypes, as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing.
- 25. HCV 1a HCV 1b HCV 1c HCV 2a HCV 2b HCV 2c HCV 3a HCV 3b HCV 4 HCV 5 HCV 6 I II III IVV VI HCV Genetic Types
- 26. HCVHCV GGGGenotypesenotypes HCVHCV SubtypesSubtypes 1 a, b,c, d, e, f, g, h, i, j, k, l, ma, b, c, d, e, f, g, h, i, j, k, l, m 2 a, b, c, d, e, f, g, h, i, k, l, m, n, o, p, q, ra, b, c, d, e, f, g, h, i, k, l, m, n, o, p, q, r 3 a, b, c, d, e, f, g, h, i, ka, b, c, d, e, f, g, h, i, k 4 a, c, d, e, f, g, h, k, l, m, n, o, p, q, r, s, t, ua, c, d, e, f, g, h, k, l, m, n, o, p, q, r, s, t, u 5 aa 6 a, b, d, f, g, h, i, j, k, l, m, n, o, p, q, r, sa, b, d, f, g, h, i, j, k, l, m, n, o, p, q, r, s HCV genotypesHCV genotypes
- 27. HCVHCV genotipebis gavrcelebagenotipebisgavrceleba msoflioSimsoflioSi
- 28. HCVHCV GenotypeGenotype 1. HCVGenetic type is very strong prognostic marker for HCV antiviral Treatment 1. HCV Genetic type is very strong prognostic marker for HCV antiviral Treatment Clinical significance of HCV genotype
- 29.
- 30. Transmission routes ofHCV Transfussion of infected blood or its products, using nonsterile syringes, needles and medical instruments, transplantation of infected donor organs or tissues, occupasional exposure with infected blood Parenteral Risk of sexual tramission of HCV is very low. In monogamous partners about 2 %. The risk is higher among persons having multiple sexual partners about 4-6% (commercial sex workers, men who have sex with men etc.) Sexual Mother to child Chance of Vertical transmission of HCV is about 5-7 %. The risk is increased if HCV viral load in mother’s blood is high. HCV is not transmitted HCV is not transmitted by air, dropltes, vectors or from animals.
- 31. Persons who shoudbe teste for HCV infection • Intravenous drug users • HIV-infected persons • Hemophilia patients • Patients on dialysis • Blood recipients • Organ transplant patients • Children born from HCV infected mothers • Healthcare professionals who had exposure to infected blood (needle stick, cut, blood contact on mucosa). • Sex partners of HCV infected persons • Persons with elevated liver enzymes
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- 33. The virusreplicates mainly in the hepatocytes of the liver, where it is estimated that daily each infected cell produces approximately fifty virions (virus particles) The virus may also replicate in peripheral blood mononuclear cells, potentially accounting for the high levels of immunological disorders found in chronically infected HCV patients
- 34. Because HCV doesnot replicate via a DNA intermediate, it does not integrate into the host genome.
- 35. To enter thehost cell, HCV E2 and E1 proteins recognize and bond with the CD81 receptors present on the surface of hepatocytes and lymphocytes After the interaction of the virus envelope with the host cell membrane, HCV enters the cell through endocytosis. In the cytoplasm, the messenger RNA then undergoes translation, and polyproteins are processed; the HCV RNA then replicates, after which the new viral 'RNA's are packaged and transported to the surface of the host cell so that they can disseminate and complete a new cycle
- 38. Pathogenesis of HCVinfection Why HCV infection is predominantly chronic? Why HCV infection is predominantly chronic?
- 39. HCV has abilityto “escape” immune response of the host Pathogenesis 1
- 40. HCV is characterizedby rapid and permanent changes in its antigenic structure; antigenic structure changes occur multiple times per minute; Such antigenic variability of this virus makes T and B lymphocytes unable to identify and respond to these permanently changed antigens. HCV is characterized by rapid and permanent changes in its antigenic structure; antigenic structure changes occur multiple times per minute; Such antigenic variability of this virus makes T and B lymphocytes unable to identify and respond to these permanently changed antigens. Pathogenesis 2
- 41. Pathogenesis 3 Antigenic variationsof HCV in the same host is called (quasispecies). Number of Such quasispecies reaches about 1010 – 1011 per day
- 42. Due to variabilityof HCV “Time competition” between new antigenic strains and the speed of neutralizing antibodies develops Due to variability of HCV “Time competition” between new antigenic strains and the speed of neutralizing antibodies develops HCV wins this competitionHCV wins this competition Pathogenesis 4
- 43. Natural History and DiseaseOutcome Natural History and Disease Outcome
- 44. CLINICAL FEATURES 2 formsof Hepatitis C exists: • Acute Hepatitis C • Chronic Hepatitis C
- 45. Acute Hepatitis C Definition Acutehepatitis C is an infectious disease caused by hepatitis C virus, which developes within 6 months after entering virus to the organizm. Disease has symptomatic (with jaundice and without jaundice) and asymptomatic course. In case of symptomatic Acute HCV disease is self limited In 50% of cases.
- 46. Acute hepatitisAcute hepatitisCCAcute hepatitisAcute hepatitis CC With symptomsWith symptoms infeqciuri paTologiis, Sidsisa da klinikuri imunologiis samecniero-praqtikuli centri Without symptomsWithout symptoms
- 47. With JaundiceWith Jaundice infeqciuripaTologiis, Sidsisa da klinikuri imunologiis samecniero-praqtikuli centri Without JaundiceWithout Jaundice Symptomatic Acute Hepatitis c Symptomatic Acute Hepatitis c
- 48. Acute HCVAcute HCV Asymptomatic 75% Asymptomatic 75% WithoutJouncesWithout Jounces JouncesJouncesJouncesJounces recovery 10% ? ? ? recovery 10% ? ? ? Chronic Infection 70-85% Chronic Infection 70-85% Recovery 50%-52% Recovery 50%-52% Symptomatic 25% Symptomatic 25% recovery 15-30% recovery 15-30% Natural History
- 49. Natural history ofHepatitis C Acute HCV Infection 60-85 % Persistent infection15-40% Recovery 20-40% cirrhoses 4-5% HCC
- 52. Fatigue Fever Nausea and vomiting Abdominal pain or discomfort, especially in the area of liver on right side under your lower ribs Clay-colored bowel movements Loss of appetite Low-grade fever Dark urine Joint pain Yellowing of the skin and eyes (jaundice) Main symptoms of Hepatitis C
- 53. Incubation period (Phase): (range,6-12 weeks) after exposed to the virus. During these period patient has no symptoms
- 54. Chronic Hepatitis C Definition Chronichepatitis C is a chronic infection caused by HCV which developes after 6 months from acute phase of infection. Chronic hepatitis C is the main form of HCV infection. It is chronic in 70-85% of infected individuals. usually progresses slowly and is characterised with non-specific clinical symptoms.
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- 56. Anti HCVAnti HCVHCV RNA qualitative and quantitative HCV RNA qualitative and quantitative Serologic and virologic markers of HBV infection
- 57. Major laboratory methodsfor HCV diagnosis 1984- ELISA 1985 -Western blot 1995 -Qualitative and quantitative PCR 2003 -HCV genotyping (INNO Lipa) 2007- HCV quantit. test – using Real Time PCR ( TaqMan technology) 2010 -HCV NS5B and 5’UTR/Core region sequencing
- 58. HCV RNA canbe detected even before acute elevation of aminotransferase activity and before the appearance of anti-HCV in patients with acute hepatitis C. HCV RNA can be detected even before acute elevation of aminotransferase activity and before the appearance of anti-HCV in patients with acute hepatitis C.
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- 60. Liver cirrhosis HHCC healthy lever Liver fibrosis COMPLICATIONS
- 61. Evaluation of liverdisease severity Invasive methodInvasive methodInvasive methodInvasive method Non invasive methodsNon invasive methodsNon invasive methodsNon invasive methods
- 62. Invasive methodInvasive methodInvasivemethodInvasive method Liver biopsyLiver biopsy Advantages Disadvantages
- 63. Noninvasive methodsNoninvasive methodsNoninvasivemethodsNoninvasive methods Instrumental methodsInstrumental methodsInstrumental methodsInstrumental methods Laboratory MethodsLaboratory Methods
- 64. ultrasonographyultrasonography Computed tomographyComputedtomography KTKT Magnetic ResonanceMagnetic Resonance InvestigationsInvestigations- MRI- MRI Liver ElastrographyLiver ElastrographyLiver ElastrographyLiver Elastrography Instrumental methods for diagnosis of HepatitisInstrumental methods for diagnosis of Hepatitis
- 65. Liver Elastrography by Fibroscan Elasticity (KPA) <5.55.5-8 8-10 10-12.5 12.5-14 >14 Metavir F0-F1 F2 F2-F3 F3 F3-F4 F4 Correlation between the KPA and METAVIR scores The method is based on ultrasound principle. A mechanical pulse (wave) is spread through the liver. The velocity of the wave is measured by ultrasound. The velocity is directly correlated to the stiffness of liver, which in turn reflects the degree of fibrosis. Non invasive method for evaluation liver Fibrosis /Cirrhosis Fibroscan
- 66. Liver Elastography Stifnness (kpa) <5.5 5.5-88-10 10-12.5 12.5-14 >14 Metavir F0-F1 F2 F2-F3 F3 F3-F4 F4 results by Fibroscan measured in kpa is correlated to Metavir score in the following way The method is based on ultrasound principle. Velocity of share wave in the liver is measured by ultrasound sensor, which than corresponds to the stiffness of the liver tissue. The stifnness correlates to the degree of liver fibrosis. New and most precise method for the measurement of liver fibrosis
- 67. Was implemented since 2007 Noninvasive method for evaluation liver Fibrosis /Cirrhosis Liver Elastrography by Fibroscan
- 68. FibroScan 2.5 cm 4 cm 1cm ∅ Explored volume The probe induces an elastic wave through the liver The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface
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- 70. The 19The 19thth internationalConference of the APASLinternational Conference of the APASL 13-16 February 2009 Hong Kong Michael P. Manns, Hanover Chronic HCV is the first and currently only chronic infection, which became curable. Announcement Michael P. Manns. APASL 2009 Hong Kong
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- 72. 6 16 34 42 39 56 75 >97>90 0 20 40 60 80 100 1986 19981991 20012002 2011 INF 6m INF 12m INF/RBV 6m INF/RBV 12m PEG 12m REG/RBV 12m SOF + REG/RBV 2014 REG/RBV + DAA SVR% SOF + REG/RBV Boceprevir Telaprevir 2013 HARVONI Milestones of hepatitis C treatment
- 73. 2001 – 2011years Standard of care (SOC) Dual therapy PEG-Interferon + Ribavirin
- 74. 2011 DAA (direct acting antiviral) Telaprevirand Boceprevir
- 75. Triple therapy PEG-Interferon +Ribavirin Telaprevir or Boceprevir + For HCV genotype 1
- 76. DAA (direct acting antiviral) Direct-actingantivirals (DAAs), are medications targeted at specific steps within the HCV life cycle. DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection.
- 77. Classes of DAAs 1.NS3/4A - protease (serin) inhibitors P 3. NS5B- polymerase inhibitors 2. NS5A- inhibitors • nucleoside polymerase inhibitors • non-nucleoside polymerase inhibitors .
- 80. HCV Life Cycleand DAA Targets Adapted from Manns MP, et al. 2007 Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly NS3/4A protease inhibitors NS5B polymerase inhibitors NS5A inhibitors “Previr’s” Boceprevir, Telaprevir, Simeprevir, Faldaprevir “Buvir’s” Sofosbuvir, Deleobuvir “Asvir’s” Daclatasvir, Ledipasvir DAA Uncoating Receptor binding
- 81. Pagilated Interferon alpha2a (Pegasys) Pagilated Interferon alpha 2b (PegIntron) Ribavirin (Copegus, Rebetol) Boceprevir (Victrelis) Telaprevir (Incivek, Incivo) Simeprevir (Olisio) Sofosbuvir (Sovaldi) Daclatasvir (Daklinza) Dasabuvir (Exviera) Sofosbuvir/ledipasvir (Harvoni) Ombitasvir/Paritaprevir/Ritonavir +dasabuvir (Viekira PaK) Ombotasvir/Paritaprevir/Ritonavir (Viekirax) Grazoprevir/Elbasvir (Zepatier) Sofosbuvir/Velpatasvir (Epclusa) 2016 July Drugs for HCV (FDA approved)
- 82. Direct Acting AntiviralsDAAs Simeprevir (Olisio) Sofosbuvir (Sovaldi) Daclatasvir (Daklinza) Dasabuvir (Exviera) Sofosbuvir/ledipasvir (Harvoni) Ombitasvir/Paritaprevir/Ritonavir +dasabuvir (Viekira PaK) Ombotasvir/Paritaprevir/Ritonavir (Viekirax) Grazoprevir/Elbasvir (Zepatier) Sofosbuvir/Velpatasvir (Epclusa) 2016 July I Generation Boceprevir (Victrelis) Telaprevir (Incivek, Incivo) II Generation 2011 2013-2014-2015-2016
- 83.
- 84. Treatment Regimens forHCV I Interferon Containing Regimens Interferon Free Regimens
- 85. April 20152015-2016 Treatment regimens InterferonContaining PEG/RBV+SOF PEG/RBV+SMV PEG/RBV+SOF PEG/RBV+SMV Interferon Free SOF/LDP (Harvoni) SOF/LDP + RBV SOF+RBV SOF+SMV SOF+SMV+RBV SOF+DCV SOF+DCV + RBV VIEKIRA PAK VIEKIRA PAK +RBV EBV/GZR EBV/GZR +RBV SOF/VEL (Epclusa) SOF/VEL +RBV SOF/LDP (Harvoni) SOF/LDP + RBV SOF+RBV SOF+SMV SOF+SMV+RBV SOF+DCV SOF+DCV + RBV VIEKIRA PAK VIEKIRA PAK +RBV EBV/GZR EBV/GZR +RBV SOF/VEL (Epclusa) SOF/VEL +RBV
- 86. April 20162016 PEG/RBV+SOF PEG/RBV+SMV PEG/RBV+SOF PEG/RBV+SMV SOF/LDP (Harvoni) SOF/LDP + RBV SOF+RBV SOF+SMV SOF+SMV+RBV SOF+DCV SOF+DCV + RBV VIEKIRA PAK VIEKIRA PAK +RBV EBV/GZR EBV/GZR +RBV SOF/VEL (Epclusa) SOF/VEL +RBV SOF/LDP (Harvoni) SOF/LDP + RBV SOF+RBV SOF+SMV SOF+SMV+RBV SOF+DCV SOF+DCV + RBV VIEKIRA PAK VIEKIRA PAK +RBV EBV/GZR EBV/GZR +RBV SOF/VEL (Epclusa) SOF/VEL +RBV Treatment regimens Interferon Containing Interferon Free
- 87. Treatment regimens EASL 2016 2Pangenotypic Regimens
- 88. EASL 2016 Treatment regimens 2Pangenotypic Regimens
- 89.
Editor's Notes
- #14 Study was performed in 2001-2002. population-based cross-sectional survey of the adult population of Tbilisi. Number of study participants were 2000 persond
- #17 In 2008 study of hepatitis C prevalence was conducted in HIV infected Georgian cohort of patients. The aim of the study was to determine the prevalence of hepatitis C among HIV positive patients and to identify most relevant risk factors of co-infection . Total 175 patients were included in analysis. The study revealed high prevalence of hepatitis C among HIV positive patients. Almost half (48.57%) HIV positive patients were co-infected with HCV. Major risk factor of co-infection was related to drug use, needle and injection equipment sharing. Prevalence of HCV among injecting drug users was (73.40%).
- #78 GT, genotype; HCV, hepatitis C virus; IFN, interferon; LLOQ, lower limit of quantification; P/R, peginterferon/ribavirin; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment; UII, Unwilling/Intolerant/Ineligible. Paul Y. Kwo, MD: To summarize our discussion of the phase III trials of sofosbuvir, the NEUTRINO study demonstrated high SVR rates with a 12-week regimen of sofosbuvir plus peginterferon/ribavirin in genotypes 1, 4, 5, and 6 HCV, and I think this will become the new gold standard for treatment-naive individuals with genotype 1 HCV infection when it is approved. Although many patients are reluctant to embark on interferon-based therapy, there are also many individuals who will not be daunted by a short 12-week course of peginterferon/ribavirin when combined with sofosbuvir, which has minimal additional adverse events. Moreover, if these patients fail, they will likely fail with virologic relapse, and it is encouraging that in this setting the likelihood of resistance associated variants will be minimal, if at all. Regarding genotypes 4, 5, and 6 HCV, there is a very high SVR rate, and it will be important to still explore this combination further in larger studies. There are not yet data in patients with genotypes 1, 4, 5, or 6 HCV infection who have previously failed interferon-based therapy, although I suspect that these areas will be explored once this combination is available. David R. Nelson, MD: All of the phase III studies suggest that sofosbuvir is a potent, safe treatment option, and consequently, sofosbuvir is likely to gain approval in the coming months, at least in North America, for patients infected with genotype 1 HCV in combination with peginterferon/ribavirin and for patients infected with genotypes 2 and 3 HCV as the first all-oral, interferon-free regimen. Stefan Zeuzem, MD: Once sofosbuvir is initially approved in combination with peginterferon/ribavirin, I will be curious to see how many patients infected with genotype 1 HCV will request to be treated with only sofosbuvir and ribavirin (without peginterferon). There is a very heterogeneous data set in the literature of small phase II studies with sofosbuvir and ribavirin. In some of these studies, although a small number of patients were included, genotype 1 HCV demonstrated SVR rates in the range of 70% or more.[1,2] I would not be surprised if some physicians and patients reviewing those data decide to attempt treatment with sofosbuvir and ribavirin dual therapy in genotype 1 HCV infection. David R. Nelson, MD: There are certainly many patients who would rather not receive interferon-based treatment. Once simeprevir is also approved—which is discussed below—and physicians will have the opportunity to offer an off-label regimen such as sofosbuvir plus simeprevir; alternatively, some might consider an extended duration of sofosbuvir/ribavirin treatment, which has been evaluated in phase II trials.[2] However, I think that for patients with the IL28B CC genotype, peginterferon is a very potent drug and, for cost reasons and for the very short 12-week duration, peginterferon will continue to play a significant role. Paul Y. Kwo, MD: In our clinic, we certainly have patients who, for SVR rates approaching 90%, will be willing to undergo 12 weeks of treatment with peginterferon/ribavirin combined with sofosbuvir. I certainly recognize, however, that there is a strong desire to move away from peginterferon-based therapies, such that all individuals with hepatitis C will be candidates for all-oral therapy. David R. Nelson, MD: I can also envision a hybrid model, in which one might encourage genotype 1 HCV–infected patients to start treatment with sofosbuvir plus peginterferon/ribavirin, since this offers the highest current SVR rates, but if patients have a difficult time tolerating peginterferon, one might discontinue peginterferon if necessary and continue therapy with an all-oral peginterferon-free regimen. References 1. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, 2013. Abstract 155LB. 2. Osinusi A, Bon D, Herrmann E, et al. High efficacy of sofosbuvir with weight-based ribavirin for 24 weeks in difficult-to-treat patients. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, 2013. Abstract 157LB.
- #81 DAA, direct-acting antiviral; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain; NS5A/B, nonstructural protein 5A/B. Now, one of the advantages of direct-antivirals for hepatitis C virus is that, unlike some of other virus, like HBV, for example, hepatitis C has a number of potential targets for drug development, and this has led to multiple classes of direct-acting antivirals being developed. So, if we look at this schematic of the HCV life cycle, you can see that after the virus enters the cell, the viral RNA is translated to lead to the viral proteins and then these are chopped up by the virally encoded protease. And of course, the first direct-acting antivirals were inhibitors of the NS3/4A protease. Subsequently, the viral RNA is replicated, and again, the HCV NS5B polymerase has been a target for inhibition, with both nucleotide polymerase inhibitors and nonnucleotide or nonnucleoside polymerase inhibitors, which act by a different mechanism of action but target the same enzyme. In addition, after viral replication occurs, the virus must be assembled and part of the replication complex involved in assembly is the nonstructural 5A protein—or NS5A—and a number of direct-acting antivirals target the NS5A protein. So, at least to date, the DAAs that have gone through clinical development include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, and NS5A inhibitors.