Dr. Siddharth Srivastava MD, DM (Gastroenterology) Associate Professor GIPMER, New Delhi Rashtriya Gaurav Award 2013 for work on hepatitis B and C Set up Liver clinic at GIPMER and in charge EUS laboratory. Multiple publications in indexed journals
Hepatitis C: Current Perspectives This Session is sponsored by MYLAN PHARMACEUTICALS (P) LTD.
Introduction Viral hepatitis kills about 1.45 million people per year globally Slightly lesser deaths than due to HIV But much more than TB and Malaria HBV and HCV cause most of viral hepatitis due to Cirrhosis and HCC Deaths due to HBV plateau since 1990 but due to HCV continues to rise Gut; 64:2015
Mortality Rates in the US, 1999-2007 Rate per 100,000 PY* 7 6 5 4 3 2 1 0 HIV Hepatitis C Hepatitis B *Mortality rates = HBV, HCV, HIV listed as cause of death Because decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection Ly KN, et al. Ann Intern Med. 2012;156:271-278. Yr
Natural History
Natural History
Natural History Depends on: Gender (Male > Female) Age at infection IL28 gene polymorphism Co infection with HIV Concomitant alcohol use
Lancet 2009 Age and Natural history
Nature 2009 IL28B and Natural history
Hepatology 2001 HIV Coinfection
Hepatology 1998 Alcoholism
Management of HCV
HCV Viral Replication: Higher All-Cause Mortality Cumulative Mortality (%) 35 30 25 20 15 10 All Causes Anti-HCV seropositives, HCV RNA detectable Anti-HCV seropositives, HCV RNA undetectable Anti-HCV seronegatives P <.001 for comparison among 3 groups P <.001 for HCV RNA detectable vs undetectable 30.1% 12.8% 12.4% 5 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up (Yrs) Lee MH, et al. J Infect Dis. 2012;206:469-477.
HCC Incidence in Cirrhotic Patients: SVR vs No SVR 50 40 No SVR SVR HCC Incidence (%) 30 20 15.6% 7.7% P =.0009 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Yrs) Median follow-up: 10 yrs Purevsambuu T, et al. EASL 2014. Abstract O125.
SVR Prevents Development of Insulin Resistance 25 P =.007 P =.1 P =.04 Rates of de Novo IR (%) 20 15 10 5 7% 17% 8% 16% 7% 20% SVR Non-SVR 0 17/230 21/124 6/78 15/94 11/152 6/30 Overall HCV GT 1/4 HCV GT 2/3 Aghemo A, et al. Hepatology. 2012;58:1681-1687.
When and whom to initiate therapy Non-Modifiable factors Fibrosis stage Inflammation grade Age at infection Gender Organ transplant Modifiable Alcohol NAFLD Obesity Insulin resistance Viral Genotype 3 Coinfection
Cirrhosis: A Continuous Spectrum of Disease ESLD Child-Pugh B Portal hypertension high risk Cirrhosis treatment candidate Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score
Severity of Disease Increases Need for HCV Therapy but Also Impairs Response May not need immediate treatment BUT Easier to treat High likelihood of response Greater need for treatment BUT Response to current IFN-based therapy may be impaired Mild disease Advanced disease/ cirrhosis
Drugs for HCV
Very Few HCV Patients treated 2.7-3.9 million infected 50% HCV detected 32% to 38% referred for care 7% to 11% treated Asrani SK, et al. Curr Gastroenterol Rep. 2014;16:381.
Milestones in Therapy of CHC: Average SVR Rates from Clinical Trials + Ribavirin Standard 1998 Interferon 1991 + DAAs Peginterferon 2011 2001 70+% 55% 34% 42% 39% 6% 16% Lawitz et al Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011
Direct acting antivirals Suffix: Asvir Suffix: buvir Suffix: Previr
EASL 2015 HCV: Tx-Naive & PR-Exp d, GT2 or 3 No Cirrhosis Compensated Cirrhosis (Child-Pugh A) Regimen GT2 GT3 GT2 GT3 SOF + PR 12 wks 12 wks 12 wks 12 wks SOF + RBV 12 wks 24 wks 16-20 wks Not recommended SOF + DCV 12 wks, no RBV 12 wks, no RBV 12 wks, no RBV 24 wks + RBV EASL HCV Guidelines. April 2015.
BOSON: SOF + PegIFN/RBV for 12 Wks vs SOF + RBV for 16 or 24 Wks in GT2/3 HCV Multicenter, randomized, open-label study Key baseline characteristics: 92% GT3, ~ 38% IL28B CC, ~ 53% previously treated, ~ 37% with cirrhosis Stratified by cirrhosis, HCV GT, previous HCV tx Wk 12 Wk 16 Wk 24 SVR12, % (n/n) GT2 GT3 GT2 HCV infected txexperienced pts with cirrhosis and GT3 HCV infected tx-naive or txexperienced pts with or without cirrhosis (N = 592) Sofosbuvir 400 mg QD + RBV* (n = 196) Sofosbuvir 400 mg QD + RBV* (n = 199) Sofosbuvir 400 mg QD + PegIFN + RBV* (n = 197) 87 (13/15) 100 (17/17) 94 (15/16) 71 (128/181) 84 (153/182) 93 (168/181) *RBV: 1000-1200 mg/day. PegIFN alfa-2a: 180 μg/wk. Foster GR, et al. EASL 2015. Abstract LO5.
BOSON: SVR12 in GT3 by Tx History and Cirrhosis Status SVR12 (%) SOF + RBV 16 wks SOF + RBV 24 wks SOF + PegIFN/RBV 12 wks 100 80 60 40 83 96 90 91 94 82 82 77 76 86 57 47 20 n/n = 0 58/ 70 65/ 72 68/ 71 12/ 21 Treatment Naive Treatment Experienced Foster GR, et al. EASL 2015. Abstract LO5. Reproduced with permission. 18/ 22 21/ 23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis 41/ 54 44/ 54 49/ 52 17/ 36 26/ 34 30/ 35
BOSON: Pts Without SVR12 and Safety/Tolerability Outcome 16 Wks SOF + RBV (n = 196) 24 Wks SOF + RBV (n = 199) 12 Wks SOF + PegIFN/RBV (n = 197) On-treatment failure, n (%) 0 3 (2) 0 Relapse, n/n (%) 52/195 (27) 24/195 (12) 9/195 (5) Other,* n (%) 3 (2) 2 (1) 5 (3) Safety Outcome, n (%) AEs 185 (94) 188 (95) 195 (99) Grade 3/4 AE 11 (6) 7 (4) 15 (8) Serious AE 8 (4) 10 (5) 12 (6) Tx discontinuation for AE 3 (2) 2 (1) 1 (<1) Grade 3/4 lab abnormality 30 (15) 29 (15) 74 (38) Hemoglobin < 10 g/dl 7 (4) 12 (6) 24 (12) Hemoglobin < 8.5 g/dl 0 0 2 (1) Platelets < 50,000 cells/mm 3 1 (1) 0 9 (5) *Pts who discont. before achieving HCV RNA < LLOQ or did not return for Wk 12 posttreatment visit. Foster GR, et al. EASL 2015. Abstract LO5. Reproduced with permission.
Treatment for GT1 Option I (12 weeks, no Cirrhosis): Daclatasvir (60mg) + Sofosbuvir (400mg) ± Riba Option II (24 weeks, cirrhosis): Daclatasvir + Sofosbuvir ± Riba Option III (12 weeks): Ledipasvir 90 mg + Sof Option IV (24 weeks): RBV+SOF Option V (12-48 weeks): PegIFN+SOF+RIba AASLD 2015
Treatment for GT3 Option I (12 weeks, no Cirrhosis): Daclatasvir (60mg) + Sofosbuvir (400mg) ± Riba Option II (24 weeks, cirrhosis): Daclatasvir + Sofosbuvir ± Riba Option III (12 weeks): PegIFN+SOF+RIba Option IV (24 weeks): RBV+SOF AASLD 2015
EASL HCV Guidelines 2014: Genotype 2-6 EASL. J Hepatology. 2014;60:392-420.
Genotype GT 2 Options Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment experienced) (A1) PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1) GT 4 PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegifn/ribavirin alone or a further 12 wks of pegifn/ribavirin + daclatasvir (response-guided therapy) (B1) Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2) Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics) (B2) GT5/6 Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced patients (ribavirin may be added in previous nonresponders and cirrhotics) (B2) PegIFN/ribavirin + sofosbuvir 12 wks (B1) Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
Conclusion Peg IFN is backbone of treatment for HCV geno 3 Inclusion of Peg IFN decreases cost by almost 50% as compared to all oral regimen Newer DAAs are better tolerated Pangenotypic DAAs have changed algorithms for management of HCV DAAs: GT 3 treatment results are suboptimal
Conclusions For hepatitis prevention is better than cure Follow 3 golden S of safety with safe: Sex Syringes (needles. Razors and tattoo equipments) Surgery (Blood and blood products, surgical instruments) Don t panic All contacts should be screened for HBV and HCV Excellent treatment options available
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