Prof Arif M. Siddiqui

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Innovative approach in the Management of Hepatitis C:

Innovative approach in the Management of Hepatitis C Prof Arif M. Siddiqui MRCP(UK)FRCP(London)FRCP(Edin)FRCP(Glasg) Professor of Medicine A.I.M.C President Pakistan Society of Gastroenterology President Elect Pakistan Society of Hepatology

PowerPoint Presentation:

Response Guided Therapy IL28B DAA’s

Patterns of Virological Response:

Patterns of Virological Response Sustained responder (cure) Nonresponder Baseline Treatment Time Relapser Partial responder HCV RNA Undetectable HCV RNA Breakthrough Detection limit 6 months

Response guided therapy:

Response guided therapy What is it and why do we need it?

Advantages:

Advantages Predicting the likelihood of a response to therapy. Determining the optimal duration of therapy. Laying down stopping rules for patients with CHC. May help in reducing toxicity of therapy. May help in cost saving.

Recommendation:

Recommendation In Genotype 3 disease it is recommended to test PCR as per following routine Base line Quantitative Week4 Qualitative (RVR) Week 12 Quantitative (EVR) Week 24 qualitative (ETR) Week 48 Qualitative (SVR)

Response guided therapy Definations:

Response guided therapy Definations RVR Week 4

Response guided therapy Definitions:

Response guided therapy Definitions EVR Week 12

Response guided therapy Definitions:

Response guided therapy Definitions DVR Week 12 PCR +ve but >2 log fall

Response guided therapy Definitions:

Response guided therapy Definitions NR Week 12

Response guided therapy Definitions:

Response guided therapy Definitions ETR Week 24

Response guided therapy Definitions:

Response guided therapy Definitions SVR Week 48

Definitions:

Definitions

Basic Principal:

Basic Principal The earlier the PCR becomes negative the higher are the chances of SVR And Vice Versa

Time to Undetectable HCV RNA Identified as Best Predictor of SVR:

PPV of HCV RNA Undetectability Determining SVR 86 80 76 0 20 40 60 80 100 Week 4 Week 12 Week 24 PPV for SVR (%) Time to Undetectable HCV RNA Davis GL. Hepatology. 2002;36(suppl 1):S145-S151. Fried MW, et al. N Engl J Med. 2002;34:7975-7982. Manns MP, et al. Lancet. 2001;358:958-965. Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa-2a/RBV phase III trials Time to Undetectable HCV RNA Identified as Best Predictor of SVR

In Genotype 3 disease:

In Genotype 3 disease If a patient develops an RVR You can stop therapy at week 16 with a slight increase in the risk of relapse. Generally advisable not to stop therapy. Can stop therapy if lot of side effects and no negative predictors of therapy

In Genotype 3 disease:

In Genotype 3 disease If NO RVR but develops an EVR then the therapy should be continued for 24 Weeks If No RVR but develops an EVR and has negative predictors of disease e.g. cirrhosis, obesity, metabolic syndrome then therapy may be prolonged to 48 Weeks.

In Genotype 3 disease:

In Genotype 3 disease If develops DVR then therapy should be prolonged to 48 Weeks If RVR and EVR not achieved and <2log drop in viral load then therapy can be stopped at 12 Weeks .

Response guided therapy:

Response guided therapy

Shorter Treatment in Genotype 2/3 Patients Achieving RVR:

82 13 80 5 Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 0 20 40 60 80 100 SVR Relapse 16 weeks (n = 71) 24 weeks (n = 71) Patients with RVR received 16 or 24 weeks PegIFN alfa-2a + weight-based RBV Shorter Treatment in Genotype 2/3 Patients Achieving RVR Patients (%)

Week 4 Response as a Predictor of SVR:

Ferenci P, et al. EASL 2006. Abstract 8. Patients with undetectable HCV RNA by Week 4 on PegIFN alfa-2a + RBV treated for total of 24 weeks SVR rate for Week 4 responders (per-protocol analysis) Overall: 87% – Genotype 1: 84% – Genotype 4: 100% Higher baseline, Week 4 viral load predictive of relapse Baseline Viral Load (IU/mL) Relapse Rate Based on Week 4 Viral Load (ITT Analysis) 7 5 15 22 10 38 0 20 40 60 80 100 All Patients < 600,000 ≥ 600,000 Patients (%) < 10 IU/mL 10-49 IU/mL Week 4 HCV RNA Week 4 Response as a Predictor of SVR

Shorter Treatment in Genotype 2/3 Patients Achieving RVR:

PegIFN alfa-2b + weight-based RBV 12 weeks for patients with RVR; 24 weeks for patients without RVR No RVR, received 24 weeks (n = 80) 85 10 64 6 Mangia A et al. N Engl J Med. 2005;352:2609-2617. 0 20 40 60 80 100 SVR Relapse RVR, received 12 weeks (n = 133) Shorter Treatment in Genotype 2/3 Patients Achieving RVR Patients (%)

Shorter Treatment in Genotype 2/3 Patients Achieving RVR:

Dalgard O, et al. Hepatology. 2004;40:1260-1265. 90 10 56 26 0 20 40 60 80 100 SVR Relapse RVR, received 14 weeks (n = 95) No RVR, received 24 weeks (n = 27) Patients (%) PegIFN alfa-2b + weight-based RBV 14 weeks for patients with RVR; 24 weeks for patients without RVR Shorter Treatment in Genotype 2/3 Patients Achieving RVR

PEGASYS® (Peginterferon Alfa-2a [40KD]) Plus RBV: Week 12 Predictability in Patients With HCV Genotype 2 or 3:

PEGASYS ® (Peginterferon Alfa-2a [40KD]) Plus RBV: Week 12 Predictability in Patients With HCV Genotype 2 or 3 *HCV RNA negative or drop of ³ 2 log 10 PCR. Early Viral Response* 97% (n = 136) 77% (n = 105) 3% (n = 4) 25% (n = 1) HCV genotype 2,3 (n = 140) Ferenci P. AASLD Annual Meeting. 2001. SVR Overall NPV = 75% Yes No

IL28b:

IL28b On Chromosome 19 there is a gene sequence named IL28b. It is the strongest pretreatment predictor of response. Three possibilities c/c c/t t/t

IL28b:

IL28b c/c c/t t/t Whites 82% 42% 33% Blacks 53% 19% 17%

IL28b:

IL28b Marked Racial differences c/c combination most frequent in Asians c/c combination intermediate in Caucasians c/c combination least frequent in African Americas Strongly associated with spontaneous clearance of HCV Test Commercially available now

Directly Acting Antiviral Agents (DAA):

Directly Acting Antiviral Agents (DAA)

DAA:

DAA In-depth understanding of viral molecular replication Various enzymes involved in viral replication are targetted. NS3 Protease Inhibitors are leading the race Teleprevir and Boceprevir SVR in Genotype 1 gone upto 65%

PowerPoint Presentation:

Mathematical modeling has projected that if the rate of response to antiviral therapy increases to 80%, which appears to be likely in the foreseeable future, 13 treatment of half of HCV-infected persons would reduce cases of cirrhosis by 15%, cases of hepatocellular carcinoma by 30%, and deaths due to liver disease by 34% after just 10 years. 13

THANK YOU:

THANK YOU

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