HCV Viral Load Determination and Therapeutic Consequences? - PowerPoint PPT Presentation

HCV Viral Load Determination and Therapeutic Consequences? Christoph Jochum Clinic for Gastroenterology & Hepatology University Hospital Essen

What Can HCV viral load possibly tell a physican? When do I need to initiate therapy? How do I have to treat a patient?

Natural Course of HCV-Infection 1 / 3 Resolve after acute Hepatitis C 1 / 3 chronic asymptomatic HCV-Carrier 1 / 3 chronic progressive Hepatitis C ( ´ Cirrhosis, ´ HCC-development)

Does the HCV Viral Load Tell Something About the Natural Course?  No! Certainly not a single meassurement.  Factors which influence the natural course:  IL28B Genotype  Inflammation in the liver (Elevated ALT)  Age at infection  Race  Alcohol consumption/ Fatty liver disease  HIV/HBV coinfection  High BMI  Iron/HFE Gene

When to Start Therapy – German Guidelines Chronic HCV Infection untreated pretreated - Chronic Extraheaptic Patients wish urgency optimizing hepatitis manifestations Other reasons + + + „watch and wait“ Contra- Control every Indications for Peg-IFN + Riba 6-12 Mo - Therapy with Peg-IFN + Riba +/- DAA +/. DAA

What can HCV viral load tell a physican? How do I have to treat a patient?

Therapeutic Options for HCV-Infection 2012 1992 1998 2001 2002 2011 Interferon Interferon Telaprevir Ribavirin Peg-Interferon Boceprevir Alpha 2b Ribavirin Peg-Interferon Alpha 2a Ribavirin

IL28B Genotype the Strongest Baseline Predictor of SVR With PegIFN/RBV Odds Ratio (95% CI) Fasting Serum Glucose < 5.6 mmol/L P < .0001 Hispanic vs Black P = .004 Metavir F0-2 P < .0001 White vs Black P < .0001 HCV RNA ≤ 600,000 IU/mL P < .0001 CC vs Non-CC P < .0001 0 1 2 3 4 5 6 7 8 Thompson AJ, et al. Gastroenterol. 2010;139:120-129. Source: CCO

IL28B Genotype Also Predicts Likelihood of Achieving SVR With BOC or TVR SPRINT-2: BOC + PR48 [1] ADVANCE*: T12PR [2] 100 100 90 80 80 73 80 71 71 SVR (%) SVR (%) 59 60 60 40 40 20 20 n/ 44/ 82/ 26/ n/ 45/ 48/ 16/ N = 55 115 44 N = 50 68 22 0 0 CC CT TT CC CT TT * IL28B testing in ADVANCE was in white pts only. 1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. Source: CCO

IL28B Genotype Predicts Likelihood of Shortened Therapy With BOC or TVR SPRINT-2: BOC + PR [1] ADVANCE*: T12PR [2] 100 100 Eligibility for Shortened 89 Eligibility for Shortened 78 80 80 Therapy (%) Therapy (%) 57 60 60 52 45 40 40 20 20 n/ 118/ 158/ n/ 39/ 39/ 10/ N = N = 132 304 50 68 22 0 0 CC CT/TT CC CT TT * IL28B testing in ADVANCE was in white pts only. 1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. Source: CCO

German Hepatitis C Guidelines Genotype 1 + 4 Stop therapy <2log decline HCV -RNA bzw positive >30000 IU/ml Tx start Week 4 Week 12 Week 24 HCV-RNA HCV-RNA HCV-RNA HCV-RNA HCV-RNA HCV-RNA HCV-RNA <12-15 IU/ml <12-15 IU/ml <12-15 IU/ml + At start <8 x10 5 IU/ml 24 weeks 48 weeks 72 weeks therapy therapy therapy

German Hepatitis C Guidelines Genotype 2 + 3 Stop therapy <2 log decline Week 8 Tx start week 4 HCV-RNA HCV-RNA HCV-RNA HCV-RNA HCV-RNA HCV-RNA <12-15 IU/ml <12-15 IU/ml >2 log Abfall + start <8 x10 5 IU/ml 16 week 24 weeks 48 weeks therapy therapy therapy

Patterns of Virologic Response 7 Null response HCV RNA (log 10 IU/mL) [1] 6 5 Partial response 4 3 Relapse 40% chance 2 of SVR with pegIFN/RBV [2] 1 Undetectable RVR EVR EOT SVR 0 -8 -4 -2 0 4 8 12 16 20 24 32 40 48 52 60 72 Wks After Start of Therapy 1. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 2. McHutchison JG, et al. N Engl J Med. 2009;361:580-593. Source: CCO

Addition of TVR or BOC to PegIFN/RBV Improves SVR in Genotype 1 Patients  HCV NS3/4A protease inhibitors BOC and TVR approved by FDA, May 2011 [1,2]  Indicated in combination with pegIFN/RBV for treatment of genotype 1 HCV–infected patients who are previously untreated or who have failed previous therapy 100 PegIFN + RBV 69-83 BOC/TVR + pegIFN + RBV 80 63-75 SVR (%) 40-59 60 38-44 29-38 40 24-29 20 7-15 5 0 Treatment Naive [3,4] Relapsers [5,6] Partial Null Responders [5,6] Responders [6,7] 1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 4. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 6. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 7. Vierling J, et al. AASLD 2011. Abstract 931. Source: CCO

Proper Use of HCV Assays Essential For Successful Management With HCV PIs  HCV RNA level important throughout treatment to determine  Eligibility for shortened therapy (response-guided therapy)  Discontinuation of therapy due to futility  Minimizes risk of resistance and unnecessary adverse events  Assessment of EOT response  Assessment of SVR  Additional genetic testing may help predict response to treatment Source: CCO

HCV RNA Levels and Relationship to LLOD and LLOQ HCV Treatment 1000000 Detectable/ quantifiable 100000 10000 1000 Viral RNA Titer 100 LLOQ Detectable/not quantifiable 10 LOD Not quantifiable 1 ± detectable 0.1 Goal of anti- Undetectable HCV therapy 0.01 SVR 0.001 Time Adapted from Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8. Source: CCO

SVR Rate by HCV RNA Status for BOC or TVR  SVR rate lower when HCV RNA not undetectable at key time points during therapy Undetectable BOC/PR RGT T12/PR Detectable/Below LLOQ Above LLOQ (> 25 IU/mL) 100 100 80 80 SVR (%) SVR (%) 60 60 40 40 20 20 0 0 4 6 8 10 12 16 20 4 8 10 12 16 20 Treatment Wk Treatment Wk Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8. Source: CCO

Predictive Value of Baseline HCV RNA for Achieving SVR ≤ 800,000 IU/mL < 800,000 IU/mL 100 100 ≥ 800,000 IU/mL > 800,000 IU/mL 85 78 76 74 75 75 63 61 SVR (%) SVR (%) 50 50 25 25 64/ 207/ 45/ 197/ 41/ 192/ n/N = n/N = 82 281 53 313 54 314 0 0 BOC/PR48 BOC/PR RGT T12PR arm ADVANCE (TVR) [1] SPRINT-2 (BOC) [2] 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Source: CCO

Patients Responding Early Can Achieve High SVR Rates With Shortened Therapy  Response-guided therapy : patients who achieve optimal virologic response at early time points can receive abbreviated therapy without reducing their chance of SVR  Patients eligible for RGT  Boceprevir : noncirrhotic treatment-naive patients, previous relapsers, and previous partial responders [1,2]  RGT criterion: Must achieve undetectable HCV RNA at Wk 8 (ie, Wk 4 of triple therapy) and maintain it at Wk 24  Telaprevir : noncirrhotic treatment-naive patients and previous relapsers* [2,3]  RGT criterion: Must achieve undetectable HCV RNA at Wk 4 of triple therapy and maintain it at Wk 12 *AASLD guidelines state that RGT may be considered with TVR in previous partial responders. 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011. Source: CCO

Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients  Indicated for all noncirrhotic treatment-naive patients HCV RNA Undetectable Undetectable < 100 IU/mL PegIFN BOC + PegIFN + RBV Early response stop at Wk 28; f/u 24 wks + RBV 0 4 8 12 24 28 36 48 HCV RNA Slow response extend triple therapy Detectable Undetectable < 100 IU/mL to Wk 36; PR to Wk 48; f/u 24 wks PegIFN BOC + PegIFN + RBV PegIFN + RBV + RBV 4 8 12 24 28 36 0 48 Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source: CCO

Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients  Indicated for noncirrhotic previous relapsers or partial responders HCV RNA Undetectable Undetectable < 100 IU/mL PegIFN Early response stop BOC + PegIFN + RBV + RBV at Wk 36; f/u 24 wks 0 4 8 12 24 28 36 48 HCV RNA Detectable Undetectable < 100 IU/mL Slow response PR to Wk 48; f/u 24 wks PegIFN BOC + PegIFN + RBV PegIFN + RBV + RBV 4 12 28 36 0 8 24 48 Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source: CCO

Response-Guided Therapy Paradigm With TVR + PegIFN/RBV  Indicated for all noncirrhotic treatment-naive patients and noncirrhotic previous relapsers HCV RNA Undetectable Undetectable Undetectable TVR + PegIFN + RBV PegIFN + RBV eRVR stop at Wk 24, f/u 24 wks 0 4 12 24 48 HCV RNA Undetectable or Detectable detectable (≤ 1000 IU/mL) (≤ 1000 IU/mL) Undetectable No eRVR extend pegIFN + RBV to Wk 48; f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV 0 4 12 24 48 Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Source: CCO