New treatment options for HCV: implications for the Optimal Use of HCV Assays

Transcription

1 New treatment options for HCV: implications for the Optimal Use of HCV Assays Hans Orlent Dept. of Gastroenterology & Hepatology AZ Sint Jan Brugge-Oostende, Brugge This program is supported by educational grants from

2 HCV treatment Aim is persistent viral eradication Treatment of finite duration Clinical endpoint: Sustained Virological response (SVR) SVR equals cure

3 Kieffer T L et al. J. Antimicrob. Chemother. 2010;65:

4 HCV Genotype and Subtype HCV classified into 6 major genotypes (1-6) [1] Genotype 1 (subtypes a and b) most common in United States (~ 75%) [2] Subtype 1a more common than subtype 1b Determining major genotype recommended for proper clinical management and predicting likelihood of response [3] No current recommendations regarding HCV subtype testing 1. Simmonds P, et al. Hepatology. 2005;42: Zein N. Clin Microbiol Rev. 2000;13: Ghany MG, et al. Hepatology. 2009;49:

5 Commercially Available HCV Genotype Assays Genotype assay Manufacturer Method Trugene 5'NC HCV Genotyping kit Siemens Direct sequence analysis of the 5' noncoding region INNO-LiPa HCV II Innogenetics Reverse hybridization analysis using genotypespecific oligonucleotide probes located in the 5' noncoding region Versant HCV Genotyping Assay 2.0 Abbott RealTime HCV Genotype II Siemens Abbott Reverse hybridization analysis using genotypespecific oligonucleotide probes located in the 5' noncoding region Genotype-specific real-time PCR of the 5' noncoding region and NS5b Incorrect typing among major genotypes rare (< 3%) Ghany MG, et al. Hepatology. 2009;49:

6 SVR: <50 IU/ml week 24 follow-up weken 24 weken Genotype 1 Genotype 2 / Peginterferon-ribavirin 0 Peginterferon-ribavirin week 12 stopping rule <2log10 drop: futility Manns, Lancet 2001; Fried, NEJM 2002, Hadziyannis Ann Int Med 2004

7 Patterns of Virologic Response HCV RNA (log 10 IU/mL) [1] Null response Partial response 3 Relapse 40% chance of 2 SVR with 1 Undetectable pegifn/rbv [2] RVR 4 8 EVR EOT SVR 72 Wks After Start of Therapy 1. Ghany MG, et al. Hepatology. 2009;49: McHutchison JG, et al. N Engl J Med. 2009;361:

8 1 0 Telaprevir 750 mg q8h median, placebo group 0.0 HCV RNA Change from Baseline (Log 10 IU/mL) * * Lowest VX-950 exposure in dose group Study Time (in Days) -6.0 Reesink et al.. Gastro 2006; 131(4):

9 TVR + PEG-IFN alfa-2a + Ribavirin 8 HCV RNA (log IU/mL Study Time (in Days) median Limit of Quantitation Limit of Detection

10 Addition of Telaprevir or Boceprevir to PegIFN/RBV Improves SVR in GT 1 Pts 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 SVR (%) Treatment Naive [3,4] RGT 24 weeks Relapsers [5,6] Partial Responders [5,6] PegIFN + RBV BOC/TVR + pegifn + RBV Null Responders [6,7] 1. Boceprevir [package insert]. May Telaprevir [package insert]. May Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Zeuzem S, et al. N Engl J Med. 2011;364: Vierling J, et al. AASLD Abstract

11 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 RGT) Discontinuation of therapy due to futility Minimizes risk of resistance and unnecessary adverse events Assessment of EOT response Assessment of SVR

12 Package inserts for BOC and TVR specify different time points for monitoring HCV RNA Different HCV RNA thresholds used for defining treatment futility with BOC vs TVR Different HCV RNA thresholds used for RGT determination vs SVR Available HCV RNA assays in practice have different quantifiable ranges

13 FDA-Approved Qualitative HCV RNA Assays Assay (Manufacturer ) Method LLOD, IU/mL Setting Amplicor HCV v2.0 (Roche Molecular Systems) Cobas Amplicor HCV v2.0 (Roche Molecular Systems) Ampliscreen (Roche Molecular Systems) Versant HCV RNA Qualitative Assay (Siemens Healthcare Diagnostics) Procleix HIV-1/HCV Assay (Chiron Corporation) Manual RT-PCR 50 Semiautomated RT-PCR 50 Diagnosis and monitoring Diagnosis and monitoring Semiautomated RT-PCR < 50 Blood screening Semiautomated TMA 10 All assays report HCV RNA as detected/not detected Diagnosis and monitoring Manual TMA < 50 Blood screening Ghany MG, et al. Hepatology. 2009;49:

14 Quantitative HCV RNA Assays Assay (Manufacturer) [1] Method Dynamic Range, IU/mL (LLOQ-ULOQ) Amplicor HCV Monitor (Roche Molecular Systems) Cobas Amplicor HCV Monitor V2.0 (Roche Molecular Systems) LLOD, IU/mL LLOQ = LLOD FDA Approved Manual RT-PCR ,000 N/A N/A Yes Semiautomated RT-PCR , Yes Yes Versant HCV RNA 3.0 Assay (bdna) (Siemens Health Care Diagnostics) Semiautomated bdna signal amplification 615-7,700, Yes Yes LCx HCV RNA-Quantitative Assay (Abbott Diagnostics) SuperQuant (National Genetics Institute) Cobas TaqMan HCV Test (Roche Molecular Systems) COBAS TaqMan HCV Test v2.0 for use with High Pure System (Roche Molecular Systems) Abbott RealTime HCV Assay (Abbott Diagnostics) Semiautomated RT-PCR 25-2,630, No No Semiautomated RT-PCR 30-1,470, Yes No Semiautomated RT-PCR Semiautomated RT-PCR 43-69,000, No Yes ,000, No Yes Semiautomated RT-PCR ,000, Yes Yes Phase III registration trials for both BOC and TVR used COBAS TaqMan HCV Test v2.0 for use with High Pure System (1.3% false-positive rate) [2] 1. Ghany MG, et al. Hepatology. 2009;49: Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy Abstract R-8.

15 LLOD Is Distinct From LLOQ LLOQ Lowest HCV RNA concentration within linear range of assay ie, smallest amount of HCV RNA that can be not only detected but also accurately quantified LLOD Lowest amount of HCV RNA concentration that can be detected with 95% probability to determine presence or absence Commercially available quantitative assays may have differing LLOQ and LLOD levels

16 Harrington et al. Hepatology 2012;55(4),

17 P Braun et al. ESCV 2012

18 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 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 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 Boceprevir [package insert]. May Ghany MG, et al. Hepatology. 2011;54: Telaprevir [package insert]. May 2011.

19 HCV Resistance With TVR/BOC Resistance-associated variants occur naturally [1] Present in 5% to 7% of subject samples prior to treatment [2,3] No apparent impact on likelihood of SVR Selected for/enriched in patients failing PI-based therapy Lower genetic barrier to resistance (number of mutations required to overcome virologic activity of the regimen) with genotype 1a vs 1b with BOC/TVR based regimens Strict adherence to futility rules, ensuring patient adherence and tolerability of regimen essential to avoid resistance Following treatment failure, resistance-associated variants decline over time after withdrawal of PI but may remain detectable for up to 2.5 yrs [4,5] 1. Pawlotsky JM. Clin Liver Dis. 2003;7: Telaprevir [package insert]. May Boceprevir [package insert]. May Vierling JM, et al. EASL Abstract Sullivan JC, et al. EASL Abstract 8.

20 Telaprevir regimen in GT1 HCVinfected patients Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (ervr) STOP Telaprevir + PR PR PR Weeks Non-cirrhotic naïves and relapsers without ervr Partial and null responders Patients with cirrhosis HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable LLOD IU/ml at Week 24 or 36: discontinue PR Telaprevir EU SmPC

21 Boceprevir regimen in G1 HCVinfected patients STOP Treatment-naïve without cirrhosis who achieve undetectable HCV RNA at Weeks 8 and 24 PR lead-in BOC + PR BOC + PR* PR Non-cirrhotic treatment-naïve with detectable HCV RNA at Week 8 but undetectable at Week 24* Non-cirrhotic relapsers and partial responders HCV RNA If 100 IU/mL discontinue all drugs If detectable LLOD IU/ml discontinue all drugs BOC + PR Null responders Patients with cirrhosis Weeks *This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

22 HCV RNA Assay Characteristics for RGT With BOC or TVR A quantitative assay with a LLOQ of 25 IU/mL and a LLOD of approximately IU/mL must be used Confirmed detectable but below limit of quantification HCV RNA result should not be considered equivalent to an undetectable HCV RNA result Boceprevir [package insert]. May Telaprevir [package insert]. May 2011.

23 SVR rate lower when HCV RNA not undetectable at key time points during therapy BOC/PR RGT T12/PR Undetectable Detectable/Below LLOQ Above LLOQ (> 25 IU/mL) SVR (%) SVR (%) Treatment Wk Treatment Wk Harrington et al. Hepatology 2012, 55(4),

24 HCV RNA Thresholds for EOT Response With BOC or TVR EOT response defined as [1,2] HCV RNA undetectable (or target not detected ) at EOT Using an assay with a sensitivity of IU/mL [1,2] Detectable but < LLOQ values while on treatment predict lower SVR rates [3] 1. Boceprevir [package insert]. May Telaprevir [package insert]. May Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy Abstract R-8.

25 Use of HCV RNA Assays to Assess SVR With BOC or TVR-Based Therapy SVR to pegifn/rbv previously defined as Absence of detectable HCV RNA in serum using assay with sensitivity of at least 50 IU/mL 6 m. after EOT [1] SVR defined by FDA in BOC and TVR package inserts as HCV RNA < 25 IU/mL (LLOQ) 6 m. after EOT [2-3] 1. Lindsay KL, et al. Hepatology. 2002;36:S114-S Boceprevir [package insert]. May Telaprevir [package insert]. May 2011.

26 Summary The same quantitative assay with an LLOQ of 25 IU/mL and an LLOD of approximately IU/mL must be used week 4 and/or 8, 12, 24, (48), wk 24 FU Qualification/Endpoint BOC TVR RGT HCV RNA undetectable at Wks 8 and 24 HCV RNA undetectable at Wks 4 and 12 Futility HCV RNA 100 IU/mL at Wk 12 HCV RNA detectable at Wk 24 HCV RNA > 1000 IU/mL at Wk 4 or 12 HCV RNA detectable at Wk 24 EOT response SVR HCV RNA undetectable at EOT HCV RNA < LLOQ 24 wks after EOT

27 Summary HCV RNA < LLOQ not identical to HCV RNA undetectable HCV RNA < LLOQ appropriate for assessing SVR HCV RNA undetectable (HCV RNA target not detected) required to qualify for RGT Report the HCV RNA assay result as HCV RNA undetected or target not detected to allow physicians to apply RGT algorithms correctly