Predictors of Response to Hepatitis C Therapy in the DAA Era Pablo Barreiro Servicio de Enfermedades Infecciosas Hospital Carlos III, Madrid
Why Predicting HCV Response? Select candidates for therapy Prioritizing expensive drugs Wait for newer compounds Determine type of therapy Dual therapy Adding DAAs Decide duration of therapy Motivate patients In summary, tailor hepatitis C treatment
Main Predictors of Response to Hepatitis C Treatment Level of viremia Genotype / Subtype Drug resistant polymorphisms Treatment history Initial response (RVR) RBV doses / levels Type of ARV and DDI Race IFN cascades genotypes Liver fibrosis stage Insulin resistance CD4 counts
HCV Genotype and HCV-RNA Level 100 90 80 70 60 Rate of Sustained Virological Response PEG-IFN -2a + RBV 100 90 80 70 60 PEG-IFN -2b + RBV % 50 % 40 30 20 10 50 40 30 20 10 0 0 Total Genotype 1 Genotype 2 or 3 Total Genotype 1 or 4 Genotype 2 or 3 HCV-RNA at baseline High (>800,000 IU/ml) Torriani et al. NEJM 2004 Low (<800,000 IU/ml) Crespo et al. J Viral Hep 2007
IL28B Polymorphisms & SVR in HIV/HCV Coinfected Patients p=0.684 p<0.0001 86% 81% 75% 65% p=0.001 p=0.087 67% 38% 30% 25% CC CT/TT SVR All HCV-1 HCV-3 HCV-4 Rallon et al. AIDS 2011; 15:F23-9
Predictors of Response in HIV-HCV Coinfection HCV-RNA <600,000 IU/ml 11.9 p<0.001 HCV genotype 3 8.0 p<0.001 rs12979860 CC genotype Liver fibrosis stage F0-F2 3.7 3.5 p=0.002 p=0.009 0 5 10 15 20 25 30 35 40 Rallon et al. AIDS 2010 Odds ratio (95% confidence interval) Prometheus Index Medrano et al. Clin Infect Dis 2010 http://www.fundacionies/prometheusindex.php
Viral Factors in DAAs Era
Baseline Viral Load as a Predictor of SVR Boceprevir for naive (SPRINT-2) 800,000 >800,000 SVR (%) n/n= PR 35/55 BOC RGT 41/54 BOC 44/PR48 45/53 PR 102/308 BOC RGT 192/314 BOC 44/PR48 197/313 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow up Week 24. If there was no such value, the follow up Week 12 value was carried forward Poordad F, et al. N Engl J Med 2011;364:1195 206
Baseline HCV-RNA Levels as Predictor in Patients with Poor IFN Response before Boceprevir Therapy Poordad F, et al. N Engl J Med 2011;364:1195 206 Bacon BR, et al. N Engl J Med. 2011;364:1207-1217
Influence of HCV-1 Subtype Telaprevir Advance Study Realize Study Relapsers Partial responders Null responders % of patients with SVR Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Influence of HCV-1 Subtype Boceprevir 100 % SVR 80 60 40 20 0 p = 0.001 p = 0.028 p < 0.001 20 11 54 54 19 35 27 33 124 43 26 61 25 44 178 1a 1b 1a 1b 1a 1b RESPOND 2 SPRINT 2 Combined Studies 47 45 96 Poordad F, et al. N Engl J Med 2011;364:1195 206 Bacon BR, et al. N Engl J Med. 2011;364:1207-1217
Lower Genetic Barrier of HCV-1a Subtype Distribution of RAVs by genotype Patients with No Sequence Data Frequency and Distribution of RAVs by genotype (Expressed as a percentage of RAVs detected for each genotype) Patients with RAVs Detected Patients with no RAVs Detected 300 Patients, n 250 200 150 100 50 0 32 117 97 G1a 15 38 43 Gt1b Variants, % 100 90 80 70 60 50 40 30 20 10 0 61 33 3 6 42 03 03 68 37 19 24 26 8 3 1 5 4 7 0 3 0 3 0 5 5 Genotype 1a Genotype 1b 32 0 10 10 03 5 0 Total n=342* *1 patient excluded due to indeterminate Genotype 1 subtype; Gt = Genotype
Differences in Virological Response to PegIFN plus RBV in HCV/HIV-Coinfected Patients by HCV Subtype (1a vs 1b) Rallón, AIDS 2011;25:1025-33
% of patients wih SVR PROVIDE Study Interim Results: 100 90 80 70 60 50 40 30 20 10 0 Boceprevir + PegIFN + RBV 79% 34% Pretreated patients 76% IFN responders IFN non-responders 23% 78% 0% 80% 50% No RAVs RAVs Hot RAVs Other RAVs * *V36M, R155K, T54S/A and V55A Brass et al. EASL 2011
Host Factors in DAAs Era
SVR by Fibrosis Stage in Naïve Patients (SPRINT-2- Boceprevir) No, minimal or portal fibrosis (F0 F2) Bridging fibrosis or cirrhosis (F3/F4) * * SVR (%) ** PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR48 n/n= 123/328 213/319 211/313 9/24 14/34 22/42 *p<0.001 for both boceprevir arms vs PR48; p=1.00 for boceprevir vs PR48 **p=0.31 for boceprevir vs PR48 Adapted from Poordad F, et al. N Engl J Med 2011;364:1195 206
SVR by Fibrosis Stage in Pretreated Patients (REALIZE- Telaprevir) SVR (%) 100 80 60 40 20 Stage Previous Relapsers Previous Partial Responders Previous Null Responders n/n= 144/ 12/ 53/ 2/ 48/ 2/ 34/ 3/ 10/ 11/ 1/ 24/ 1/18 15/ 7/ 167 38 62 15 57 15 47 17 18 0/5 32 5 59 38 0/9 50 0 86 32 No, minimal, or portal fibrosis 85 13 Bridging fibrosis 84 13 Cirrhosis 72 18 No, minimal, or portal fibrosis 56 0 Bridging fibrosis 34 20 Cirrhosis 41 6 No, minimal, or portal fibrosis Pooled T12/PR48 Pbo/PR48 39 0 Bridging fibrosis 14 10 1/ 10 Cirrhosis Zeuzem S, et al. EASL 2011. Abstract 5.
SVR rates by IL28B genotype Telaprevir for naive (ADVANCE) CC CT TT SVR (%) n/n= 35/55 38/45 45/50 20/80 43/76 48/68 6/26 19/32 16/22 PR T8/PR T12/PR PR T8/PR T12/PR PR T8/PR T12/PR Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCE SVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned dose Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
SVR rates in IL28B CC with RVR Telaprevir for naive (ADVANCE) RVR SVR in RVR+ Patients (%) n/n= 9/55 42/50 9/9 39/42 PR48 T12PR PR48 T12PR 78% of CC patients in the T12PR arm were treated with 24 weeks of treatment RVR: rapid viral response (undetectable HCV RNA at Week 4) Jacobson IM, et al. J Hepatol 2011;54(Suppl. 1):S542
SOUND-C2: Efficacy According to Study Arm, HCV Subtype, and IL28B SVR According to IL28B and HCV Subtype (ITT) 100 All patients 1a non-cc All 1b and 1a-CC SVR12 (%) 80 60 40 59 32 71 61 38 71 56 42 62 68 32 82 39 53 20 0 TID 16 wks RBV TID 28 wks RBV TID 40 wks RBV BID 28 wks RBV 0 TID 28 wks Zeuzem S, et al. EASL 2012. Abstract 101.
Lower SVR in Blacks Regardless of IL28B Genotype Ge D, et al. Nature. 2009
SPRINT-2: SVR to Boceprevir According to Race Phase III: genotype 1, treatment naive SVR (%) 100 P <.0001 80 P =.004 68 67 P =.044 60 53 42 40 40 BOC/PR48 BOC/PR RGT PR48 20 23 0 n = 311 316 311 55 52 52 Nonblack Race Black Poordad F, et al. AASLD 2010. Abstract LB-4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
ADVANCE: SVR to Telaprevir According to Race and Ethnicity Phase III: genotype 1, treatment naive 100 T12PR T8PR PR48 SVR (%) 80 60 40 75 70 46 62 58 25 74 75 66 39 69 44 20 0 n = 325 315 318 26 40 28 35 44 38 328 320 323 White Black Latino Non-Latino Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Race/Ethnicity
IFN-gamma Inducible Protein 10 kda (IP-10) Expressed in HCV-infected hepatocytes Role in recruitment of T- lymphocytes? Inverse association of IP-10 plasma levels with SVR after dual and triple therapy Casrouge A, et al. J Clin Invest 2011 Vijgen L, et al. EASL 2012 (abstract 1167)
IP-10 in HIV-HCV Coinfected Patients % % % % HCV replication upregulates IP10 levels that tend to normalize after therapy Baseline IP10 plus IL28B genotype improves prediction of treatment responses IP-10 not an independent predictor Rallón et al. AASLD 2011
Antiviral Therapy 2012; 17: 571-5. IFN experience HCV genotype IL28B Advanced liver fibrosis No 59% Yes 41% Others G4 8% G1a 20% 39% G3 11% G1b 22% CC 30% CT/TT 70% No Yes 47% 53% 424 HIV/HCV-coinfected patients in 2011
Predicted Effect of DAA in HIV-HCV Coinfected Patients % of HIV-HCV Coinfected Patients HCV subtype 1a IFN exposure IL28B noncc Metavir F3-F4 0 1 2 3 4 No. of unfavorable factors Poveda E et al. Antiviral Therapy 2012;17:571-5
Similar Response to DAA in Naïve Patients Despite HIV Infection Boceprevir Telaprevir % of patients 208 368 27 64 243 368 40 64 246 363 26 38 288 363 28 38 Poordad F. N Engl J Med. 2011; 364:1195-1206 Mallolas J et al. EASL Barcelona-Spain. April, 2012 Jacobson IM, et al. N Engl J Med 2011;364:2405 16 Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8 DT Dieterich et al., CROI 2012
Too Favorable Factors in HIV-HCV Coinfected Patients Treated with DAA Boceprevir Telaprevir Naive All All HCV 1a 66% 64% High HCV-RNA 88% 87% Cirrhosis 6% 0% Median CD4 count 577 535 (cells/ul) IL28B noncc NA NA Mallolas J, et al. EASL 2012 Sulkowski MS, et al. CROI 2012
Aproach to DAA Therapy Treatment history Predictors RVR IL28B F4 Treatment duration Chances of reponse Naive Relapsers Partial responders Null responders Yes CC No Yes CT/TT No No Any Yes No Any No 12 weeks? 24 weeks 48 weeks Defer Optimization of therapy
Summary HCV-genotype 2 or 3 4 1 Therapy pifn-rbv pifn-rbv-pi IFN-Free HCV-RNA level ++ +++ + + HCV-1 subtype -- -- ++ ++ IL28B - +++ + ++ RBV doses ++ ++ - ++ Liver fibrosis + ++ +++ - RVR ++ +++ ++ (R) / ++++ (F) - LIP - - High VL / Nulls - RAVs - - IFN resistance? Prior pegifn-rbv failure Any Any Null / Partial response?
Acknowledgements Molecular Biology Clinicians Computing and Administration Carmen de Mendoza Pablo Labarga Gustavo Manuzza Eva Poveda Eugenia Vispo Alma González Ana Treviño Francisco Blanco Carmen Solera Norma Rallón José V Fernández-Montero José Miguel Benito Dolores Herrero Mariola López Ivana Maida Lourdes Anta Luz Martín-Carbonero Natalia Zahonero Fernanda Rick Zulema Plaza Vicente Soriano Eduardo Seclén pm.barreiro@gmail.com