Individual Optmizaton of therapy Graham R Foster Professor of Hepatology QMUL
Conflicts of Interest Speaker and consultancy fees received from AbbVie, BI, BMS, Gilead, Janssen, Roche, Merck, Novarts, Springbank, Achillion, Idenix
Optmisaton of Therapy The Theory The Practce The costs
Optmisaton of therapy Theory 100 100 % SVR 50 0 0 4 8 12 Duraton of therapy - weeks
Optmisaton of therapy Theory 100 100 % SVR 50 0 0 4 8 12 Duraton of therapy - weeks
Optmisaton of therapy Theory 100 100 % SVR 50 0 0 4 8 12 Duraton of therapy - weeks
Optmisaton of therapy Theory 100 100 % SVR 50 0 0 4 8 12 Duraton of therapy - weeks
100 Optmisaton of Therapy Theory Huge trial needed to distnguish a real difference % SVR 50 0 0 4 8 12 Duraton of therapy - weeks
Optmisaton of Therapy Theory Shorter duratons of therapy are cheaper BUT They have a higher risk of relapse
Optmisaton of Therapy Theory 100 % SVR 50 Some patents respond to short duraton therapy 0 0 4 8 12 Duraton of therapy - weeks
Optmisaton of Therapy Theory We could identfy patents who will beneft from short duraton therapy We can then treat them with short courses
Optmisaton of Therapy Theory We could identfy patents who will beneft from short duraton therapy We can then treat them with short courses In theory this should save money
Optmisaton of Therapy The Theory The Practce The costs
TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotc patents by HCV genotype 88.6 94.2 98.5 100 100 3D + RBV 12-week arm 80 24-week arm SVR12, % Patents 60 40 20 0 124 140 GT1a 114 121 67 68 GT1b 51 51 Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869.
TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotc patents by HCV genotype SVR12, % Patents 100 80 60 40 20 88.6 94.2 98.5 100 3D + RBV 12-week arm No significant difference between 12 and 24 weeks License is for 24 weeks in G1a 24-week arm 0 124 140 GT1a 114 121 67 68 GT1b 51 51 Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869.
Sofosbuvir/ledipasvir ± RBV for 8 weeks vs 12 weeks in treatment-naive non-cirrhotc G1 HCV-infected patents Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 LDV/SOF n=215 LDV/SOF + RBV n=216 LDV/SOF n=216 Stratfed by HCV subtype (1a or 1b) G1 treatment-naive patents without cirrhosis SVR12 SVR12 SVR12 SVR12 (%) 100 80 60 40 20 0 SVR12 G1 treatment naive 202/215 201/216 206/216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 weeks 12 weeks Kowdley K.V, et al. NEJM 2014;370:1879 8 weeks without RBV not statstcally inferior Without cirrhosis 8 weeks is the right duraton
Optmisaton of Therapy The Practce Properly powered, prospectve, randomised trial shows 8 weeks is equal to 12 weeks Is this widely used?
SVR achieved (n=251) 8 wks LDV/SOF (n=263) Patent dispositon TN, non-cirrhotc (n=895) SVR not achieved (n=3) SVR achieved (n=604) *21 patents were on 12 weeks of LDV/SOF + RBV 12 wks LDV/SOF ± RBV (n=632)* Real-world experience from the TRIO Network: Effectveness of 8- or 12-week LDV/SOF in treatment-naive, noncirrhotc, G1 SVR not achieved (n=6) 3 out of 4 patents received the long regimen Relapse 9 Death 0 LTFU 6 d/c 3 251/263 Curry M, et al. AASLD 2015, San Francisco. #1046
Patent dispositon TN, non-cirrhotc (n=895) Real-world experience from the TRIO Network: Effectveness of 8- or 12-week LDV/SOF in treatment-naive, noncirrhotc, G1 SVR12 by fibrosis 95 98 98 97 95 96 97 95 SVR achieved (n=251) 8 wks LDV/SOF (n=263) SVR not achieved (n=3) SVR achieved (n=604) *21 patents were on 12 weeks of LDV/SOF + RBV Curry M, et al. AASLD 2015, San Francisco. #1046 12 wks LDV/SOF ± RBV (n=632)* 95 96 Relapse 9 Death 0 LTFU 6 d/c 3 SVR12 by duraton Relapse 6 Death 2 LTFU 16 d/c 4 251/263 604/632 SVR not achieved (n=6) SVR12(%) SVR12(%) 42/ 44 52/ 53 79/ 81 143/ 147 76/ 80 194/ 203 31/ 32 F0 F1 F2 F3 SVR12 by baseline viral load 95 100 96 95 <6MM 6MM+ 8 weeks 12 weeks 144/ 151 242/254 436/456 8/8 162/170
Optmisaton of Therapy The Practce Clinicians and patents are conservatve They do not like to take risks Persuading people to use shorter duratons will not be easy
Optmisaton of Therapy What about shorter treatments? Can we fnd predictors of response to short duraton therapy?
Optmisaton of Therapy Theory 100 % SVR 50 Some patents respond to short duraton therapy 0 0 4 8 12 Duraton of therapy - weeks
102 G1 ± cirrhosis treated with grazoprevir 100 mg/elbasvir 50 mg FDC QD + SOF 400 mg QD G3 G1 Noncirrhot c C-SWIFT: Grazoprevir)+ Elbasvir) + SOF in untreated G1 pts with/without cirrhosis, for 4, 6, or 8 weeks Cirrhot c Noncirrhotc Cirrhotc D1 n=31 n=30 n=20 n=21 n=20 n=15 n=10 TW4 TW8 TW12 G1a 76 87% Viral load >6 million IU/mL in 17 19% non-cirrhotcs and 0 5% in cirrhotcs Primary endpoint: SVR12 SVR4/8 (%) 100 80 60 40 20 0 38,7 Non-cirrhotc 86,7 80 Cirrhotc 94,7 4 wks 6 wks 6 wks 8 wks 12/31 26/30 16/20 18/19 Lawitz E, et al. AASLD 2014, Boston. #LB-33
Short Duraton Therapy Some patents respond Some patents don t respond
Short Duraton Therapy Some patents respond Some patents don t respond Can we predict who will respond and who won t?
C-SWIFT: Grazoprevir)+ Elbasvir) + SOF in untreated G1 pts with/without cirrhosis, for 4, 6, or 8 weeks High viral load and non CC predictve of failure with 4- week duraton Lawitz E, et al. AASLD 2014, Boston. #LB-33
Short Duraton Therapy Response Guided Therapy? With Peg/Riba response guided therapy was popular and effectve With all oral regimes most patents are negatve after 4 weeks
Response Guided Therapy All-Oral Triple-DAA regimens 26 non-cirrhotc Chinese patents (G1b) Response-guided therapy: RVR (= HCV RNA <500 IU/mL by Day 2): Tx duraton 3 weeks Non-RVR: Tx duraton 8 12 weeks Group / Tx regimen RVR SVR 1: SOF, LDV, ASV (n=12) 6/12 6/6 2: SOF, DCV, SMV (n=6) 6/6 6/6 3: SOF, DCV, ASV (n=8) 6/8 6/6 Patents <500 IU/ml by day 3 had 100% SVR after 3 weeks therapy Lau GK, et al. AASLD 2015, San Francisco. #LB-23
Factors influencing SVR in English EAP Univariate Multvariate Odds rato 95% CI Odds rato Treatment Sof/DCV/Riba Ref Ref 95% CI Sof/LDV/Riba 0.9 0.5-1.7 2.7* 1.2-6.3 Without Riba 2 0.8-5.0 9.0* 2.5-31.0 Genotype Type 1 Ref Ref Type 3 5.1 2.6-10.1 10.3* 4.4-24.6 Other 0.9 0.2-4.0 0.8 0.2-4.2 Viraemic at 2 weeks? No Ref Ref Yes 2.3* 1.1-4.6 2.6* 1.1-6.3
Factors influencing SVR in English EAP Univariate Multvariate Odds rato 95% CI Odds rato Treatment Sof/DCV/Riba Ref Ref 95% CI Sof/LDV/Riba 0.9 0.5-1.7 2.7* 1.2-6.3 Without Riba 2 0.8-5.0 9.0* 2.5-31.0 Genotype Type 1 Ref Ref Type 3 5.1 2.6-10.1 10.3* 4.4-24.6 Other 0.9 0.2-4.0 0.8 0.2-4.2 Viraemic at 2 weeks? No Ref Ref Yes 2.3* 1.1-4.6 2.6* 1.1-6.3 Trial of 24 vs 12 weeks sof/dac/riba in G3 slow responders under way
Optmisaton of Therapy The Theory The Practce The costs
Resistance Associated Variants (RAVs) may reduce response SVR12 by Y93H or any NS5A RAV and IL28B genotype* With Y93H No Y93H With RAVs No RAVs 97 100 98 100 97 89 93 98 Pts (%) 74/ 76 429/ 431 153/ 156 350/ 351 54/ 61 1164/ 1196 259/ 280 959/ 977 Zeuzem S, et al. AASLD 2015, San Francisco. #91
Resistance Associated Variants (RAVs) may reduce response SVR12 by Y93H or any NS5A RAV and IL28B genotype* With Y93H No Y93H With RAVs No RAVs 97 100 98 100 97 89 93 98 Pts (%) 74/ 76 429/ 431 153/ 156 350/ 351 54/ 61 1164/ 1196 259/ 280 959/ 977 Zeuzem S, et al. AASLD 2015, San Francisco. #91
Resistance analyses (NS5A) Phase 2/3 studies of LDV/SOF ± RBV Phase 2/3 studies of LDV/SOF ± RBV 2144 G1 patents treated (51 (2.4%) no SVR) Deep sequencing at baseline NS5A RAVs in 16% 92% SVR Deep sequencing at virologic failure (VF) NS5A RAVs in 38 (74.5%) Sarrazin C, et al. AASLD 2014, Boston. #1926 *One baseline NS5A RAV no longer detected at VF
Resistance analyses (NS5A) Phase 2/3 studies of LDV/SOF ± RBV Phase 2/3 studies of LDV/SOF ± RBV 2144 G1 patents treated (51 (2.4%) no SVR) Deep sequencing at baseline NS5A RAVs in 16% 92% SVR Deep sequencing at virologic failure (VF) NS5A RAVs in 38 (74.5%) Sarrazin C, et al. AASLD 2014, Boston. #1926 *One baseline NS5A RAV no longer detected at VF
Resistance analyses (NS5A) Phase 2/3 studies of LDV/SOF ± RBV Phase 2/3 studies of LDV/SOF ± RBV 2144 G1 patents treated (51 (2.4%) no SVR) Deep sequencing at baseline NS5A RAVs in 16% 92% SVR Deep sequencing at virologic failure (VF) NS5A RAVs in 38 (74.5%) Resistance analysis in patents with Virologic Failure Subjects with NS5A RAVs n (%) Variants G1a G1b Total G1 (n=42) (n=9) (n=51) Present at BL 19 (45.2) 3 (33.3) 22 (43.0) Present at VF 30 (71.4) 8 (88.9) 38 (74.5)* Sarrazin C, et al. AASLD 2014, Boston. #1926 *One baseline NS5A RAV no longer detected at VF
RAVs Associated with failure More common post therapy in treatment failures Will short course therapy generate resistance?
102 G1 ± cirrhosis treated with grazoprevir 100 mg/elbasvir 50 mg FDC QD + SOF 400 mg QD G3 G1 Noncirrhot c C-SWIFT: Grazoprevir)+ Elbasvir) + SOF in untreated G1 pts with/without cirrhosis, for 4, 6, or 8 weeks Cirrhot c Noncirrhotc Cirrhotc D1 n=31 n=30 n=20 n=21 n=20 n=15 n=10 TW4 TW8 TW12 G1a 76 87% Viral load >6 million IU/mL in 17 19% non-cirrhotcs and 0 5% in cirrhotcs Primary endpoint: SVR12 SVR4/8 (%) 100 80 60 40 20 0 38,7 Non-cirrhotc 86,7 80 Cirrhotc 94,7 4 wks 6 wks 6 wks 8 wks 12/31 26/30 16/20 18/19 Lawitz E, et al. AASLD 2014, Boston. #LB-33
C-SWIFT retreatment : 12 weeks of EBR/GZR + SOF + RBV successfully treated G1-infected subjects who failed shortduraton all-oral therapy SVR12 100 100 100 100 100 100 100 23/* 23 18/ 18 5/ 5 15/ 15 8/ 8 5/ 5 18/ 18 Cirrhosis Prior Tx duraton Baseline NS5A RAVs *Excludes 2 patents LTFU at Day 3 and treatment Week 4 Lawitz E, et al. AASLD 2015, San Francisco. #LB-12
RAVs Might be less problematc in patents treated with short courses BUT Lengthy re-treatment needed
Individual Optmisaton of Therapy Theory Short course therapy with extended therapy for failures may be cost-effectve Careful selecton of patents will be critcal Robust re-treatment regimens will be necessary Studies in the UK are on-going
Individual Optmisaton of Therapy Physicians Response?
Individual Optmisaton of Therapy Physicians Response?