ARE PAN-GENOTYPIC THERAPIES READY FOR PRIME TIME? 3 Rd International HIV/Hepatitis Coinfection Meeting Durban SA Marina B. Klein, MD, MSc FRCP(C) Chronic Viral Illness Service McGill University Health Centre

How times have changed….. The bad old days Interferon/Ribavirin ■Injectable and multi-pill regimens ■Long duration ■Poor efficacy ■Severe side effects

That was then….this is now! Sunny ways…Sunny daysDAAs ■Simple once daily all oral regimens ■Few side effects ■Short duration ■Highly Effective

Consequences of the HCV treatment revolution for drug development ■Previously G1 infections were most difficult to treat ■Highest concentration of G1 infections in the developed world/markets ■R&D efforts concentrated on drugs for G1 ■Trials lumped “easy to treat” G2 and G3 infections together ■Few studies if any on more rare genotypes 4 and beyond ■Current low efficacy for G3 infections

Genotype Map

The World viewed (very) differently World mapper.limited

All Genotypes are NOT created equal ■Learned that G1a and G1b differ, with G1b being far easier to treat ■G2 responds much better than G3 ■G4 variation in response according to different subtypes ■Little know about “orphan” genotypes (5+)

The challenge of Genotype 3: virus or host…or both? ■Genotype 3 is estimated to affect 54.3 million people and is the second most common worldwide behind genotype 1 (83.4 million) ■G3 infections have worse clinical prognosis –More rapid development of liver disease and cirrhosis –More steatosis –Higher rates of HCC ■G3 infections have emerged as the most difficult to treat with DAAs, with response rates as much as 20% lower than other genotypes

■US VA COHORT of 110,484 patients with chronic HCV (8,337 with G3) ■Compared with G1, pts with G3 were: –31% more likely to develop cirrhosis (aHR=1.31; 95% CI, ) – 80% more likely to develop HCC (aHR=1.8; 95% CI, ). ■Association was independent of age, diabetes, BMI or antiviral therapy. Kanawal et al Hepatology, 2014

Clinically important HCV G1 2K/1B Chimeras ■Genotyping usually by “hybridization assay (LIPA)” of core, but NS3 or NS5 typing can be important N Core E1 E2 p7 C NS2 NS3 NS4ANS4BNS5ANS5B G2k Core E1 E2 p7 C NS2 NS3 NS4ANS4BNS5ANS5B N G1b Core E1 E2 p7 C NS2 NS3 NS4ANS4BNS5ANS5B N G2k/ 1b Susser et al PS001- EASL 2016

Genotype 2K/1B Chimeras – more common in immigrants from Russia Germany: 17 patients Rx’d Sof/RBV: 15 relapsed – all responded to G1 rescue therapy Susser et al PS001- EASL 2016.

The Real World mimics or exceeds trial data for G1: Sofosbuvir/Ledipasvir Sof/LDV in cirrhotic, TE (n=507) Curry et al. Poster SAT-214, EASL / / / /45 97/99 311/ / 30 8/8 8 wks for GT-1 (n= 752) Buggisch et al. Poster SAT-242, EASL 2016.

But G3 still a challenge German National HCV registry – DHC-R n=688 33/5832/41164/ /167115/156112/133121/135119/12740/5340/47 Cornberg M et al. Poster SAT-208, EASL 2016.

Especially in cirrhotics…. Relapse:853 Lost to follow-up:321 Death:110 Sof/LDV/RBV in Canada – n=111 Feld et al. Poster SAT-183, EASL /11131/3966/70

Is SOF/DCV the answer? In cirrhotics: adding ribavirin increases cure rates to 88% with 12 weeks and 92% with 16 weeks of treatment.

SVR12, % HCV genotype ALLY-2 (HIV Coinfection) SVR12 by HCV Genotype: 12-Week Groups NaiveExperienced Wyles, CROI 2015

Truly the Pangenotypic Era? Sofusbuvir/Velpatasvir (ASTRAL 1,2,3 ) Agarwal, Poster SAT-195, EASL SVR12 (%) Total GT 1GT 2GT 3GT 4GT 5GT 6 2 relapse 2 LTFU 1 D/C 11 relapse 2 D/C 1 death

ASTRAL-5: 12 weeks Sofosbuvir/Velpatasvir in HIV/HCV Co-infection 106 co-infected patients any HCV genotype treatment-naïve or –experienced On stable ARV regimens for HIV, fully suppressed HIV RNA GT1a: 62%; 1b: 11%; GT2: 10%; GT3:11%, GT4: 5% 18% cirrhotic Wyles D et al. PS104 EASL /28 99/ / 65 11/ 12 4/ 4 11/ 11 HIV medications at baselinen (%) NRTI backbone TDF-based w boosted agent56 (53) TDF-based w/o boosted agent35 (33) ABC/3TC base15 (14) ART use PI (DR, LPV or ATV)50 (47) NNRTI (RPV)13 (12) Integrase inhibitor (RAL or EVG)36 (34) Other (> 1 of above classes)7 (7)

Kwo P, et al. 51 st EASL; Barcelona, Spain; April 13-17, Abst. LB01. ABT-493 and ABT-530 +/- RBV in G3 with Cirrhosis Results: SVR12 by ITT Analysis ABT ABT-530 ABT ABT RBV SVR12, % Patients 24 / / 24

Market access REGISTRATION ACCESS TAG: mapcrowd.org/public/p df/EN_mapCrowd_Rep ort.pdf

Sunny days really are here!! …...at least in some places