Rockstroh J. и др. «High efficacy of grazoprevir/elbasvir in HCV genotype 1, 4, and 6-infected patients with HIV co-infection: the phase 3 C-EDGE co-infection study» 8th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Vancouver, 2015. TUAB0206.

1. AIDS 2015
Vancouver, BC
Session:TUAB02
AIDS 2015
Vancouver, BC
Session:TUAB02
C-EDGE CO-INFECTED: PHASE 3
STUDY OF GRAZOPREVIR /
ELBASVIR IN PATIENTS WITH
HCV/HIV
Jürgen K. Rockstroh, Mark Nelson, Christine Katlama, Jay Lalezari,
Josep Mallolas, Mark Bloch, Gail Matthews, Michael S. Saag,
Philippe Zamor, Chloe Orkin, Jacqueline Gress, Melissa Shaughnessy,
Stephanie Klopfer, Janice Wahl, Bach-Yen Nguyen, Eliav Barr,
Heather L. Platt, Michael Robertson, Mark Sulkowski

2. AIDS 2015
Vancouver, BC
Session:TUAB02
BACKGROUND
• HCV NS3/4A inhibitor, 100 mg
Grazoprevir
(MK-5172)
Elbasvir
(MK-8742)
• HCV NS5A inhibitor, 50 mg
 Broad genotypic activity1-3
 Retains activity against many clinically relevant RAVs1-3
 All-oral, once-daily regimen
1. Summa V, et al. Antimicrobial Agent Chemother 2012:56;4161-67
2. Coburn CA, et al. ChemMedChem 2013; 8: 1930–40
3. Harper S, et al. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6.

3. AIDS 2015
Vancouver, BC
Session:TUAB02
BACKGROUND AND AIM
• HCV infection is a leading cause of morbidity and
mortality among patients with HIV-11-3
– rapid progression of liver disease
– increased risk of cirrhosis, end-stage liver disease, and
HCC4,5
• The aim of the phase 3 C-EDGE Co-infection study
was to evaluate the efficacy, safety and tolerability of
the HCV regimen, grazoprevir / elbasvir fixed-dose
combination in patients with HIV/HCV coinfection
1. Monga HK, et al. Clin Infect Dis 2001;33(2):240-247. 2. Konerman MA, et al. Hepatology 2014;59(3):767-775
3. Pinchoff J, et al. Clin Infect Dis 2014;58(8):1047-1054. 4. Lo Re V, III, et al. Ann Intern Med 2014;160(6):369-379.
5. Rockstroh JK, et al. J Hepatol 2013;59(2):213-220.

4. AIDS 2015
Vancouver, BC
Session:TUAB02
STUDY DESIGN
• An open-label, single-arm, multicenter study across Europe, The US and
Australia
• Primary endpoint: SVR12 (HCV RNA <15 IU/mL*)
• Treatment-naive patients with HCV GT1, 4 or 6 infection with or without
cirrhosis
• Co-infected with HIV-1:
– Naive to ART with CD4+ >500 cells/mm3 and HIV RNA <50,000 copies/mL
– On stable on ART† for ≥8 weeks and CD4+ >200 cells/mm3 and undetectable
HIV RNA
GZR 100 mg / EBR 50 mg
D1 TW4 TW8 TW12 FUW4 FUW8 FUW12
n=218
*COBAS TaqMan v2.0 [LLoQ <15 IU/mL]
† Stable antiretroviral therapy (ART) included tenofovir or abacavir, and either emtricitabine or lamivudine plus raltegravir,
dolutegravir, or rilpivirine
Follow-up

5. AIDS 2015
Vancouver, BC
Session:TUAB02
DEMOGRAPHICS: HCV DISEASE
All Patients
N = 218
Age, years mean (SD) 48.7 (8.9)
Sex, n (%)
Male, 183 (83.9)
Female 35 (16.1)
Race, n (%)
White 167 (76.6)
Black or African-American 38 (17.4)
Asian 6 (2.8)
Other 7 (3.2)
Ethnicity, n (%)
Hispanic / Latino 14 (6.4)
Not Hispanic / Latino 194 (89.0)
Not reported 10 (4.6)
HCV genotype, n (%)
1a 144 (66.1)
1b 44 (20.2)
4 28 (12.8)
6 2 (1.0)
Baseline HCV RNA >800,000 IU/mL, n (%) 130 (59.6)
Cirrhotic*, n (%) 35 (16.1)
IL28B CC (%) , n (%) 77 (35.3)
*Of the 35 patients (16.1%) with cirrhosis, 27 were diagnosed by Fibroscan, 6 by biopsy,
and 2 by Fibrotest and APRI.

6. AIDS 2015
Vancouver, BC
Session:TUAB02
DEMOGRAPHICS: HIV DISEASE
All Patients
N = 218
Antiretroviral therapy, n (%)
Receiving ART with undetectable HIV RNA 211 (96.8)
Naïve to ART 7 (3.2)
Baseline CD4 count (cells/µL)
Mean (SD)
Median (1st quartile – 3rd quartile)
613 (0.57)
568 (424-766)
Antiretroviral therapy, n (%)
Abacavir containing regimen 47 (21.6)
Tenofovir containing regimen 164 (75.2)
Raltegravir 113 (51.8)
Dolutegravir 59 (27.1)
Rilpivirine 38 (17.4)

7. AIDS 2015
Vancouver, BC
Session:TUAB02
SVR12
Discontinued
unrelated to VF
1 0 1 0
Relapse 5 4 0 1
Reinfection 2 1 1 0
*2 patients with GT6 infection were also included; both patients achieved SVR12.
GT = genotype
210
/217*
96.3% 96.5% 95.5% 96.4%
0%
25%
50%
75%
100%
Full Analysis
Set
GT1a GT1b GT4
Patients,%
139
/144
42
/44
210
/218*
27
/28

8. AIDS 2015
Vancouver, BC
Session:TUAB02
SVR12
Variable n/m % (95% CI)
ALL 210/218 96.3 (92.9, 98.4)
Gender
Male 175/183 95.6 (91.6, 98.1)
Female 35/35 100.0 (90.0, 100.0)
Age
<65 years 204/212 96.2 (92.7, 98.4)
≥65 years 6/6 100.0 (54.1, 100.0)
Race
White 161/167 96.4 (92.3, 98.7)
African American 36/38 94.7 (82.3, 99.4)
Asian 6/6 100 (54.1, 100.0)
IL28B
genotype
CC 76/77 98.7 (93.0, 100.0)
Non-CC 134/141 95.0 (90.0, 98.0)
Cirrhosis
No 175/183 95.6 (91.6, 98.1)
Yes 35/35 100 (90.0, 100.0)
Baseline
viral load
≤800,000 IU/mL 89/91 97.8 (92.3, 99.7)
>800,000 IU/mL 121/127 95.3 (90.0, 98.2)
SVR12 – SUBGROUP ANALYSES
FULL ANALYSIS SET
80 90 100
SVR12 (95% CI)

9. AIDS 2015
Vancouver, BC
Session:TUAB02
SVR12
Variable n/m % (95% CI)
ALL 210/218 96.3 (92.9, 98.4)
ART regimen
Abacavir-containing 44/47 93.6 (82.5, 98.7)
Tenofovir-containing 160/164 97.6 (93.9, 99.3)
ART third
agent
Raltegravir 109/113 96.5 (91.2, 99.0)
Dolutegravir 59/59 100.0 (93.9, 100.0)
Rilpivirine 36/38 94.7 (82.3, 99.4)
SVR12 ACCORDING TO ART REGIMEN
FULL ANALYSIS SET
80 90 100
SVR12 (95% CI)

10. AIDS 2015
Vancouver, BC
Session:TUAB02
RELAPSE AND REINFECTION
• 5 patients relapsed
– All noncirrhotic
– GT1a n=4; GT4 n=1
– Four patients were receiving ART
• Tenofovir-based ART n=3
• Abacavir-based ART n=1
• 2 patients were reinfected
– One patient with GT1a at enrolment; GT3 at FW12
– One patient with GT1b at enrolment; GT3 at FW12
– Per protocol, these patients was classified as a failure for analysis, but
sequencing and phylogenetic data are consistent with post-treatment
reinfection

11. AIDS 2015
Vancouver, BC
Session:TUAB02RESISTANCE ASSOCIATED VARIANTS IN PATIENTS
WITH RELAPSE OR REINFECTION
Baseline
HCV GT
ARV regimen
Resistance Associated Variants
At baseline At failure
NS3 NS5A NS3 NS5A
RELAPSES
56 yr black/AA male 1a
tenofovir, emtricitabine,
rilpivirine
V36M/L L31M/L Q80K, D168A Q30K, L31M
63 yr black/AA male 1a None Q80K Y93S Q80K, D168A Q30R, Y93S
37 yr white male 1a
tenofovir, emtricitabine,
raltegravir
WT WT WT Q30R/Q
43 yr white male 1a
abacavir, lamivudine,
raltegravir
WT WT WT WT
53 yr white male 4
tenofovir, emtricitabine,
raltegravir
WT WT WT L28S
REINFECTIONS
35 yr white male 1b
abacavir, lamivudine,
raltegravir
WT WT (GT3) (GT3)
43 yr white male 1a
tenofovir, emtricitabine,
rilpivirine
V55A/V WT (GT3) (GT3)
Bold indicates RAV detected at virologic failure not previously detected at baseline.

12. AIDS 2015
Vancouver, BC
Session:TUAB02NS5A PHYLOGENETIC ANALYSIS OF REINFECTION:
AN191535
Day 1
At failure

13. AIDS 2015
Vancouver, BC
Session:TUAB02NS5A PHYLOGENETIC ANALYSIS OF REINFECTION:
AN191554
Day 1
At failure

14. AIDS 2015
Vancouver, BC
Session:TUAB02
ADVERSE EVENTS
Patients with:
All Patients
N = 218
Serious AE, n (%) 8* (2.8)
Serious drug-related AE, n (%) 0 (0)
Discontinuation due to AE, n (%) 0 (0)
Deaths, n (%) 0 (0)
Any adverse event†, n (%) 167 (76.6)
Fatigue 29 (13.3)
Headache 27 (12.4)
Nausea 20 (9.2)
Late ALT or AST >5.0 x ULN‡, n (%) 2 (0.9)
Lowest hemoglobin on treatment, n (%)
≥8.5 to <10 g/dL 1 (0.5)
Elevation of total bilirubin¶, n (%)
>2.5 – 5.0 × baseline 8 (3.7)
>5.0 × baseline 1 (0.5)
Creatinine >2.5 x baseline, n (%) 0 (0)
*2 SAEs were reported during the treatment period (convulsion and pneumonia) and 6 SAEs were reported during follow-up (erysipelas;
acute psychosis and urinary retention; ulnar fracture; spontaneous bacterial peritonitis, cellulitis, and urinary retention)
†All AEs, regardless of relationship to study drug reported in >5% of patients.
‡ALT/AST >5× ULN after TW4 with an ALT/AST ≤ ULN between TW2 and TW4
¶ Bilirubin elevations were not associated with simultaneous ALT increases

15. AIDS 2015
Vancouver, BC
Session:TUAB02
HIV PARAMETERS
• Two patients receiving ART experienced transient HIV viremia
during treatment
– Both patients subsequently achieved undetectable HIV RNA with
additional compliance education, and without a change in ARV
regimen.
• No notable change in CD4+ cells from baseline compared to
TW12
– Mean change of 52.9 cells/µL (SD 156.14, n=207)

16. AIDS 2015
Vancouver, BC
Session:TUAB02
CONCLUSIONS
• High rates of SVR were achieved in patients with HCV GT1,
4 and 6 and HIV co-infection receiving the all-oral, fixed-dose
combination of GZR / EBR
– Comparable response rates to other studies in HCV mono-infected
patients
– Comparable response rates across all patient subgroups, including
black/African American
– Comparable response rates in cirrhotic and non-cirrhotic patients
– Generally well tolerated with few SAEs, and no discontinuation
• Low rates of adverse events, once-daily administration, and
suitability for use in patients also receiving antiretroviral
therapy suggest GZR / EBR may represent a highly effective
treatment option for patients with HCV/HIV co-infection.

17. AIDS 2015
Vancouver, BC
Session:TUAB02
PUBLISHED 09-JULY-15

18. AIDS 2015
Vancouver, BC
Session:TUAB02
ACKNOWLEDGEMENTS
• We extend our gratitude to the patients, their families, investigators and
site personnel who participated in this study.
– Australia: Gail Matthews, Mark Theo Bloch
– Canada: Jason Brunetta, Brian Conway
– Denmark: Jan Gerstoft, Nina Weis, Alex Lund Laursen
– France: Marc Bourliere, Christine Katlama, Stanislas Pol
– Germany: Stefan Mauss, Jürgen K. Rockstroh, Michael Sabranski
– Israel: Yaacov Baruch, Oren Shibolet, Ziv Ben Ari
– Spain: Juan Gonzalez Garcia, Josep Mallolas, Christina Tural
– United Kingdom: Mark Nelson, Chloe Orkin
– United States: David Michael Asmuth, Michael David, Laveeza Bhatti, Edwin DeJesus,
Princy N. Kumar, Jacob Paul Lalezari, Kristen Marks, Frederick Nunes, Ponni
Perumalswami, Peter Jerome Ruane, Alyssa So Young Shon, Mark S. Sulkowski, David
Wyles, Philippe J. Zamor, David J Prelutsky, Michael S Saag, Anthony Mills.
• This study and medical writing support by ApotheCom were funded by
Merck & Co., Inc

19. AIDS 2015
Vancouver, BC
Session:TUAB02
CONCLUSIONS
• High rates of SVR were achieved in patients with HCV GT1,
4 and 6 and HIV co-infection receiving the all-oral, fixed-dose
combination of GZR / EBR
– Comparable response rates to other studies in HCV mono-infected
patients
– Comparable response rates across all patient subgroups, including
black/African American
– Comparable response rates in cirrhotic and non-cirrhotic patients
– Generally well tolerated with few SAEs, and no discontinuation
• Low rates of adverse events, once-daily administration, and
suitability for use in patients also receiving antiretroviral
therapy suggest GZR / EBR may represent a highly effective
treatment option for patients with HCV/HIV co-infection.

20. AIDS 2015
Vancouver, BC
Session:TUAB02
BACK UP SLIDES

21. AIDS 2015
Vancouver, BC
Session:TUAB02BACKUP SLIDES
Treatment N n (%) 95%
Confidence
Interval†
p-Value‡
GZR/EBR for 12 Weeks 218 210 (96.3) (92.9, 98.4) <.001
†Based on Clopper-Pearson method.
‡Based on a one-sided exact test for a binomial proportion. A one-sided p-value<0.025
supports a conclusion that the true SVR12 is >70%.
N = Number of subjects included in the analysis.
n (%) = Number of subjects who achieved SVR12 and the percentage calculated as (n/N)*100.
LLoQ is 15 IU/mL.
Analysis of Sustained Virologic Response
(HCV RNA < LLoQ) at Follow-up Week 12
Visit (SVR12) in Treatment-Naïve Subjects
Full Analysis Set
Full Analysis Set: 210/218
• 5 relapses
• 2 reinfections
• 1 discontinuation

22. AIDS 2015
Vancouver, BC
Session:TUAB02
BACKUP SLIDES
Treatment N n (%) 95% Confidence
Interval†
GZR/EBR for 12 Weeks 217 210 (96.8) (93.5, 98.7)
†Based on Clopper-Pearson method.
N = Number of subjects included in the analysis.
n (%) = Number of subjects who achieved SVR12 and the percentage calculated as
(n/N)*100.
LLoQ is 15 IU/mL.
Data Source: [16.4]
Analysis of Sustained Virologic Response
(HCV RNA < LLoQ) at Follow-up Week 12
Visit (SVR12) in Treatment-Naïve Subjects
Per Protocol
Per Protocol Analysis: 210/217
• 5 relapses
• 2 reinfections

23. AIDS 2015
Vancouver, BC
Session:TUAB02
BACKUP SLIDES: SUBGROUP ANALYSIS
GZR/EBR for 12 Weeks
N n (%) 95% Confidence
Interval†
Gender
Male 183 175 (95.6) (91.6, 98.1)
Female 35 35 (100.0) (90.0, 100.0)
Age
<65 212 204 (96.2) (92.7, 98.4)
>=65 6 6 (100.0) (54.1, 100.0)
Race
White 167 161 (96.4) (92.3, 98.7)
African American 38 36 (94.7) (82.3, 99.4)
Asian 6 6 (100.0) (54.1, 100.0)
Other 7 7 (100.0) (59.0, 100.0)
Ethnicity
Hispanic or Latino 14 14 (100.0) (76.8, 100.0)
Not Hispanic or Latino 194 186 (95.9) (92.0, 98.2)
Other 10 10 (100.0) (69.2, 100.0)
Genotype
1a 144 139 (96.5) (92.1, 98.9)
1b 44 42 (95.5) (84.5, 99.4)
1-other 0 0 (0.0) NA
4 28 27 (96.4) (81.7, 99.9)
6 2 2 (100.0) (15.8, 100.0)
IL28B CC genotype
CC genotype 77 76 (98.7) (93.0, 100.0)
Non-CC genotype 141 134 (95.0) (90.0, 98.0)
Fibrosis Stage
Non-Cirrhotic 183 175 (95.6) (91.6, 98.1)
Cirrhotic 35 35 (100.0) (90.0, 100.0)
Baseline HCV RNA
<=800,000 IU/mL 91 89 (97.8) (92.3, 99.7)
>800,000 IU/mL 127 121 (95.3) (90.0, 98.2)
<=2,000,000 IU/mL 135 131 (97.0) (92.6, 99.2)
>2,000,000 IU/mL 83 79 (95.2) (88.1, 98.7)
<=10,000,000 IU/mL 214 206 (96.3) (92.8, 98.4)
>10,000,000 IU/mL 4 4 (100.0) (39.8, 100.0)
Summary of Sustained Virologic Response (HCV RNA < LLoQ) at Follow-up Week 12
Visit (SVR12) by Subgroup
Full Analysis Set

24. AIDS 2015
Vancouver, BC
Session:TUAB02BACKUP SLIDES: SUBGROUP ANALYSIS CONTINUED
GZR/EBR for 12 Weeks
N n (%) 95% Confidence
Interval†
Naïve 194 186 (95.9) (92.0, 98.2)
Naïve – Interferon Ineligible 11 11 (100.0) (71.5, 100.0)
Naïve – Interferon Unwilling 13 13 (100.0) (75.3, 100.0)
Antiretroviral therapy with NRTI
backbone
Abacavir containing regimen‡ 47 44 (93.6) (82.5, 98.7)
Tenofovir containing regimen 164 160 (97.6) (93.9, 99.3)
Antiretroviral therapy with 3rd agent in
ARV Regimen
Raltegravir 113 109 (96.5) (91.2, 99.0)
Dolutegravir 59 59 (100.0) (93.9, 100.0)
Rilpivirine 38 36 (94.7) (82.3, 99.4)
†Based on the Clopper-Pearson method.
‡Includes one subject who was on abacavir, lamivudine, and tenofovir.
N = Number of subjects included in the analysis.
n (%) = Number of subjects who achieved SVR12 and the percentage calculated as (n/N)*100.
LLoQ is 15 IU/mL.
Data Source: [16.4]

25. AIDS 2015
Vancouver, BC
Session:TUAB02
PHYLOGENETIC DATA

26. AIDS 2015
Vancouver, BC
Session:TUAB02NS5A PHYLOGENETIC
TREE

27. AIDS 2015
Vancouver, BC
Session:TUAB02NS3 PHYLOGENETIC
TREE