Professor Douglas Dieterich - BHIVA · Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Icahn School of Medicine at Mount Sinai . 15/12/2014 2 Disclosure

15/12/2014

1

in partnership

with

Mount Sinai Medical Center, NYC, USA

Professor Douglas Dieterich

Five Nations Conference on

HIV and Hepatitis

The Beginning of the End for HCV in HIV:

Or the End of the Beginning ?

Douglas T. Dieterich, M.D

Professor of Medicine

Division of Liver Diseases,

Icahn School of Medicine at Mount Sinai

15/12/2014

2

Disclosure

● Consultant/Advisor, Honorarium, Advisory Board for AbbVie,

BMS, Boehringer Ingelheim, Gilead, and Roche

Change in Causes of Death in Patients with HIV

Swiss HIV Cohort Study (SHCS)

● 446 deaths between 2005 and 2009

● Causes of death

– #1 Non-AIDS defining cancers (n=85, 19.1%)

• including HCC (n=13, 2.8%)

– #2 AIDS (n=73, 16.4%)

– #3 Liver Diseases (n=67, 15.0%)

Weber R, et al. HIV Medicine. 2013;14:195–207.

When deaths due to HCC are included among liver-related deaths

(instead of non-AIDS defining cancers)

Liver Diseases = #1 Cause of Death (17.9%)

15/12/2014

3

Kaplan Meier Estimates of Events:

HIV HCV Patients

SVRNo SVR

100

0

Pro

po

rtio

n f

ree

fro

m e

ve

nt

(%)

Follow-up (months)

95

90

8515

10

5

0

12 24 36 48 60 72 84 96

Overall mortality

100

0

Pro

po

rtio

n f

ree

fro

m e

ve

nt

(%)

Follow-up (months)

95

90

8515

10

5

0

12 24 36 48 60 72 84 96

Liver-related mortality

100

0

Pro

po

rtio

n f

ree

fro

m e

ve

nt

(%)

Follow-up (months)

95

90

8515

10

5

0

12 24 36 48 60 72 84 96

Liver decompensation

100

0

Pro

po

rtio

n f

ree

fro

m e

ve

nt

(%)

Follow-up (months)

95

90

8515

10

5

0

12 24 36 48 60 72 84 96

Liver related events

p=0.010 p=0.024

p=0.010 p<0.001

SVRNo SVR

SVRNo SVR

SVRNo SVR

HCV Infection Can Be Cured in HIV + Patients

and Extend Life

● Testing and counseling

● Treatment of chronic

infection

– SVR is possible1

– SVR is durable2

– SVR prevents death3

1. Torriani FJ, et al. New Engl J Med. 2004;351:438-450.

2. Soriano V, et al. Antivir Ther. 2004;9:987-992.

3. Berenguer J, et al. Hepatology. 2009;50:407-413.

SVR – sustained virological response

Survival after HCV treatment for

493 patients with no SVR and

218 patients with SVR

Months after HCV treatment

SVRNo SVR

0

Pe

rce

nta

ge

(%

)

100

p≤0.001 by log-rank test

80

60

40

20

0

6 12 18 24 30 36 42 48

Slide 5

LH1 This slide is shown in this ICAAC abstract. I can't be sure it's not from another source however:

http://www.natap.org/2013/ICAAC/ICAAC_59.htmLynn Hayne, 13/11/2014

15/12/2014

4

Summary of Results:

Coinfection Trials Pre-DAA

SVR (%)

Study N Treatment All G1Genotype

non-1

Ribavic1 412PEG IFN α-2b + RBV 800

IFN α-2b + RBV 800

27

20

17

6

44

43

ACTG2 133PEG IFN α 2a + RBV 600

IFN α -2a + RBV 600

27

12

14

6

73

33

APRICOT3 860PEG IFN α 2a + RBV 800

IFN α -2a + RBV 800

40

12

29

7

62

20

Laguno4 93PEG IFN α-2b + W/B RBV

IFN α-2b + W/B RBV

44

21

38

7

53

47

PRESCO5 389

PEG IFN α-2a + W/B RBV

G1 48 w 31 72w 52

G2 24 w 67 48w 82

50 36 72

1. Carrat F, et al. JAMA. 2004;292:2839-2848.

2. Chung RT, et al. N Engl J Med. 2004;351:451-459.

3. Torriani FJ, et al. N Engl J Med. 2004;351:438-450.

4. Laguno M, et al. AIDS. 2004;18:F27-36.

5. Nunez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982.

17% 14%

29%

38% 36%

74%

61%

74% 74% 76%

98%

0%

20%

40%

60%

80%

100%

Fixed-dose

ribavirin

Weight-based

ribavirin

Direct-acting antiviral agents

Progression of SVR in HCV Treatment in HIV

Carrat F, et al. JAMA. 2004;292:2839-2848. Chung RT, et al. N Engl J Med. 2004;351:451-459.

Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Laguno M, et al. AIDS. 2004;18:F27-36.

Nunez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982.

15/12/2014

5

PegIFN + RBV

Telaprevir +

(750 mg q8h)

PegIFN + RBV

Telaprevir-Based HCV Therapy in HCV/HIV

Coinfection (SVR 12)

Phase 2HCV treatment-naïve, G1

No decompensated cirrhosis

PegIFN + RBV

Placebo + PegIFN + RBV

Telaprevir +

(750 mg q8h)

PegIFN + RBV

Follow-Up

Follow-Up

Follow-Up

T12/

PR48

PR48

T12/

PR48

PR48

PegIFN + RBVFollow-Up

Part A: No ART

CD4: ≥500 cells/mm3

HIV RNA ≤100K copies/mL

EFV/TDF/FTC or ATV/r + TDF + (FTC or 3TC)

Part B: ART

CD4: ≥300 cells/mm3

HIV RNA <50 copies/mL

0 12 24

Week

48 72

Dieterich D, et al. CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 46.

71

33

69

50

80

50

74

45

T/PR PR0

20

40

60

80

100

Pa

tie

nts

wit

h S

VR

(%

)

No ART EFV/TDF/FTC ATV/r/TDF/FTC Total

n/N = 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22

* Patient was defined as SVR12 if HCV RNA

was < LLOQ in the visit window

Dieterich D, et al. CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 46.

SVR Rates 12 Weeks Post-Treatment (SVR12*)

15/12/2014

6

Boceprevir Study Design

● Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV– 2:1 randomization (experimental : control)

– Boceprevir dose 800 mg TID

● 4-week lead-in with PEG2b/RBV for all patients– PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID

● Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered

open-label PEG2b/RBV+BOC via a crossover arm

Sulkowski M, et al. CROI 2012, March 5-8, 2012; Seattle, WA. Abstract 47.

Weeks 12 24 28 48 72

PEG2b

+RBV

4 wk

Placebo + PEG2b + RBV

44 wk

Boceprevir + PEG2b + RBV

44 wk

Follow-up

SVR-24 wk

Follow-up

SVR-24 wk

PEG2b

+RBV

4 wk

Arm 1

Arm 2

Futility rules

Virologic Response Over Time†

8.814.7

23.5

32.429.4

26.5

4.7

42.2

59.4

73.4

65.660.7

0

20

40

60

80

100

4 8 12 24 EOT SVR12

Treatment Week

PR B/PR

%

HC

V R

NA

Un

de

tect

ab

le

3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 9/3442/64 37/61

† Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.

Sulkowski M, et al. CROI 2012, March 5-8, 2012; Seattle, WA. Abstract 47.

15/12/2014

7

The University of Liverpool. http://www.hep-druginteractions.org.

On-treatment and Sustained Virologic

Responses Rates of Telaprevir-based

Hepatitis C Treatment

Do Not Differ Between HIV/HCV Co-infected

and HCV Mono-infected Patients

Martel-Laferrière V, Brinkley S,

Bichoupan K, Posner S, Stivala A,

Perumalswami P, Schiano T, Sulkowski M,

Dieterich DT, Branch AD

Martel-Laferrière V, et al. IAPAC. June 2-4, 2013. Miami, FL.

15/12/2014

8

Baseline Characteristics

Co-infected

(N = 33)

Mono-infected

(N = 117)P-value

Median age (IQR) 57 (52–59) 56 (51–61) 0.82

Male (% of total) 26 (78.8%) 79 (67.5%) 0.21

Race (% of total)

White

Black

Other

16 (48.5%)

14 (42.4%)

3 (9.1%)

65 (55.6%)

19 (16.2%)

34 (28.2%)

<0.01

Prior treatment response (% of total)

Naïve

Relapser

Non responder/intolerant

3 (9.1%)

5 (15.2%)

25 (75.8%)

36 (30.8%)

23 (19.7%)

58 (49.6%)

0.02

Bridging fibrosis/cirrhosis (% of total) 16 (48.5%) 40/113 (35.4%) 0.17

Baseline HCV viral load log10

IU/mL

(IQR)

6.46

(5.92–7.00)

6.46

(5.91–6.73)0.42


42%

70%

36%

76%

70%

61%

44%

66%

40%

58%54%

43%

0%

10%

20%

30%

40%

50%

60%

70%

80%

RVR EVR eRVR Week 24 EOT SVR12

Co-infected Mono-infected

p=0.10 p=0.07p=0.07p=0.44p=0.68p=0.91

Virologic Responses

Trend for better virologic responses in co-infected patient is

potentially explained by a selection bias


15/12/2014

9

HIV Co-infection Did not Increase Rates of

Discontinuation or Severe Anemia

HIV/HCV

co-infected

patients

HCV

mono-infected

patients

P-value

Discontinuation due to side effects (%) 6 (18.2%) 16 (13.7%) 0.58

Hospitalization (%) 9 (27.2%) 21 (17.9%) 0.42

Emergency room visits (%) 6 (18.2%) 16 (13.7%) 0.52

Anemia (%) 29 (87.8%) 107 (91.5%) 0.53

Severe anemia (%) 15 (45.5%) 68 (58.1%) 0.20

Rash (% of total) 5 (15.2%) 40 (34.2%) 0.04

Rectal symptoms (%) 4 (12.1%) 51 (43.6%) <0.01


Simeprevir in Combination with Peginterferon/Ribavirin in

Patients Co-infected with HCV Genotype-1 and HIV-1

Primary Analysis of the C212 Study

Investigational, one-pill, once-daily,

oral HCV NS3/4A protease inhibitor

● Multigenotypic: antiviral activity in patients

infected with HCV G1, 2, 4, 5 and 61–4

● SMV is being investigated in both PR and

IFN-free combinations

● Phase III trials of SMV + PR in G1 HCV

mono-infected treatment-naïve patients and

relapsers to IFN-based treatment showed

SVR12 rates of approximately 80%5-7

● Safe & well tolerated

(~3,800 patients treated to-date)1. Reesink HW, et al. Gastroenterology. 2010;138:913–921;

2. Moreno C, et al. J Hepatology. 2012;56:1247–1253;

3. Fried MW, et al. Hepatology. 2013;58:1918-1929;

4. Zeuzem S, et al. Poster presented at EASL 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB-2998;

5. Manns M, et al. EASL 2013; April 24-28, 2013; Amsterdam, Netherlands. Oral Presentation;

6. Jacobson I, et al. EASL 2013; April 24-28, 2013; Amsterdam, Netherlands. Abstract 1425;

7. Lawitz E, et al. Presented at DDW; May 18-21, 2013; Orlando, FL. Abstract 869b.

15/12/2014

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C212 Study DesignPhase III, Open-label, Single-arm, International Trial

● Primary endpoints: SVR12, safety and tolerability

● Secondary endpoints: virologic response at other time points, meeting RGT criteria* for

shortened treatment to 24 weeks, on-treatment failure and relapse rates

● Primary analysis: All patients included in the analysis (N=106) had completed 24 weeks of

treatment, or had reached the time point of the primary efficacy endpoint SVR12 (Week 60),

or discontinued prior to that point (for those on 48 weeks of treatment)

+After PR treatment;*RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Wk 4 and undetectable at Wk 12(measured using Roche COBAS TaqMan HCV/HPS assay, v.2)

Follow-up

Follow-up

PRSMV

150 mg/PR

PR● HCV treatment-naïve

● Prior relapse+

● Partial response

● Null response

● Cirrhotic patients (F4)

RGT*

Week12 24 36

Primary analysis

SMV 150 mg/PR

PRSMV

150 mg/PR

Follow-up

48 72

PR, peginterferon-α2a + ribavirin; RGT, response-guided treatment; SMV, simeprevir; SVR12, sustained virologic response 12 weeks’ after end of treatment.

Dieterich D, et al. Presented at CROI; March 3-6, 2014; Boston, MA. Abstract 24.

60

C212

SVR12 Primary Endpoint

7479

87

70

57

0

10

20

30

40

50

60

70

80

90

100

Overall Naïves Relapsers Partial Null

SV

R1

2 (

%)

78/106 42/53 13/15 7/10 16/28

SVR12, sustained virologic response 12 weeks after end of treatment


15/12/2014

11

89

7167

72

0

10

20

30

40

50

60

70

80

90

100

G1b G1a G1a with Q80K G1a without Q80K

C212

SVR12 by HCV-1 G1 Subtype and Baseline NS3

Q80K Polymorphism

16/18 62/88 20/30 42/58

G, genotype; SVR12, sustained virologic response 12 weeks’ after end of treatment


SV

R1

2 (

%)

Daclatasvir (BMS-052)

● NS5a inhibitor currently under investigation as part of a QD

(60 mg) STR regimen

● Dosing recommendations from ongoing clinical trials

(specific data not public)

– PI regimens: dose reduction � 30 mg QD• ATZ/r

– NNRTIs: increase dose � 90 mg QD• Efavirenz

– NRTIs: no dose adjustment � 60 mg QD• TDF

● Birth Control: Oral contraceptive efficacy is likely to be maintained

when combined with estrogen / progestin-containing OCP

● Hepatic impairment: dosing adjustments are not anticipated

http://clinicaltrials.gov. NCT02159352 Accessed June 25, 2012

Bifano M, et al. Presented at: AASLD; November 4-8, 2011; San Francisco, CA. Abstract 1340.

Bifano M, et al. Presented at: AASLD; November 4-8, 2011; San Francisco, CA. Abstract 1362.

Bifano M, et al. Presented at: CROI 2012; March 5-8, 2012; Seattle, WA. Abstract 618.

15/12/2014

12

Drug Interactions between Sofosbuvir and HIV

Antiretrovirals in Healthy Volunteers

Kirby B, et al. Presented at: AASLD; November 9-13, 2012; Boston, MA. Abstract 1877.

TFV = tenofovir

FTC = emtricitabine

EFV = efavirenz

RPV = rilpivirine

DRV = darunavir

RTV = ritonavir

RAL = raltegravir

Effect of Co-administration of Sofosbuvir on HIV ARVs

GM

R%

(9

0%

CI)

com

bin

ati

on

/alo

ne

200

TFV

150

100

50

0

FTC EFV RPV DRV RTV RAL

AUCtau

Cmax

Ctau

143%

70%

Sofosbuvir and Peginterferon Alfa-2a/Ribavirin

for Treatment-Naïve Genotype 1–4

HCV-Infected Patients Who Are Coinfected

With HIV

Rodriguez-Torres M, et al.. Poster presented at: IDWeek 2013; October 2-6, 2013; San Francisco, CA. Poster 714.

SVR24, SVR 24 weeks after end of treatment; SVR4, SVR 4 weeks after end of treatment

0Week 6 12 16 24 36

SOF 400 mg/d +

PEG 180 µg/wk/RBV

1000–1200 mg/d

GT 1–4

SVR4 SVR12

Primary endpoint

SVR24

Study design

15/12/2014

13

96 100 10091 91

Week 2 Week 4 EOT SVR4 SVR120

25

50

75

100

HC

V R

NA

<LLO

Q

(%)

Efficacy

● No on-treatment HCV virologic breakthrough

● 2 patients did not achieve SVR12:

– Patient 1: white Latino man aged 41 years with HCV GT 1a and IL28B TT GT,

who discontinued treatment after 6 weeks due to withdrawal of consent

– Patient 2: white Latino man aged 53 years with HCV GT 1a and IL28B CT GT,

who completed study treatment and subsequently relapsed

Rodriguez-Torres M, et al.. Poster presented at: IDWeek 2013; October 2-6, 2013; San Francisco, CA. Poster 714.

89 87100 100 100 100

1 1a 1b 2 3 40

25

50

75

100

HC

V R

NA

<LLO

Q

(%)

17/19 13/15 4/4 1/1 2/2 1/1

21/2321/2323/2323/2322/23

Virologic response and SVR

SVR12 by HCV GT

Sofosbuvir label

Sofosbuvir [Prescribing information]. Gilead Sciences, Inc. 2013.

15/12/2014

14

Sofosbuvir label

Sofosbuvir [Prescribing information]. Gilead Sciences, Inc. 2013.

GT 1- 4 HIV-HCV (PHOTON-1 and 2)

● PHOTON-1 and -2: GT 1, 2, 3 (US, EU, Australia)

● PHOTON-2: GT 4 (EU, Australia)

● Broad inclusion criteria– Targeted 20% enrollment of patients with compensated cirrhosis, no platelet cutoff

– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)

● Wide range of ART regimens allowed – Undetectable HIV RNA for ≥8 weeks, on stable ART regimen

● Baseline CD4 count– ART treated: >200 cells/mm3

– ART untreated: >500 cells/mm3

Wk 0 Wk 12 Wk 24 Wk 36

SOF + RBV (n=45) SVR12

SVR12GT 1, 3, 4 TN

GT 2, 3 TE

GT 2 TN

SVR12

SOF + RBV (n=314)

SOF + RBV (n=96)

GT 3 TN SOF + RBV (n=42) SVR12

Sulkowski MS, et al. JAMA. 2014;312:353-361.

Molina J, et al. AIDS 2014; Melbourne, Australia. Abstract MOAB0105LB.

15/12/2014

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PHOTON-1 and 2

Demographics: ART Regimens

Regimen, n (%) Total (N=497)

On ART 477 (96)

Tenofovir DF (TDF) / emtricitabine (FTC) plus

Efavirenz (EFV) 143 (30)

Raltegravir (RAL) 97 (20)

Atazanavir (ATV) / ritonavir (RTV) 83 (17)

Darunavir (DRV) / ritonavir 90 (19)

Rilpivirine (RPV) 26 (5)

Other

3TC/DRV/RTV, DRV, DRV/RTV, DRV/RTV/TDF,

ATV/FTC/RAL/RTV, DRV/EFV/RTV, DRV/FTC/RAL/RTV,

DRV/RAL/RPV/RTV, DRV/RAL/RTV, DRV/RAL/RTV/TDF

20 (4)



8189

8484

0

20

40

60

80

100

Results: SVR12

GT 1-4 HIV-HCV (PHOTON-1 and 2)

182/226 67/75 138/165 26/31

SV

R1

2 (

%)



TN

GT 1

TN + TE

GT 2

TN + TE

GT 3

TN

GT 4

Relapse, n (%) 39 (17) 3 (4) 23 (14) 5 (16)

Breakthrough, n (%) 1 (0.4) 1 (1) 1 (0. 6) 0

Lost to follow-up, n (%) 2 1 2 0

Withdrew consent, n (%) 2 3 1 0

15/12/2014

16

Results: SVR12 in GT 1 and GT 4

Cirrhosis vs No Cirrhosis (PHOTON-1 and 2)

*1 patient could not be subtyped.

Treatment-Naïve

24 Weeks SOF + RBV

82 8567

83

6465

6088

0

20

40

60

80

100

GT 1 GT 1a GT 1b GT 4

SV

R (%)

No cirrhosis Cirrhosis

14/22 11/17 3/5168/204* 147/173 20/30 7/819/23



88 88

67

91 95100 10067

100

79

0

20

40

60

80

100

49/546/6

Results: SVR12 in GT 2 and GT 3

Cirrhosis vs No Cirrhosis (PHOTON-1 and 2)

GT 2 GT 3

38/43 21/24 24/36 3/3 23/292/2

TN

12 weeks

TE

24 weeks

4/6 35/37



No cirrhosis Cirrhosis

SV

R (%)

TN

12 weeks

TN

24 weeks

TE

24 weeks

15/12/2014

17

ERADICATE

Study Design

● Open label

– LDV 90mg / SOF 400 mg STR for 12 wks

● Treatment-naïve GT-1 patients without cirrhosis

● No ribavirin administered

Wk 0 Wk 12

GT 1

(N=13)

ARV Untreated

● CD4 count stable + HIV RNA <500 copies

or

● CD4 count >500 cells/mm3

ARV Treated

● CD4 count >100 cells/mm3

● HIV RNA <40 copies

● Current ARVs ≥8 weeks

GT 1

(N=37)

Wk 36

SVR 24

ARVs: TDF/FTC, EFV, RILP and RALT

Treatment Response – Week 4

100 100 100 100 100100 10097 97 97

Wk 4 EOT SVR4 SVR8 SVR12 VR120

20

40

60

80

100

% o

f p

ati

en

ts w

ith

HC

V R

NA

< L

LOQ

ARV untreated ARV treated

13/13 37/37 13/13 37/37 36/37 13/13 13/13 36/37 13/13 36/37 49/50

Overall 98%

15/12/2014

18

ION-4: Ongoing study of LDV/SOF

in HCV/HIV Co-infection

Inclusion criteria:

● HCV treatment naïve and experienced (including PI failures)

● HCV GT 1 and 4

● HIV-1 virologic suppression for at least 6 months prior to screening

● Stable, protocol approved ARV regimen for ≥ 8 weeks prior to screening

– FTC/TDF plus EFV or RPV or RAL

● CD4 T-cell count >100 cells/mm3 at screening and no opportunistic infection

within 6 months prior to screening

● US, Canada, New Zealand

12 24Study weeks

SVR 12

GT 1 and 4

HCV/HIV co-infection

Stable HIV disease

20% cirrhotics

N = 335

LDV/SOF STR

‡

Clinicaltrials.gov NCT02073656

Fully enrolled

Data due in 1Q 2015

SOF/LDV Drug Interaction ProfileCo-administration not recommended

a) Based on drug interaction studies or predicted interaction; this information is not all inclusive

b) Coadministration of SOF/LDV with these medications is expected to decrease concentrations of ledipasvir and sofosbuvir, leading to a reduced

therapeutic effect

c) These interactions have been studied in healthy adults

d) Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir

e) The safety of increased tenofovir concentrations in the setting of SOF/LDV and elvitegravir/cobicistat/emtricitabine/tenofovir DF has not been

established

f) Coadministration of SOF/LDV with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased

risk of myopathy, including rhabdomyolysis

Cross-Discipline Team Leader Review NDA 205834 (ledipasvir/sofosbuvir)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000CrossR.pdf. Accessed November 18, 2014.

Co-administration of SOF/LDV with the following drugs is not recommended

Anticonvulsantsb carbamazepine, phenytoin, phenobarbital, oxcarbazepine

Antimycobacterialsb rifabutin, rifampin,c rifapentine

HCV product simeprevirc,d

Herbal supplement St. John’s wortb

HIV antiretrovirals elvitegravir / cobicistat / emtricitabine / tenofovir DF,e

tipranavir / ritonavirb

Statin rosuvastatinf

15/12/2014

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Concomitant drug class

Drug nameClinical comments

Acid reducing agentsLedipasvir solubility decreases as pH increases. Drugs that increase gastric pH are

expected to decrease concentration of ledipasvir

Antacids

(e.g., aluminum and magnesium hydroxide)It is recommended to separate antacid and SOF/LDV administration by 4 hrs

H2-receptor antagonistsb

(e.g., famotidine)

H2-receptor antagonists may be administered simultaneously with or 12 hours

apart from SOF/LDV at a dose that does not exceed doses comparable to

famotidine 40 mg twice daily

Proton-pump inhibitorsb

(e.g., omeprazole)

Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be

administered simultaneously with SOF/LDV under fasted conditions

Antiarrhythmics: digoxin

Coadministration of SOF/LDV with digoxin may increase the concentration of

digoxin. Therapeutic concentration monitoring of digoxin is recommended when

coadministered with SOF/LDV

HIV Antiretroviralsc

Efavirenz/emtricitabine/tenofovir DF

Regimens containing TDF + PI/r, including

● ATV/r + TDF/FTC b

● DRV/r + TDF/FTC b

● LPV/r + TDF/FTC

Monitor for TDF-associated adverse reactions in patients receiving SOF/LDV

concomitantly with EFV/ FTC / TDF

The safety of increased TDF concentrations in the setting of SOF/LDV and an HIV

PI/r has not been established. Consider alternative HCV or ART to avoid increases

in TDF exposures. If co-administration is necessary, monitor for TDF-associated

adverse reactions.

a) Based on drug interaction studies or predicted interaction; this information is not all inclusive. b) These interactions have been studied in healthy adults.c) Refer to the appropriate prescribing information for recommendations on renal monitoring with these medications.

SOF/LDV Drug Interaction ProfileOther potentially significant drug interactionsa



SOF/LDV Drug Interaction ProfileNo clinically significant interactions

● Antiretrovirals

– abacavir

– atazanavir/ritonavira

– darunavir/ritonavira

– efavirenz

– emtricitabine

– lamivudine

– raltegravir

– rilpivirine

– tenofovir DF

● Immuno-suppressants

– cyclosporine

– tacrolimus

● Opioid

– methadone

● Oral contraceptives

● Statin

– pravastatin

● Calcium channel blocker

– verapamil

aWhen not used in combination with tenofovir DF

No clinically significant drug interactions (observed or expected)

when SOF/LDV is used with the following drugs individually



15/12/2014

20

C-WORTHY Study DesignHCV Mono- and HIV/HCV Co-infected Non-cirrhotic Patients

1a+1b

1a+1b

1a+1b

D1 TW12 SVR12TW4 TW8 SVR24

1aN=30Grazoprevir + Elbasvir(50 mg) + RBV

Follow-up

N=29Grazoprevir + Elbasvir (50 mg)+ RBV

Follow-up

HCV

Sub-GT

1a+1b

Mo

no

-in

fect

ed

N=

15

9

Co

-in

fect

ed

N=

59

N=85Grazoprevir + Elbasvir (20 or 50 mg) + RBV

Follow-up

N=44Grazoprevir + Elbasvir (50 mg)No RBV

Follow-up

N=30Grazoprevir + Elbasvir (50 mg) No RBV

Follow-up

80 93 98 97 87

0

20

40

60

80

100

SV

R1

2 (

%)

24

30

43

44

79

85

26

30

28

29

C-WORTHY Primary Efficacy results SVR12; ITT

HCV Mono-infected HIV/HCV Co-infected

Treatment duration 8 weeks 12 weeks 12 weeks 12 weeks 12 weeks

RBV + RBV + RBV No RBV + RBV No RBV

LTFU* or discontinued

early not due to VF1 3 0 0 2

Breakthrough 0 1† 0 0 2

Relapse 5 2‡ 1 1 0

* LTFU=Lost to follow-up

† Breakthrough was due to HCV GT2b (minor GT2b variant at baseline)‡ One of the patients who relapsed did not receive grazoprevir and only received only elbasvir + RBV for the first

month of treatment

Only

GT1a

15/12/2014

21

95 9292 95

+ RBV No RBV0

20

40

60

80

100

SV

R1

2 (

%)

GT1a

GT1b

SVR12 RATE by subtype AND RIBAVIRIN 12 week regimens

● This figure combines mono- and co-infected patients who received 12 weeks of

treatment with grazoprevir + elbasvir with or without RBV

● It excludes 2 patients who had HCV subtypes that were not GT1a or GT1b and

30 patients who were in the 8 week, mono-infected arm

72

76

33

36

48

52

21

22

SVR12 Rates in Subgroup Analysis*

* 12 week arms only

Co-inf. Mono-inf.Subgroup

GT1b

GT1a

Female

Male

>50 years

≤50 years

IL28B Non-CC

IL28B CC

HCV RNA >2 million

HCV RNA ≤2 million

Overall SVR12=94%

50 60 70 80 90 100

% SVR12 (Mean; 95% CI)

N

4682

1345

4763

1266

1770

4259

40100

1928

3767

2262

15/12/2014

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TURQUOISE-IPart 1 Study Design (N = 63)

● 3D: coformulated parataprevir/r/ombitasvir, 150 mg/100 mg/25

mg QD; dasabuvir, 250 mg BID

● RBV: 1000 or 1200 mg daily according to body weight in 2 divided

doses (<75 kg and ≥75 kg, respectively)

Day 1 Week 12 Week 24

Open-label treatment SVR12

All patients will be followed

for 48 weeks

after HCV treatment end3D + RBV

(N = 31)

3D + RBV

(N = 32)

SVR4

Week 36

Sulkowski MS, et al. Presented at: AIDS 2014; July 20-25, 2014; Melbourne, Australia. Abstract MOAB0104LB.

Paritaprevir (ABT-450)

10096.8

93.593.5

10096.9 96.9

RVR

(Week 4)

EOTR

(Week 12 or 24)

SVR4 SVR120

20

40

60

80

100

% p

ati

en

ts

12-week 3D + RBV 24-week 3D + RBV

TURQUOISE-1 ResultsITT Virologic Response Rates

Adapted from the Trinh presentation at HIV Glasgow on 4th November 2014

* 2 patients in the 24-week group had recurrence of HCV viremia, believed to be due to HCV reinfection

31/31 32/32 30/31 31/32 29/31 31/32 29/31

*

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TURQUOISE-1 ResultsIntent-to-Treat SVR12 Rates

93.5 90.6

Overall0

20

40

60

80

100

SV

R1

2,

% p

ati

en

ts



29/31 29/32


93.5 93.890.6100

Overall Atazanavir0

20

40

60

80

100

SV

R1

2,

% p

ati

en

ts



29/31 29/32 15/16 12/12

15/12/2014

24


93.5 93.8 93.390.6100

85

Overall Atazanavir Raltegravir0

20

40

60

80

100

SV

R1

2,

% p

ati

en

ts



* 2 patients in the 24-week group had recurrence of HCV viremia, believed to be due to HCV reinfection

29/31

*

29/32 15/16 12/12 14/15 17/20

Real-world Data on HIV Patients with HCV G 1,2

and 3 Treated with Sofosbuvir- and/or

Simeprevir-containing Regimens

Mount Sinai Health System

● Total n = 80

● The vast majority (84%) had genotype 1

– 52/67 (77%) had genotype 1a

– 15/67 (22%) had genotype 1b

● Seven out of 80 (9%) had genotype 2

● Six out of 80 (8%) had genotype 3

● 34 (43%) patients received treatment with SMV/SOF +/- RBV

● 46 (57%) patients received treatment with SOF/RBV for 12 or 24 wks

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Categorical: n (%)

Continuous: median (IQR)

Gender, male 67 (84%)

Age 57 (52–61)

Race, black 20 (25%)

Ethnicity, Hispanic 30 (38%)

BMI >25 49 (61%)

History of diabetes 13 (16%)

History of hypertension 40 (50%)

History of depression prior to treatment 30 (28%)

Baseline characteristics Co-infected patients

Categorical: n (%)

Continuous: median (IQR)

Baseline HCV viral load, log IU/mL 6.31 IU/mL (IQR: 5.9X-6.7X IU/mL)

IL28B non-CC genotype 19/25 (70%)

Q80K mutation 2/4 (50%)

Treatment experienced

PEG-Interferon/ribavirinNon-responder

Partial responder

Relapser

Unknown response

PEG-Interferon alone

Telaprevir/PEG/RBV

Boceprevir/PEG/RBV

46/79 (58%)

36/46 (78%)10/36 (28%)

12/36 (33%)

9/36 (25%)

5/36 (14%)

1/79 (1%)

6/79 (8%)

3/79 (4%)

Cirrhosis, FibroScan >12.5 kPa 21/35 (60%)

Cirrhosis, biopsy 4/18 (22%)

FIB-4 score ≥3.25 41/80 (51%)

History of hepatocellular carcinoma 6/80 (8%)

History of liver transplant 2/80 (3%)

HCV Baseline Characteristics

15/12/2014

26

36

9285

28

95 92

Week 2 SVR4 rate SVR12 rate0

20

40

60

80

100

% u

nd

ete

cta

ble

Mono-infected

Co-infected

Week 2, SVR4, and SVR12 results are similar between

mono- and co-infected patients receiving SMV/SOF ± RBV

54/148 7/25 117/127 21/22 82/96 11/12

p=0.35

p=1.00 p=1.00

Cirrhosis among the SMV/SOF patients

● 19/34 (54%) genotype 1 patients receiving SMV/SOF +/- RBV

had cirrhosis based on FIB-4 score

● An additional 4 patients had cirrhosis based on Fibroscan

score ≥13.5 kPa and/or liver biopsy

● In all, 23/34 (67%) of SMV/SOF patients had cirrhosis

15/12/2014

27

SVR4 and SVR12 results for co-infected patients

receiving SMV/SOF ± RBV with and without

cirrhosis

9/10

(90%) 4/5

(80%)

12/12

(100%)

7/7

(100%)90

80

100 100

SVR4 SVR120

20

40

60

80

100

Pe

rce

nta

ge

(%

)

Non-cirrhotic

Cirrhotic

9/10 12/12 4/5 7/7

Conclusions

● HCV is a ticking time bomb for both Baby Boomers and our

health care system with and without HIV

● New medications of different classes will be approved within

months and more are coming

● The new DAAs have astonishingly high cure rates

● The cure rates in HIV patients are exactly the same in clinical

trials but are actually better in real life settings

● The only caveat is DDI’s with HIV medications

● Will we be able to treat enough patients in time to avert the

looming health care catastrophe?

Documents

Professor Douglas Dieterich - BHIVA · Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Icahn School of Medicine at Mount Sinai . 15/12/2014 2 Disclosure