Overview on latest data on IFN-sparing and IFN-free regimens in HCV/HIV patients

10th HIV and hepatitis coinfection workshop June 2014

Paris, France

Patrick Ingiliz, Berlin

Conflicts of Interest

Boards, Consulting, Teaching, Travel: Gilead, Janssen-Cilag, Roche, MSD, Abbvie, BMS, Boehringer-Ingelheim Coinvestigator in clinical trials: Roche, Vertex, Janssen-Cilag, MSD, Gilead, BMS, Boehringer-Ingelheim, ViiV, Abbvie

New online EASL HCV recommendations

Indications for HCV treatment in HIV/HCV co-infected patients are identical to those in HCV mono-infection (A1)

Same treatment regimens can be used in HIV/HCV patients as in patients without HIV infection, as the virological results of therapy are identical (A1)

EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

Overview over current/upcoming DAA-free regimens in coinfection...

...basically the same as in HCV monoinfection:

• SOF-RBV • SIM-SOF • SOF-DAC • 3D-RBV • SOF-LDV-FDC • ...whatever comes next: ASV/DCV/-325, MK-5172/8472, etc.

Are there particularities in HIV-HCV coinfection?

• Drug-drug interactions

• Acute HCV infection • Fast fibrosis progresion

• Reinfection

P/R/TVR P/R/BOC

P/R/SMV P/R/FDV

NRTIs

Zidovudine a a a a

Stavudine b b b b

Didanosine b b b b

Lamivudine

Emtricitabine

Abacavir c c c c

Tenofovir

NNRTIs

Nevirapine ? ? ? ?

Efavirenz 1125 240

Etravirine ?

Rilpivirine

Combination possible

Combination possible under reserve

Combination not recommended or contra-indicated

Peg+RBV+HCV PI: DDI with ART

P/R/TVR P/R/BOC P/R/SMV P/R/FDV

Protease Inhibitors

Lopinavir/r 120

Fosamprenavir/r 120

Atazanavir/r 120

Darunavir/r 120

Integrase Inhibitors

Raltegravir

Dolutegravir

Elvitegravir/COBI ? ? ? ?

Entry Inhibitors

Maraviroc 150mgBID 150mg BID

a Increased risk of anemia

b Increased risk of lactic acidosis in association with ribavirin

c Interaction possible with ribavirin, but no proof of lesser efficacy

Use hep-druginteractions.org !!

DCV SOF SMV

NRTIs

Zidovudine

Stavudine

Didanosine

Lamivudine

Emtricitabine

Abacavir

Tenofovir

NNRTIs

Nevirapine ? ? ?

Efavirenz 90

Etravirine ?

Rilpivirine

DCV SOF SMV

Protease Inhibitors

Lopinavir/r 30

Fosamprenavir/r 30

Atazanavir/r 30

Darunavir/r 30

Integrase strand Inhibitors

Raltegravir

Dolutegravir

Elvitegravir/C ? ?

Entry Inhibitors

Maraviroc

Interferon/Ribavirin-free DAA combos: DDI with ART

Use hep-druginteractions.org !! Combination possible

Combination possible under reserve

Combination not recommended or contra-indicated

Acute HCV in HIV patients

Medical Center for Infectious Diseases, Berlin: ~1500 HIV+, 218 cases of acute HCV 2002 to 10/2013 6 cases in HIV-, 4 female, 32 reinfections

Steininger K, Ingiliz P et al., not yet published

What do we know about DAAs in acute HCV?

12 0 24 Weeks 4 -4 36 16 -12

Follow-up TVR + pIFN+RBV change ARVs

ETR SVR 4 SVR 12 SVR 24

Total 16/19 16/19 16/19 16/19

Success rate 84% 84% 84% 84%

Fierer et al., CID 2014

Ongoing/upcoming trials acute HCV/HIV: • DAHHS, Holland: BOC-P-R, 12 weeks • CHAT-Study, Germany: TVR-P-R, 12 weeks • Swift-C, USA: SOF-R, 8 vs 12 weeks • SOF/LDV, Europe, 6 weeks • SOF/LDV, US: 12 (8) weeks

EASL Recommendations 2014

Although no data is available yet, IFN-free regimens can theoretically be used in these patients and are expected to achieve high SVR rates. The same doses and durations as for patients with chronic hepatitis C must be used, until new data indicate whether shorter and/or less intensive treatment is sufficient to achieve high infection cure rates. (Recommendation B1)

EASL HCV recommendations: Acute hepatitis C

Is there an evidence for fast fibrosis progression after unsuccesful treatment?

Boesecke C et al., CROI 2014

↓ PPARγ Fibrosis

Steatosis

HIV ART

↑SREBP1

HIV ART

Lipodystrophy/dyslipidemia/ insulin resistance/Metabolic syndrome

HCV

GT3

GT1, 4

ART

Drug toxicity

Lactic acidosis

NASH Steatosis

IRIS

Alcohol Illicit drugs

HIV

↑STAT1

Insulin resistance

Ingiliz P, Lemoine M, Benhamou Y, 2011

Philip, actor, Berlin

• 2011: 35 year old, homosexual male

• HIV infection CDC B3 (2002, MSM)

• History of secondary syphilis, 3x

• 5x gonorrhea, 2x chlamydia

• No others concomitant illnesses

• Party drugs, moderate drinker

• CD4 nadir: 180/μL, HIV-PCR 747.500 c/ml • no opportunistic infections

• ARV:

• CBV+TDF+LPV/r 2002-2003 • STI 2003-2005 • TDF/FTC + FPV/r 2005-now no resistance-associated mutations

• 2011 CD4: 1009/μL (40%), HIV-PCR <50 c/mL

HIV/ARV history

• Sept. 2004: chlamydial urethritis, ALT 55 U/mL.

• No other clinical symptoms

• Syphilis negative, HBV negative

• HCV Ab negative

• HCV-PCR: 2.3mio IU/mL

• HCV genotype 1a

• acute sexually acquired HCV infection

Another year, another STD

• 2004 acute HCV: Pegα-2a + RBV (800mg)

• 24 weeks: RVR, EoTR: Relapse

• 2nd treatment 2005: Pegα-2b + RBV (1.000mg) • Stop at week 24: null response (HCV RNA reduction <2log)

• 3rd treatment 2008: Pegα-2a + RBV (1.200mg)

• Stop at week 12, null response (HCV RNA reduction <2log)

HCV treatment history

Boesecke, Curr Opin HIV AIDS, 2011

•11/2011: Genotyp 1a, IL28B C/T •HCV-VL: 3.180.000 IU/ml, ALT 1,5x ULN

• FibroScan®, 19.08.11: 26,3 KPa = consistent with liver cirrhosis

• Ultrasound: no direct signs of liver cirrhosis, no lesion, no ascites, spleen

13cm

• EGD: no esophageal varices

• Liver biopsy 03.11.11: nodular liver cirrhosis with minimal inflammatory activity and mild steatosis

• Retreatment in study C212: Simeprevir+PEG+RBV

HCV cirrhosis within 7 years: a coinfection reality

Dieterich et al. CROI 2014. Abstract 24.

C212 study design: Phase III, open-label, single-arm, international trial

Primary endpoints: SVR12, safety and tolerability Secondary endpoints: virologic response at other time points, meeting RGT

criteriab for shortened treatment to 24 weeks, on-treatment failure, viral relapse

Follow-up

Follow-up

PR SMV

150 mg/PR

PR • HCV treatment-naïve • Prior relapsea

• Prior partial responsea

• Prior null responsea • Cirrhotic patients (F4)

RGTb

Week 12

24 36

60

SMV 150 mg/PR

PR SMV

150 mg/PR

Follow-up

48 72

Antiretrovirals permitted during SMV therapy: lamivudine, emtricitabine,

tenofovir, abacavir, rilpivirine, enfuvirtide, raltegravir, maraviroc

aAfter prior PR treatment; bRGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Week 4 and undetectable at Week 12 (measured using Roche COBAS TaqMan HCV/HPS assay, v.2)

Dieterich et al. CROI 2014. Abstract 24.

C212: SVR12 by METAVIR fibrosis score (ITT population)

0

20

40

60

80

100

Overall Naïves Relapsers Partial Null

SVR

12 (%

)

67 57 60

METAVIR F0–F2 METAVIR F3–F4 89

57 64

80

100

78

50

36/45 14/22 4/7 2/2 2/3 6/10 4/7 1/2 7/9 24/27

ITT, intent-to-treat; SVR12, sustained virologic response 12 weeks after end of treatment

Primary Analysis C212 Study: Response-guided Therapy Allows Shortened Treatment Duration with High SVR12

Patients without cirrhosis meeting RGT criteria: 89% (54/61) of patients eligible for 24 weeks of treatment met RGT criteria

• 41/48 treatment-naïve patients • 13/13 prior relapsers

Proportion of patients achieving SVR12

Prop

ortio

n of

pa

tient

s, %

47/54 36/41 11/13

RGT, response-guided treatment in HCV treatment-naïve or relapse patients; SVR12, sustained virologic response 12 weeks’ after end of treatment

Dieterich et al. CROI 2014. Abstract 24.

No side effects

Response pattern in a cirrhotic P/R-null-responder

Baseline HCV VL 3.180.000 IU/mL Day 3: HCV VL 12.200 IU/mL Day 7: HCV VL 914 IU/mL Day 14: HCV VL <25 IU/mL, TD Day 28: HCV VL <25 IU/mL, TD

Week 24: HCV VL TND Week 48: HCV VL TND

Week 12: HCV VL TND

Baseline HCV VL 3.180.000 IU/mL Day 3: HCV VL 12.200 IU/mL Day 7: HCV VL 914 IU/mL Day 14: HCV VL <25 IU/mL, TD Day 28: HCV VL <25 IU/mL, TD

Week 24: HCV VL TND Week 48: HCV VL TND

Week 12: HCV VL TND

Week 60: HCV VL TND Week 72: HCV VL 14.500.000 IU/ml

Lab results 05/2013: ALT 32 U/L, AST 34 U/L, γGT 32 U/L, total bilirubin: 0.45 mg/dL HCV-Genotyp 1a HCV-RNA 14.500.000 IU/mL platelets 152/nL PT 98% albumin 45 g/L Hb 14,0 g/dL

Phylogenetic analysis C/E1: different virus: reinfection (study lab

comfirmed)

Relapse or reinfection?

Reinfection – an alarming reality!

Ingiliz et al., EASL 2014, Martin et al., AIDS 2013

553 patients from 7 NEAT centers with cured acute HCV since 6/2001 141 with at least one reinfection (25.5%) 1509 patient-years of FU, median 2.1 years Incidence rate: 7.82/100 patient-years Treated patients: 7.9/100 patient years Spontaneous clearers: 3.3/100 patient-years

What would you do next (06/2014 in Germany)? 1.) Treat with SOF/P/R 2.) Treat with SOF/R 3.) Treat with SMV/P/R 4.) Wait for DCV/P/R 5.) Treat with SIMSOF 6.) Wait for SOFDAC 7.) Wait for SOF/LDV-FDC 8.) Wait for other options 9.) No more treatment

Question

SOF + PegIFN + RBV in Treatment-Naïve HIV/HCV Co-infected Patients

Phase 2 Study 1910 Design

♦ Single-center, open-label, single-arm trial to assess the safety and efficacy of a 12-week course of SOF + PegIFN + RBV for the treatment of patients with chronic HCV, co-infected with HIV

No response guided therapy

Week 0 12 16 24 36

Primary endpoint SVR4 SVR12 SVR24

HCV GT 1–4 Treatment-naïve,

on stable HIV ARV N=23

SOF 400 mg QD + PegIFN alfa-2a 180 µg/week +

RBV 1000‒1200 mg/day

Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

Similar response rates in HIV/HCV co-infected patients compared to HCV mono-infected patients

SVR

12 (%

)

Short Duration of SOF + PegIFN + RBV x 12 Weeks Comparison of HCV Mono-infected to HIV/HCV Co-infected

Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

PHOTON-1: Study Design

♦ Broad inclusion criteria – Cirrhosis permitted with 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: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL

– ART untreated: CD4 T-cell count >500 cells/mm3

Wk 0 Wk 12 Wk 24 Wk 36

SOF + RBV, n=114 GT 1 TN

SOF + RBV, n=41 GT 2/3 TE

SOF + RBV, n=68 GT 2/3 TN

Wk 48

SVR 12 SVR 24

Naggie et al. CROI 2014. Abstract 26.

96 100

76

0

20

40

60

80

100

Week 4 EOT SVR12

GT 1

HC

V R

NA

< 25

IU/m

L (%

)

110/114 87/114

96 9688

0

20

40

60

80

100

Week 4 EOT SVR12

GT 2

HC

V R

NA

< 25

IU/m

L (%

)

25/26 23/26 22/23

♦ An all-oral regimen of SOF + RBV for 12–24 weeks resulted in high SVR12 rates in TN HIV-infected patients with GT 1, 2 and 3 coinfection – with SVR12 rates similar to mono-infection

♦ No HCV resistance (S282T) was observed in virologic failures via deep sequencing ♦ Two patients had HCV breakthrough; both had documented non-adherence to SOF ♦ Two patients had transient HIV breakthrough; both had documented non-adherence to ART

100 98

67

0

20

40

60

80

100

Week 4 EOT SVR12

GT 3

HC

V R

NA

< 25

IU/m

L (%

)

41/41 28/42

SOF + RBV x24 weeks SOF + RBV x12 weeks SOF + RBV x12 weeks

All-Oral Therapy of SOF + RBV in Treatment-Naïve HIV/HCV Coinfection

PHOTON-1 Virologic Response

100/100 39/40

Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212

1. Osinusi A, et al. JAMA. 2013;310(8):804-811. 2. Naggie S, et al. CROI 2014. Boston, MA. Oral #26. 3. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. 4. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. 5. SOVALDI™ [PI]. Gilead Sciences, Inc. Foster City, CA December 2013

GT 1 SOF + RBV 24 weeks

GT 2 SOF + RBV 12 weeks

GT 3 SOF + RBV 12 weeks

GT 3 SOF + RBV 24 weeks

SVR1

2 (%

)

68 76*

0

20

40

60

80

100

SPARE1

HCV PHOTON-12

HCV/HIV

SVR1

2 (%

) 93 88

0

20

40

60

80

100

VALENCE3

HCV PHOTON-12

HCV/HIV SV

R12 (

%) 56

67

0

20

40

60

80

100

FISSION4 HCV

PHOTON-12 HCV/HIV

SVR1

2 (%

)

85 94*

0

20

40

60

80

100

VALENCE3 HCV

PHOTON-15 HCV/HIV

Similar response rates in HCV/HIV co-infected patients compared to HCV mono-infected patients

68/73 23/26 87/114 28/42 16/17 212/250 17/25 102/183

SVR12 in HCV Mono-infected and HCV/HIV Co-infected All-Oral SOF+RBV x 12 or 24 weeks

SVR12 from VALENCE includes pooled analysis from all patients (treatment-naïve and –experienced) by genotype and duration of therapy *GT1 SVR24 of 75%; GT3 TE SVR24 of 88%

GS-US-334-0124 GT 1 treatment naïve (TN) and GT 2/3 TN and treatment experiences (TE) and GT 4 subjects

PHOTON 2: SOF Phase 3 Study in HIV/HCV Co-infection

♦ Study being conducted in Europe and Australia ♦ HIV treatment status

– Stable approved ART with CD4 >200 cells/mm3; or – No ART with CD4 >500 cells/mm3 (up to 10%)

♦ Enrollment complete

0 12 24 36 Week

SOF+RBV, n=50 SVR12

SOF+RBV, n=50 SVR12

SOF+RBV, n=170 SVR12

GT 2 TN

GT 2/3 TE

GT 1/3/4 TN

Clinicaltrials.gov NCT01783678

Fifty HIV/HCV genotype 1, treatment-naive subjects, HAI fibrosis stage 0 – 3

Sofosbuvir/Ledipasvir in patients with HIV/HCV coinfection

Interim results

ARV Treated (n=37) - CD4 count > 100 cells/mm3

- HIV RNA < 40 copies - Current ARVs ≥ 8 weeks

SVR 12

SVR 4

ARV Untreated (n=13) CD4 count stable + HIV RNA <500 copies

OR - CD4 count > 500 cells/mm3

ARVs: tenofovir, emtricitabine, efavirenz, rilpivirine and raltegravir

Wk 0 Wk 12 48 week follow up

SOF/LDV (400/90mg)

Osinusi et al, EASL 2014

ARV - 13/ 13 13/13 13/ 13 12/12 10/10 10/10 ARV + 37/37 37/37 30/30 22/22

Osinusi et al, EASL 2014

Sofosbuvir/Ledipasvir response rates

Phase 2: Protease + NS5A-Inhibitor +/- Ribavirin

Sulkowski et al, EASL 2014

Sulkowski et al, EASL 2014

12 weeks PI + NS5A in coinfected patients

ART: Stable raltegravir-based regimen

Sulkowski et al, EASL 2014

Incomplete list of ongoing/upcoming trials for HIV/HCV-coinfected patients

• Ally 2: Sofosbuvir/Daclatasvir, all genotypes, 8-12 weeks

• Turquoise-1: 3D/RBV, genotype 1, 12-24 weeks

• C-EDGE: MK-5172/MK-8742, genotypes 1, 4-6, 12 weeks

• ION-4: SOF/LDV, genotypes 1 and 4, 8-12 weeks

• ANRS: SOF/LDV, Tx-experienced, genotype 1, 24 weeks

Acknowledgements:

Medical Center for Infectious Diseases, Berlin:

Axel Baumgarten, Andreas Carganico, Stephan Dupke, Ivanka Krznaric, Martin Obermeier, Robert Ehret, Hauke Walter, Gordon Weinberg, Andreas Wienbreyer, Daniela Behrendt, Janina Motsch, Marcel Schütze, Tine Steininger

University of Bonn:

Jürgen Rockstroh, Christoph Boesecke, Jakob Nattermann

Thank you for your attention