dr ranjababu (babu) kulasegaram consultant physician in ... · miller et al. cid. 2005;41:713-720....

HIV Infection with HCV Future Directions

Dr Ranjababu (Babu) Kulasegaram Consultant Physician in HIV/GU Medicine Guy’s and St Thomas’ NHS Foundation Trust London, UK

Presenter disclosure information

Dr Ranjababu Kulasegaram has received grants and research support from MSD, abbvie, BMS, ViiV, Gilead, Boehringer Ingelheim and Janssen. He has also undertaken speaker, advisory board and consultancy work for ViiV,MSD, Abbott, BMS, Jannsen and Gilead

Objective

•  Background - Natural History and epidemiology

•  Impact of HIV on HCV •  Impact of HCV on HIV

•  Treatment options now •  Future

Background

HIV

•  DNA •  HIV1 and 2 - subtypes •  1010 virions / day •  Mutation rates •  Long-lived proviral reservoir •  Potential cure •  No effective vaccine

HCV

•  RNA •  Genotypes and subtypes •  1012 virions /day •  Mutation rates •  No integration •  Cure (SVR) •  No effective vaccine

Epidemiology

Where we are with HIV

Cause of death in Treated HIV •  Swiss HIV cohort study (449 deaths) from 2005-2009

•  Non-AIDs caused 85% of deaths

•  HCV infection played an important role

M Ruppik et al, Abs: 789

Patients are growing older 100%

80%

60%

40%

20%

0 2010 2006 2002 1998 1994 1990 1986

Year

Adapted from: Swiss Cohort Study 2013 Update. Available at http://www.shcs.ch/userfiles/file/graphiques/shcs_fig19.JPG. Last Accessed Jul 2013

<30 years

30–39 years

40–49 years

>50 years

% o

f pa

tien

ts p

er a

ge c

ateg

ory

Co-morbidities in HIV+ vs HIV- people

HIV+ patients are more likely to n  Develop co-morbidities earlier n  Suffer from multiple illnesses concurrently

Guaraldi G et al. Clin Infect Dis 2011;53:1120–1126

No age-related diseases 1 co-morbidity 2 co-morbidities 3 co-morbidities 4 co-morbidities

≤40 yrs

80%

n=542 3.9% Prevalence

41–50 yrs

60%

n=1,724 9.0%

51–60 yrs

42%

n=452 20.0%

>60 yrs

21%

n=136 46.9%

≤40 yrs

90%

n=1,626 0.5%

41–50 yrs

80%

n=5,172 1.9%

51–60 yrs

65%

n=1,356 6.6%

>60 yrs 40%

n=408 18.7%

0%

25%

50%

75%

100% 9%

0% 1%

17%

0% 2%

28% 42%

6% 1%

15%

0.25% 2%

16% 31%

35%

31%

1% 3%

8% 17%

29%

1% 6%

15%

4%

Cas

es C

ontrols

Polypathology prevalence among patients and control subjects

Impact of HIV on HCV

Natural history of HCV infection

Exposure (Acute phase)

Resolved Chronic

Cirrhosis Stable

Slowly Progressive

HCC Transplant

Death

20% (17)

15% (15) 85% (85)

25% (4)

80% (68)

75% (13)

HIV and Alcohol

Alter MJ Semin Liver Dis 1995; 15: Management of Hepatitis C NIH Consensus Statement 1997; March 24-26:15(3).

Metabolic syndrome

Stop Cirrhosis / Extra Hepatic manifestations

HCV mono-infected vs HIV(+)/HCV(+)

44

25

74

6154

40

0

10

20

30

40

50

60

70

80

90

100

1 2 5Years

Survival

HCV

HCV/HIV

Outcome of cirrhosis after 1st

decompensation

Pineda, J A, Romero-Gómez, et al. Hepatology 2005; 41: 779-789

Impact of HCV on HIV

Effects of HCV on HIV Disease Meta-analysis involving 6216 patients from 8 trials n Mean increase in CD4 cell count among was 33.4

cells/mm3 less than that observed in HIV-monoinfected patients

EuroSIDA n After adjusting for baseline factors, investigators

concluded that HIV/HCV-coinfected patients do not have a greater risk of progressing to AIDS

n ARV – Liver toxicity

Miller et al. CID. 2005;41:713-720. Rockstroh et al. JID. 2005;192:992-100

Acute HCV in HIV MSM transmission

LGV Acute HCV N = 1993 cases since 2003

E Bottieau et al. Eurosurveillance, 2010; 15, 39 (15), 30 September 2010

Case review Patient 1: 45 year-old MSM

n  HIV-1 2009 n  CD4 nadir 350 n  Atripla n  CD4 513 (35%) HIV RNA <20 copies/mL

n  Acute HCV Sept 2013 n  Genotype 1a n  ???

Acute HCV - When to initiate Treatment

negative

< 2 log10 reduction

positive

rebound

further decay

Diagnosis of acute HCV (HCV RNA – positive)

Decay HCV RNA

HCV RNA

HCV RNA

repeat HCV RNA according to local protocol

Treat

Treat

Treat

Week 4

Week 8

Week 12

>2log10 reduction

What next?

He wants treatment now

HCV – Direct-Acting Antiviral (DAA)

*For genotype 1 TIW: three times per week SMV: simeprevir; SOF: sofosbuvir; FDV: faldaprevir

IFN TIW

IFN + RBV

Peg-IFN + RBV

‘Triple therapy’ TVR + PR BOC + PR

SOF + PR SMV + PR

SOF + RBV (IFN-intolerant or ineligible)

1990 1995 2000 2005 2010 2015

FDV + PR

DAAs*

Importance of weight-based Ribavirin

(1000mg <75kg/1200mg >75kg)

Soriano, et al. AIDS 2007. 21: 1073-89

Triple therapy in HIV/HCV DAA NS3/4A

Telaprevir (TVR) + PR

Boceprevir (BOC) + PR Simeprevir (SMV)+ PR Faldaprevir (FDV)+ PR

Study 110: HCV-treatment-naïve patients – SVR rates 24 weeks post treatment (SVR24*)

*Patient was defined as SVR24 if HCV RNA was <LLOQ in the visit window ART: antiretroviral therapy; LLOQ: lower limit of quantification Sulkowski MS, et al. Ann Intern Med 2013;159:86–96

SVR

(%)

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

No ART EFV/TDF/FTC ATV/r/TDF/FTC or 3TC Total

• Randomised, double-blind, placebo-controlled trial in 62 patients receiving/not receiving ARV: TVR + PR vs placebo + PR for 12 weeks followed by PR to week 48

Study 110: AEs and premature discontinuations due to AEs1

Discontinuation of TVR only due to AE, n=1 (due to jaundice); discontinuation of all study drugs due to AE (overall treatment phase),n=2 (due to cholelithiasis and hemolytic anemia)2

1. Sulkowski MS, et al. Ann Intern Med 2013;159:86–96 2. Sherman KE, et al. Hepatology 2011;54(Suppl. S1). Abstract LB-8

AEs

TVR treatment Phase (Weeks 1–12)

Overall treatment Phase (Weeks 1–48)

TVR/PR (n=38)

PR (n=22)

Difference (95% CI)

TVR/PR (n=38)

PR (n=22)

Difference (95%CI)

Overall

Any AE 37 (97) 21 (95) 2 (–8, 12) 38 (100) 22 (100) -

AEs leading to death 0 (0) 0 (0) - 0 (0) 0 (0) -

Serious AEs 2 (5) 0 (0) 5 (–2, 12) 7 (18) 2 (9) 9 (–8, 26)

AEs leading to treatment discontinuation

2 (5) 0 (0) 5 (–2, 12) 3 (8) 0 (0) 8 (–1, 16)

Special interest

Pruritus‡ 13 (34) 1 (5) 30 (12, 47) 15 (39) 2 (9) 30 (11, 50)

Rash 11 (29) 4 (18) 11 (–11, 32) 13 (34) 5 (23) 11 (–12, 35)

Anemia 5 (13) 4 (18) –5 (–24, 14) 7 (18) 4 (18) 0.2 (–20, 20)

Anorectal discomfort 5 (13) 1 (5) 9 (–5, 22) 5 (13) 2 (9) 4 (–12, 20)

§  Overall safety and tolerability profile of TVR combination therapy was comparable

with that previously observed in chronic genotype 1 HCV mono-infected patients1,2

BOC + PR for the treatment of HCV treatment-naïve coinfected patients: virologic response over time

Sulkowski M, et al. Lancet Infect Dis 2013; 13:597–605

n/N= 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64

Patie

nts

with

und

etec

tabl

e

HC

V R

NA

(%)

10/34 42/64 40/64 9/34 40/64 10/34

§ Phase II, randomised, double-blind (BOC), open-label (PR) trial in 98 patients receiving ARV: 4 week PR lead-in then BOC + PR (vs placebo + PR) for 44 weeks

PR BOC+PR

Dieterich D. et al., Oral presentation at CROI 2014

Simeprevir (SMV/TMC435)

•  Single-pill, once-daily, oral HCV NS3/4A protease inhibitor approved in Japan, Canada, and the US, and under regulatory review in Europe and other regions

•  Multigenotypic: antiviral activity in patients infected with HCV GT1, 2, 4, 5, and 61–4

•  SMV is being investigated in IFN-free combinations

•  In Phase III trials of SMV + PR in GT1 HCV mono-infected patients, SVR12 rates of 80–81% (treatment-naïve patients) and 79% (relapsers to IFN-based treatment) were reported5–7

•  Safe and well tolerated (~3,800 patients treated to-date)

1Reesink HW et al. Gastroenterology 2010;138:913–921; 2Moreno C et al. J Hepatology 2012;56:1247–1253; 3Fried MW et al. Hepatology 2013: epub;

4Zeuzem S et al. Poster LB-2998 presented at EASL 2011; 5Manns M et al. Oral presentation at EASL 2013; 6Jacobson I et al. Poster 1425

presented at EASL 2013; 7Forns et al. Gastroenterology In press GT, genotype; IFN, interferon; PR, peginterferon-α + ribavirin; SMV, simeprevir;

SVR12, sustained virologic response 12 weeks after end of treatment


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

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


0

20

40

60

80

100

Overall Naïves Relapsers Partial Null

SVR

12 (%

) C212: SVR12 ― Primary endpoint and versus historic PR-only control (ITT population)

p<0.001a

78/106

p<0.001a

42/53 51/176 2/37 16/28 13/15 7/10

SMV/PR Historical PR

74 79

29b

5c

87

70

57

n/a n/a n/a

aFormal hypothesis testing was used (one-sample single-sided z-test) to allow comparison of primary efficacy variable with historical data for naïves and null responders bFrom PEGASYS® USPI, co-infected patients; cFrom INCIVEKTM USPI, mono-infected patients; n/a, not applicable ITT, intent-to-treat; PR, peginterferon-α2a + ribavirin; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment


C212: SVR12 by IL28B genotype (ITT population)

CC CT TT

15/15 19/27 8/10 7/7 6/6 1/1 5/7 1/2 4/5 10/19 2/4 27/28 11/18 40/59

*0/2 patients; SVR12, sustained virologic response at 12 weeks after planned end of treatment


C212: Conclusions

§  SMV QD + PR led to high SVR12 in HCV GT1/HIV-1 patients regardless of prior HCV treatment response, with overall rates of 74% (range: 57–87%)

§  Baseline characteristics did not have an impact on SVR12 rates: –  METAVIR fibrosis score, HCV GT1 subtype, presence of

Q80K polymorphism and baseline CD4+ count §  89% of treatment-naïve and prior relapsers without cirrhosis met RGT criteria

and were eligible to shorten therapy to 24 weeks, with 87% achieving SVR12 §  HIV virologic suppression was maintained during SMV therapy §  SMV QD + PR was well tolerated with a safety profile similar to that observed in

mono-infected patients –  Only 1.9% (2/105) of patients had Grade 3 hemoglobin or bilirubin

abnormalities –  All rash and pruritus AEs were Grade 1 or Grade 2 and none were

considered serious. No Grade 3 or Grade 4 rash or pruritus AEs were reported.

AE, adverse event; GT, genotype; PR, peginterferon-α2a + ribavirin; RGT, response-guided therapy; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment

36

Background §  Faldaprevir (FDV) is a potent inhibitor of HCV NS3/4A,

with antiviral activity against HCV genotypes (GT) 1, 4, 5, and 6 in vitro1

§  FDV is a substrate of CYP3A4, a moderate inhibitor of CYP3A4 at 240 mg QD2, and a weak inhibitor of CYP3A4 at 120 mg QD

§  The Phase III STARTVerso4 trial evaluated the safety and efficacy of FDV + pegylated interferon α-2a /ribavirin (PR) in patients co-infected with HCV and HIV

1. White PW, et al. Antimicrob Agents Chemother 2010;54:4611–4618; 2. Sabo J, et al. ICAAC 2012; Abstract A-1248.

37

Study design rationale

120 or 240 mg QD

ART regimen

FDV dosage

RANDOMIZED

120 mg QD 240 mg QD

ALLOCATED

FDV with ART (in healthy subjects) Change in FDV AUC1

FDV with darunavir/ritonavir 130% ↑

FDV with efavirenz 35% ↓

ART, antiretroviral therapy; AUC, area under the curve; FDV, faldaprevir; QD, once daily. 1. Sabo J, et al. CROI 2013; Abstract 35.

Darunavir/ritonavir or atazanavir/ritonavir

based

Efavirenz based No ART

Raltegravir or maraviroc

based

38

Study design

FDV 120 mg QD + PR

24 weeks

ARM A (N=123)a

PR, 12 weeks

FDV 240 mg QD + PR, 12 weeks ARM B

(N=187)a

PR 24 weeks

STOP TREATMENT

FDV 240 mg QD + PR

12 weeks ETS: YES

ETS: NO

PR 24 weeks

STOP TREATMENT

Re-randomization (1:1) Primary endpoint: SVR12

aNumber randomized/allocated. ART, antiretroviral therapy; ETS, early treatment success; FDV, faldaprevir; PR, pegylated interferon α-2a and ribavirin; QD, once daily; SVR12, sustained virologic response (HCV RNA <25 IU/mL, not detected) 12 weeks after the planned end of treatment.

Large, multicenter, open-label, sponsor-blinded, randomized, Phase III study in patients co-infected with HCV GT-1 and HIV-1

ETS: YES

ETS: NO

ETS: HCV RNA <25 IU/mL at Week 4 and undetectable at Week 8

FDV dose: randomization (1:1) or allocation according to ART

Day 1

Wk 12

Wk 12

Wk 24

Wk 24

Wk 48

39

Conclusions §  FDV was highly efficacious and well tolerated in difficult-to-treat patients co-infected

with HIV and HCV GT-1

§  Treatment with FDV resulted in a total SVR12 rate of 72%

–  A high proportion of patients (80%) achieved ‘early treatment success’ (ETS) and 86% of these patients achieved SVR12

§  High SVR12 rates achieved regardless of

–  HCV genotype

–  Presence of compensated cirrhosis

–  FDV doses and durations studied

§  Among patients with ETS, 24 weeks total duration of therapy was possible without compromising SVR12 rates

§  The safety profile of FDV in HIV and HCV GT-1 co-infected patients was similar to that observed in HCV GT-1 mono-infected patients1,2

1. Jensen DM, et al. AASLD 2013; Poster 1088; 2. Jacobson IM, et al. CROI 2013; Poster 1100.

Sofosbuvir

NS5B

41

‡ SOF + PegIFN + RBV in Treatment-Naïve HIV/HCV Co-infected Patients Phase 2 Study 1910 Design

§  Single-centre, 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

42

‡ SOF + PegIFN + RBV in HIV/HCV Coinfection SVR12 According to HCV Genotype and HIV ARV Regimen

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

GT 1 GT 2 GT 3 GT 4 GT 1a GT 1b

NNRTI, non-nucleoside reverse transcriptase inhibitor

87

17/19 13/15

89

4/4 1/1 2/2 1/1

100 100 100 100

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0

1 0 0 H

CV

RN

A <L

LOQ

(%)

FTC/TDF + Protease Inhibitor

8/9 7/8 6/6

89 88 100

0 10 20 30 40 50 60 70 80 90 100

SVR

12 (%

)

FTC/TDF + NNRTI

FTC/TDF + Raltegravir

43

‡

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

91 91

0

20

40

60

80

100

NEUTRINO(HCV Mono-‐infected)

Study 1910(HIV/HCV Co-‐infected)

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

All oral HCV

45

‡

Osinusi A, et al. JAMA. 2013;310(8):804-811.Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87.

Similar response rates observed in HIV/HCV coinfected patients compared with HCV monoinfected patients

GT 1 SOF + RBV 24 weeks



All-Oral Therapy of SOF + RBV Comparison of HCV Monoinfected to HIV/HCV Coinfected


SVR

12 (%

) 68 76

0 20 40 60 80 100

SPARE PHOTON-‐1

SVR

12 (%

)

93 88

0 20 40 60 80 100

VALENCE PHOTON-‐1

SVR

12 (%

)

56 67

0

20

40

60

80

100

FISSION PHOTON-‐1

SVR

12 (%

)

85

0 20 40 60 80 100

VALENCE

TURQUOISE-‐I (M14-‐004)

–  Phase 3 trial, randomized, open-‐label design –  Genotype 1, HIV-‐1-‐HCV co-‐infected subjects (N=300) –  Primary endpoint: SVR12

3 DAAs + RBV

PaIent PopulaIon GT Treatment Arms

HIV-‐1-‐HCV co-‐infecteda 1 Arm 1: ABT-‐450/r/ABT-‐267 + ABT-‐333 + RBV for 12 weeks Arm 2: ABT-‐450/r/ABT-‐267 + ABT-‐333 + RBV for 24 weeks

a Co-‐infected subjects had a plasma HIV-‐1 RNA <40 copies/mL during screening and were on a stable HIV-‐1 an\retroviral therapy regimen

NCT01939197. ClinicalTrials.gov Web site: hap://www.clinicaltrials.gov/ct2/show/NCT01939197?term=01939197&rank=1 Updated October 18, 2013. Accessed November 27, 2013.

On-treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV-Coinfected Patients: The C-WORTHY Study

Mark Sulkowsky et al CROI 2014 #654LB

Aim and study design

•  To compare on-treatment HCV RNA responses (defined as proportion of patients with HCV RNA <25 IU/mL) in HIV/HCV GT1 co-infected patients treated with MK-5172 + MK-8742 ± RBV with those in HCV mono-infected patients

50 Adapted from: Mark Sulkowsky et al CROI 2014 #654LB

Virologic Responses: Intent to Treat (Full Analysis Set) Population


Summary

Efficacy •  All co-infected and mono-infected

patients had an HCV RNA <25 IU/mL independent of RBV by week 4 of therapy

•  HCV kinetics over the first 4 weeks of therapy were similar in patients

–  with and without HIV co-infection –  with G1a or G1b infection

•  Two co-infected subjects with low PK levels of MK-5172 and/or MK-8742 experienced virologic breakthrough at TW8

–  both cases with low blood levels of MK-5172 and/or MK-8742)

Safety

•  The safety profile of MK-5172/MK-8742 was comparable among mono- and co-infected patients

•  The most common AEs in co-infected patients were fatigue and headache

•  All co-infected patients had suppressed HIV and stable CD4 counts

•  There were no early discontinuations due to drug-related adverse events


Country USA

Status: Recrui\ng

BMS AI444-‐216 (ALLY2): phase 3, open-‐label, randomised efficacy study of daclatasvir and sofosbuvir in pa\ents co-‐infected with HIV

www.clinicaltrials.gov NCT02032888

Pa\ents Es\mated enrolment: 200

Treatment naive or experienced

HCV/HIV co-‐infected

GT1–6

DCV, daclatasvir; SOF, sofosbuvir; SVR, sustained virologic response

24-week follow-up

Week 0 Week 12 Week 24 (SVR12)

Treatment-naive 12

weeks 24-week follow-up DCV 30, 60 or 90 mg QD

+ SOF 400 mg QD

Treatment-naive 8 weeks

Treatment-experienced

8 weeks

DCV 30, 60 or 90 mg QD + SOF 400 mg QD

Week 8 Week 20 (SVR12)

DCV 30, 60 or 90 mg QD + SOF 400 mg QD

24-week follow-up

Week 36 (SVR24)

Stop Cirrhosis / Improve QOL

www.hep-druginteractions.org

57

HIV/HCV

§  HIV stable §  HCV – Liver health, Fibrosis (can you wait, how long) §  Co-morbidity (renal, Metabolic, BMI, Mental health) §  Readiness/choice §  Success (SVR) §  Safety, drug-drug interactions (polypharmacy) §  Trial options §  Timeline §  Team approach §  Access

•  Sick & dying in early 80s to long term chronic illness

•  How did we achieve it - mid 90s •  HAART-ARVs community response &

Government listens •  Global access – Testing, TasP (Zero

transmission) •  MTCT •  PEP & PEPSE •  PrEP

•  HCV - IFN – Peg IFN, Peg IFN + RBV, All oral DAA •  Access, affordable

•  HCV •  Testing, Cure HCV and care •  Liver health - Follow up, HCC, Liver Transplant

•  HCV free world •  HIV free world (ZERO Transmission) •  Stigma (Education) •  Treat HIV reduce transmission •  Cure HCV, reduce cirrhosis, HCC, ESLD and

improve QOL •  Not just a virus •  We can do it, work together

Thank You

dr ranjababu (babu) kulasegaram consultant physician in ... · miller et al. cid. 2005;41:713-720....

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