how to manage virologic non-responders, non-genotype 1, relapsers

www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013

How to manage virologic non-responders, non-genotype 1, relapsers

IAS 2013, Session: HCV – Is your patient being left behind? New options and unmet needs., Kuala Lumpur, Malaysia

Jürgen K. RockstrohDepartment of Internal Medicine I

University Hospital BonnGermany


Disclosure slide: Jürgen Rockstroh

• Receipt of grants/research supports:– Gilead

• Receipt of honoraria or consultation fees:– Abbvie, Abbott, Bionor. BMS, Boehringer, Gilead,

GSK, Janssen, Merck, Novartis, Tobira, ViiV


How to manage:

Virologic non-responders and relapsers


Definition of Treatment Response of PEG-IFN and RBV Time HCV RNA Rapid Virological Response (RVR)

Week 4 on treatment Undetectable (<50 IU/mL)

Early Virological Response (EVR)

Week 12 on treatment Undetectable (<50 IU/mL)

Delayed Virological Response (DVR)

Week 12 on treatment > 2*log10 decrease from baseline but not undetectable

Null Response (NR) Week 12 on treatment < 2*log10 decrease from baseline

Partial Non-Response (PR) Week 12 and week 24 on treatment

> 2*log10 decrease at week 12 but detectable at week 12 and 24

Sustained Virological Response (SVR)

24 weeks post-treatment Undetectable (< 50 IU/mL)

Breakthrough Any time during treatment Reappearance of HCV-RNA at any time during treatment after virological response

Relapse (RR) End of treatment and week 24 post-treatment

Undetectable HCV-RNA at end of therapy, detectable by week 24 post-therapy

Adapted from EASL HCV CPG 2011 (see online www.easl.eu/assets/application/files/d0df9f948c85a72_file.pdf )

EACS guidelines 2012


Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 36.

Telaprevir + PegIFN + RBV in HIV/HCV Co-infected Patients with Virologic Failure on IFN + RBV

• Complete RVR8 (HCV-RNA <15 IU/mL): 32 weeks PR phase (Total treatment: 48 weeks)

• Partial RVR8 (15 IU/mL <HCV-RNA <1,000 IU/mL) 56 weeks PR phase (Total treatment: 72 weeks)

Single Arm, Phase 2 Clinical Trial

(Lead in)PegIFN α-2a

RBV

TelaprevirPegIFN α-2a

RBV

PegIFN α-2aRBV

PegIFN α-2aRBV

Follow-up

Follow-up

D0 W4 W8RVR8

W16EVR16

W48 W72SVR24

W96

SVR24

Complete RVR8

Partial RVR8

www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 36.

Telaprevir + PegIFN + RBV in HIV/HCV Co-infected Patients with Virologic Failure on IFN + RBV

• Main Inclusion Criteria– Chronic HCV genotype 1 infection and HIV-1 infection– Previous virological failure after ≥12 weeks

PegIFN + RBV ≥600 mg/day– Stable ART for ≥3 months– Authorized antiretrovirals: ATV, ATVr, EFV, RAL, TDF, FTC, 3TC– CD4 ≥200 cells/mm3 and ≥15%, plasma HIV-RNA levels

<50 copies/mL– Liver biopsy <3 years or cirrhosis on any previous biopsy

• Main Exclusion Criteria– HVB coinfection, HIV-2 infection– Past history of decompensated cirrhosis– Previous null response with cirrhosis

• Important patient characteristics– F3 16%, F4 23%; HCV GT1a 70%


W4 W8 W12 W160%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1.5%

88% 88%

74%

87%

88%

<LLOQ (<15 IU/mL) U

%H

CV

-RN

AVirological response (ITT, n=69)

Only 3 patients with partial RVR8 treatment 72 weeks

RVR8 EVR16

7

TND

88%


Associated ARVs Fibrosis Stage Previous Response

0%

20%

40%

60%

80%

100%88%

92%85%

92%87%

83%

92%

82%

100%

80%

94%86%

% H

CV-

RN

A <

15 IU

/mL

Telaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Early virologic response by patient group

Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abstract 36

n= 34 13 12 10 12 30 11 16 27 6 15 21

ATVrEFV

RAL

Others F1 F2 F3 F4 RRBrkT

h PR NR


Grade 3–4 AEs and treatment discontinuations up to W16

N (%), n=69Grade 3 AEs

BloodGeneralGICutaneousNeurologicalPsychiatricOthers

18 (26%)6 (9%)5 (7%)2 (3%)3 (4%)2 (3%)1 (1%)2 (3%)

Grade 4 AEsBloodPsychiatric

5 (7%)4 (6%)1 (1%)

Reasons for treatment discontinuationsPsychiatric AEsCutaneous AEsOthers AEsVirological failure

3 (4%)3 (4%)1 (1%)1 (1%)


Boceprevir + PegIFN + RBV for HIV-HCV Co-Infected Patients with Previous Virologic Failure

on PegIFN + RBV

**BOC+PegIFN + RBV

W815≤HCV VL-

≤1,000 IU/mL

BOC+PegIFN + RBV

Weeks

*PegIFN + RBV W12-HCV VL> 1,000 IU/ mL: PegIFN + RBV

PegIFN + RBV W12- 15< HCV VL≤ 1,000 IU/ mLBOC+ PegIFN + RBV

Follow-up

Follow-up

2812 160 48 724 8 96

Lead- inPhase

* PegIFNα2b: 1.5 μg/kg/wk RBV: 800 to 1,400 mg/day** BOC:800 mg 3 times/ day

Stop BOC Stop All Drugs

RVR8: % HCV RNA <15 IU/mLEVR16:% HCV RNA <15 IU/mL

EPO, G-CSF, TPO-R agonists allowed

Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 37.

Study Design

HCV VL > 1,000 IU/mL

SVR24 W72

Follow-upW8-HCV VL < 15 IU/ mL: BOC+ PegIFN + RBV

SVR24 W96

W8-HCV VL > 1,000 IU/ mL: PegIFN + RBV Follow-up

HCV RNA Still Detectable

HCV RNA > 100 IU/mL


Inclusion/Exclusion Criteria• Inclusion

– body weight 40-125 kg– Chronic HCV genotype 1– Previous virologic failure on PegIFN + RBV– Stable antiretroviral therapy with 3 or more ARV agents among TDF, ABC,

FTC, 3TC, ATV (boosted or not), and RAL– CD4+ count ≥200 cells/mm3 and VL <50 c/mL for ≥6 months– Any fibrosis level on liver bx within past 3 years or any

bx showing cirrhosis

• Exclusion– HBV co-infection– Childs B or C; decompensated cirrhosis– Previous null response with cirrhosis

• Important patient characteristics– F4 17%; previous null responders 33%, GT1a 78%

Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 37.


BOC/IFN/RBV following virologic failure: results by previous response to Peg-IFN + RBV

Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3–6, 2013. Abstract 37

Relapse n= 20 (31%)

Breakthrough n= 5 (8%)

Partial Responsen= 18 (28%)

Null Respondern= 21 (33%)

0%10%20%30%40%50%60%70%80%90%

100%

70%

40%

55%

10%

90%

60% 61%

38%

W4 W6 W8 W12 W16

% H

V-R

NA

<15

UI/m

L

RVR 8

EVR 16


BOC/IFN/RBV following virologic failure: Results by ARV regimen

Pizot-Martin I, et al. 20th CROI; Atlanta, GA, 2013; Abstract 37

All (n=64) 2NRTI/ATVr (n=32)

2NRTI/RAL (n=27)

Others (m=5)0%

10%20%30%40%50%60%70%80%90%

100%

44%37%

52%40%

63%56%

70%

60%

Patients (%) with HV-RNA <15 IU/mLW4 W6 W8 W12 W16

RVR 8

EVR 16


F0F1

F2F3

F4

Naive Relapser Nonresponder

Individual decision

Individual decision/

triple therapyDefer

Triple therapy Triple therapyIndividual decision

according to disease

progression

Triple therapy Triple therapy Triple therapy

Management of HIV-HCV GT1-co-infected patients (chronic) according to prior treatment outcome

Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9; EACS guidelines version November 2012


Classification of and Interventions for HCV GT 2,3 or 4 in non-responders/relapsers to Prior IFN-based Therapies with HCV/HIV-Co-infection CATEGORY SUBGROUP SUGGESTED INTERVENTION

Suboptimal treatment

Suboptimal schedule IFN (monotherapy or with RBV) Low RBV dose Short length of therapy

Re-treatment using combination therapy with PEG-IFN plus weight-based RBV dosing

Limiting toxicities & poor adherence

Optimal support (SSRI, Paracetamol/NSAID, adherence support, use of haematopoietic growth factors(i)

Optimal treatment with virological failure

Relapse (HCV-RNA negative at the end of treatment)

For Gts 2, 3 and 4 for patients with mild fibrosis, wait and monitor. If rapid progression or > moderate fibrosis, re-treatment using combination therapy with PEG-IFN plus weight-based RBV dosing (consider longer treatment duration)

Non response (no undetectable HCV-RNA during treatment)

Wait for new DAAs with activity against non-GT1

(i) Data on the use of haematopoietic growth factors in HCV/HIV- co-infection is so far limited to an improvement in quality of life but not antiviral efficacy; treatment with growth factors is currently mostly off-label in Europe



How to manage:

Non-genotype 1


Pivotal RCTs for Peg-IFN/RBV in HIV/HCV co-infection

1. Carrat F, et al. JAMA 2004;292:2839–48; 2. Laguno M, et al. Hepatology 2009;49:22–31; 3. Chung RT, et al. N Engl J Med 2004;351:451–9; 4. Torriani FJ, et al. N Engl J Med 2004;351:438–50;

5. Núñez M, et al. AIDS Res Hum Retroviruses 2007;23:972–82

Study Regimen SVR (%) G1 or G4

SVR (%)G2 or G3 Take home observations

RIBAVIC1

France(N = 412)

Peg-IFN α-2bRBV 800 mg 17 44

Low-dose RBVToxicity with ddI + RBVFailure to suppress HCV RNA at week 4 <460,000 IU/mL → 100% NPV

Laguno et al2

Spain(N =182)

Peg-IFN α-2bRBV 800 – 1200 mg

28 62Weight-based RBV → higher SVRShort (24-week) therapy for genotype 2/3 not effective

ACTG A50713

USA(N = 133)

Peg-IFN α-2aRBV 600 - 1000 mg

14 73Low-dose RBVFailure to achieve week 12 EVR → 100% NPV ZDV + RBV → more anemia

APRICOT4

International(N = 868)

Peg-IFN α-2aRBV 800 mg 29 62

Low-dose RBVDecompensation with advanced fibrosis Genotype 1/High HCV RNA –18% SVR

PRESCO5

Spain(N = 389)

Peg-IFN α-2aRBV 1000 – 1200 mg

35 72Weight-based RBV → higher SVRNo increase in anemiaLong (72-week) therapy not well tolerated


Proposed Optimal Duration of Dual HCV-Therapy in Persons with HCV/HIV-Co-infection Not Eligible for Triple Therapy Including DAA against HCV

Week 4 W12 W24 W48 W72

HCV-RNA neg

G2/3 24 weeks therapy(ii)

G1(i)/4 48

weeks therapy

HCV-RNA

neg G2/3

HCV-RNA pos

> 2*log drop in HCV-RNA

G1/4 72

weeks therapy

HCV-RNA pos Stop

< 2*log drop in HCV-RNA

Stop

(i) Where no access to DAAs available or high chances of cure even with dual therapy (favourable IL28B GT, low HCV VL and no advanced fibrosis) (ii) In patients with baseline low VL (< 600 000 IU/mL) and minimal liver fibrosis.



Ongoing clinical trials in HIV/HCV coinfection

• PHOTON 1 and 2 Studies: GT1 or 4 HIV/HCV co-infected treatment-naïve (TN) and GT- 2/3 TN and Experienced Subjects with sofosbuvir + RBV 12-24 weeks

how to manage virologic non-responders, non-genotype 1, relapsers

Documents

malaysia jrgen

orgkuala lumpur

virologic nonresponders

virologic failure

ifn rbvcomplete rvr8

infected patients

consultation fees

gileadreceipt of honoraria