P-1

DAA’s in the treatment of HCV: Managing Side Effects

Douglas T. Dieterich, M.DProfessor of Medicine

Division of Liver Diseases,Gastroenterology and Infectious Diseases

Department of MedicineMount Sinai School of Medicine

New York, New York

Telaprevir/Boceprevir in Combination with PEG-IFN/RBV in Genotype 1 HCV Treatment Helpful data prior to initiating treatment :

• HCV genotype 1a/1b• Quantitative viral level• IL-28 genotype (treatment naïve)• Previous viral kinetics if non-responder

IL-28 not as helpful with accurate viral kinetics• Fibrosis assessment• CBC/Platelets (cirrhotics), CMP (creatinine)• Concomitant medicines/Drug-Drug interaction query• Management plan for side effects

Rash, anemia, GI side effects Identify Dermatologist

Clinical Pharmacology and Drug Interactions Boceprevir

• Strong inhibitor of CYP3A4/5 • Partly metabolized by CYP3A4/5• Potential inhibitor of and substrate for P-gp

Telaprevir• Substrate of CYP3A• Inhibitor of CYP3A• Substrate of P-gp

Must perform DDI survey or work with clinic pharmacology

http://www.hep-druginteractions.org/

P-gp = p-glycoprotein Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011.Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Medicines that are contraindicated with boceprevir and telaprevir *

1. Boceprevir package insert. May 2011. 2. Telaprevir package insert. May 2011.

Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2]

Alpha 1-adrenoreceptor antagonist

Alfuzosin Alfuzosin

Anticonvulsants Carbamazepine, phenobarbital, phenytoin

N/A

Antimycobacterials Rifampin RifampinErgot derivatives Dihydroergotamine, ergonovine,

ergotamine, methylergonovineDihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agents Cisapride CisaprideHerbal products Hypericum perforatum (St John’s

wort)Hypericum perforatum

HMG CoA reductase inhibitors

Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin

Oral contraceptives Drospirenone N/ANeuroleptic Pimozide PimozidePDE5 inhibitor Sildenafil or tadalafil when used for tx

of pulmonary arterial HTNSildenafil or tadalafil when used for tx of pulmonary arterial HTN

Sedatives/hypnotics Triazolam; orally administered midazolam

Orally administered midazolam, triazolam

*Studies of drug-drug interactions incomplete.

Telaprevir + PegIFN/RBV: Genotype 1 Treatment-Naive Patients

Dosage and Administration 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (standard fat meal 20

g,)eg, ½ cup nuts or 2 oz cheddar cheese) Must be administered with both pegIFN and RBV Telaprevir dose must not be reduced or interrupted

Treatment duration Patients with extended RVR (eRVR, undetectable* HCV RNA at Week 4 and 12)

receive 24 wks of therapy• Patients without eRVR continue on pegIFN + RBV for a total of 48 wks

Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Week 48)

F/u 24 wks

TVR + PegIFN RBV

Wks480 24124

eRVR; stop at Wk 24/ f/uPegIFN + RBV

No eRVR; PegIFN + RBV

*Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.Telaprevir package insert. May 2011.

Week 4 HCV RNA> 1000 IU/ml

Week 12 HCV RNA> 1000 IU/ml

Week 24 HCV RNAdetectableFutility

What can we tell our patients?Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to

Peg IFN/Ribavirin Alone

SVR

75

44

P<0.0001

271/363 158/361n/N =

Perc

ent o

f pat

ient

s w

ith S

VR

0

10

20

30

40

50

60

70

80

90

100

T12PR PR

Jacobson IM, et al. Hepatology 2010;52(Suppl 1):Abstract 211.

Virologic Responses from Illuminate study with response guided treamtent– ITT Population

0

20

40

60

80

100

389/540 352/540n/N=

RVR eRVR

Patie

nts W

ith U

ndet

ecta

ble

HC

V R

NA

leve

ls (%

)

7265

469/540

EOT

87

388/540

SVR

72

0

20

40

60

80

100

4.5% (2-sided 95% CI = -2.1% to +11.1%)

Patie

nts W

ith S

VR

(%)

T12PR24 T12PR48149/162 140/160n/N=

92 88

SVR Rates - Noninferiority of 24-week Regimen

SVR was comparable regardless of race or ethnicity and liver fibrosis stage

Undetectable HCV RNA over time

Sherman KE, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. LB-2

Telaprevir: Most Common AEs (≥ 25%) and Discontinuation Rates from Advance

% of Patients With T12/PR(n = 363)

T8/PR(n = 364)

PR48(n = 361)

Any AEa 99 99 98

Fatigue 57 58 57

Pruritus 50 45 36

Headache 41 43 39

Nausea 43 40 31

Rash 37 35 24

Anemia 37 39 19

Insomnia 32 32 31

Diarrhea 28 32 22

Influenza-like illness 28 29 28

Pyrexia 26 30 24

a Reported in ≥ 25% of patients regardless of severity in any treatment arm

• 7% of T12PR, 8% of T8PR, and 4% of PR48 patients discontinued all drugs due to AEs during TVR/placebo phase. • 11% of T12PR, 7% of T8PR, and 1% of PR48 patients discontinued TVR/placebo only during TVR/placebo phase.

Jacobson IM, et al. AASLD 2010. # 211.

Telaprevir: Rash Patients treated with telaprevir

• Rash reported in 56% of subjects (vs 34% with PR48); 4% severe• Typically eczematous, maculopapular, and papular-lichenoid• In most subjects, the rash was mild-moderate• Rash events resulted in discontinuation of TVR in 6% of subjects• Occurred early, usually within first 4 weeks, but can occur at

anytime• < 1% Stevens Johnson Syndrome or DRESS

Mechanism of rash remains unknown; however, pyrazinoic acid is a major metabolite of TVR & may contribute to rash/pruritus• Structural analog of niacin

Improvement occurs after dosing completion or D/C; may take weeks for complete resolution

Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011. Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Telaprevir rash

10

Mild Rash Moderate Rash

• Oral antihistamines early!• Topical steroid creams (prescription)• Avoid sun exposure• Continue telaprevir with Peg IFN/RBV

Localized Diffuse

Telaprevir: Severe Rash

11

• Generalized rash, or rash with vesicles, bullae, or ulcerations• No Stevens Johnson Syndrome/DRESS• Stop telaprevir, if no improvement in 7 days, stop Peg IFN/RBV• Do not reintroduce telaprevir• If no improvement, refer to Dermatologist

Stevens-Johnson Syndrome(SJS)/Drug rash with eosinophilia and systemic

symptoms (DRESS) SJS: Fever, target lesions, mucosal

erosions/ulcerations Drug rash with eosinophilia and systemic

symptoms• Rash, fever, facial edema, internal organ

involvement• ±eosinophilia

Stop all medicines Urgent Dermatology referral

Gastrointestinal Side effects

• Nausea: metoclopramide, ondansetron• Telaprevir should be taken with 20 grams of fat

to help with absorption• Perianal symptoms

• Anal Pruritus with telaprevir: antihistamines• Topical therapies: Witch hazel topical,

hydrocortisone cream, mesalamine suppositories, anusol HC

• Diarrhea: loperamide, Bulk/fiber supplement• Reassurance, it goes away in a few weeks

13

Telaprevir: Anemia Mechanism of anemia thought to be result of bone

marrow suppressive effect associated with telaprevir, not RBC hemolysis

Early bump in creatinine may increase RBV levels Patients treated with telaprevir had

• More anemia, hemoglobin level < 10 g/dL (36% vs 17%) • More hemoglobin reductions to Grade 3 or higher toxicity (7.0

to < 8.9 g/dL or any decrease> 4.5 m/dL) levels (55% vs 25%)

• More hemoglobin < 8.5 g/dL (14% vs 5%)• More anemia-related SAEs (2.5% vs < 1%) • More anemia-related discontinuations (4% vs < 1%)

Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.

ADVANCE/ILLUMINATE: Anemia and Ribavirin dose reduction did not affect SVR in Telaprevir arms

Anemia No Anemia RBV Dose Reduction

No RBV Dose Reduction

145/196

116/165

247/344

44/92

206/265

173/255

164/534

135/262

135/172

106/148

241/300

37/48

226/293

163/272

434/545

117/245n/N = n/N =

Anemia :Hgb < 10 g /dl

Week 4 Week 48

PR + BOC (24 weeks)Non-cirrhotic

Week 28 Week 72

TW 8-24 HCV-RNA Undetectable*

Follow-up

Follow-up

Boceprevir for genotype 1 naïve HCV

PRlead-in Week 36

TW 8 HCV-RNA Detectable/TW 24 undetectable

PR

Week 12 FutilityHCV > 100 IU/ml

Week 12 Week 24

Week 24 FutilityDetectable HCV RNA

PR+BOC(32 weeks)

*assay should have a lower limit of HCV-RNA quantification < 25 IU/mL, and limit of HCV-RNA detection of approximately 10-15 IU/mL

• PR + BOC (44) weeks for cirrhotic patients/poorly responsive patients

2342

53

14 12 17

0

20

40

60

80

100

48 P/R BOC RGT BOC/PR48Pe

rcen

t

SPRINT 2: SVR

40

67 68

239 8

0

20

40

60

80

100

48 P/R BOC RGT BOC/PR48

Perc

ent

p < 0.0001

p <0.0001

Non-Black Patients

p = 0.044

p =0.004

Black Patients

SVR

Relapse Rate

*SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post-treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively.

125311

211316

213311

1252

2252

2955

37162 21

23218

2302

143

25

635

97 96

50556065707580859095

100

BOC RGT BOC/PR48

SVR in patients with undetectable HCV RNA

between Weeks 8-24S

VR

(%)

74 74

50556065707580859095

100

BOC RGT BOC/PR48

SVR in patients with detectable HCV RNA at

least once between Weeks 8-24

5270

4865

* Remaining patients discontinued prior to treatment week 28 due to futility, adverse events or non-medical reasons

143147

137142

22%* of non-black patients in RGT arm were treated with >28 weeks of therapy

47% of non-black patientsin RGT arm were treatedwith short duration

Adverse Event Arm 1 (PR48); n=363 (%) Arm 2 (RGT); n=368 (%) Arm 3 (BOC/PR48); n=366 (%)

Fatigue 59 52 57

Headache 42 45 43

Nausea 40 46 42

Anemia 29 49 49

Dysgeusia 18 37 43

Chills 28 36 33

Pyrexia 32 33 30

Insomnia 32 31 32

Alopecia 27 20 28

Decreased Appetite 25 26 24

Pruritis 26 23 25

Neutropenia 21 25 25

Influenza Like Illness 25 23 22

Myalgia 26 21 24

Rash 22 24 23

Irritability 24 22 22

Depression 21 23 19

Diarrhea 19 19 23

Dry Skin 18 18 22

Dyspnea 16 18 22

Dizziness 15 21 17

Most Common Treatment-Related Adverse Events*

*Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

Boceprevir: Anemia

Mechanism of anemia thought to be result of bone marrow suppressive effect associated with boceprevir, not due to RBC hemolysis

Patients treated with boceprevir had• Average additional decrease of Hgb of

approximately 1 g/dL• Anemia reported as a serious AE (1% vs none with

PR)• A higher frequency of hemoglobin reductions to

Grade 3 or higher toxicity

US Food and Drug Administration; April 27, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252341.pdf. Accessed April 28, 2011. Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2011.

Use of Erythropoietin and/or RBV in Boceprevir Clinical Trials

ESA use and serious AE: including death, CV events, thromboembolic events, stroke, and risk of tumor progression or recurrence. In boceprevir trials, AEs associated with ESA use included pulmonary embolism (n = 2), arterial thrombosis (n = 1), DVT (n = 4), cerebral ischemia (n = 1), MI (n = 1), and 1 case of pure red cell aplasia.

US Food and Drug Administration; April 27, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252341.pdf. Accessed April 28, 2011.

Treatment Arm (Pooled)

EPO Usen (%)

RBV Dose Reduction n (%)

EPO Use OR RBV Dose Reduction n (%)

EPO Use AND RBV Dose Reductionn (%)

RBC Transfusion n (%)

All Boceprevir-treatedsubjects(N = 1057)

458 (43) 327 (31) 543 (51) 242 (23) 39 (4)

All PR-treatedsubjects(N = 443)

104 (24) 81 (18) 135 (31) 50 (11) 2 (< 1)

Dose Reduction in Phase 3 Trials (Sprint-2/Respond-2)

Anemia management: SVR According to EPO Use and Ribavirin (R) Dose

Reduction: Anemia also associated with SVR with BOC

SVR rate in patients managed with R dose reductions alone were comparable to those in patients managed with EPO, with or without R dose reduction

Sulkowski M, et al. EASL 2011, Abst. 476.

SVR

(%)

No Anemia

EPO Alone Both Neither

Anemia

Previously Untreated(SPRINT-2)

BOC arms only

212363

95129

109153

3044

SVR

(%)

Previous Treatment-Failures(RESPOND-2)BOC arms only

2937

R DoseReduction

Alone

SVR

(%)

83165

4759

4867

1926

56

No Anemia

EPO Alone Both NeitherR DoseReduction

Alone

Anemia

Historical Perspective on Anemia in HCV

PEG-IFN/RBV experience• Complicated by RBV-related hemolysis and PEG-IFN–related

bone marrow suppression• Anemia observed in up to 30% of treated patients

May be higher in patients who would not qualify for phase 3 trials• Epoetin alfa shown to maintain ribavirin dose in HCV-infected

patients, enhance SVR, and improve HRQOL• FDA issued advisories on potential AEs with ESAs

(thrombovascular events, shortened time to tumor progression or recurrence, shortened survival time in patients with cancer, and pure red blood cell aplasia)

• erythropoietin and other erythropoiesis-stimulating agents (ESAs) are not FDA-approved for treatment of anemia in patients with chronic hepatitis

Pockros PJ, et al. Hepatology. 2004;40(6):1450-1458. Sulkowski MS, et al. Gastroenterology. 2010;139(5):1602-1611. Afdhal NH, et al. Gastroenterology. 2004;126(5):1302-1311. Shiffman ML, et al. Hepatology. 2007;46(2):371-379. Sievert W, et al. Hepatology. 2011;53(4):1109-1117.

Methods – Treatment: Boceprevir Response-Guided Therapy

BOC, boceprevir; PEG-IFN, peginterferon alfa-2b; RBV, ribavirin; SVR, sustained virologic response; TW, treatment week; wk, weeks.Patients with a <2-log decline at week 12 or HCV RNA above the lower limit of quantitation at week 24 met protocol futility rules and were discontinued from the study.

PEG-IFN/RBV

BOC + PEG-

IFN/RBV

BOC + PEG-IFN/RBV for 20 wk

BOC + PEG-IFN/RBV for 40 wk

4 12*8 24* 480

Undetectable HCV RNA at TW8-TW24

Detectable HCV RNA at TW8-TW24

SVR24

SVR24

*Futility rules.

28

Methods – Anemia Management: Erythropoietin vs Ribavirin Dose Reduction (cont)

After completion of 4 week PEG-IFN/RBV lead In, all patients initiated

boceprevir

Hemoglobin≤10 g/dL

RBV DR

EPO (40,000 IU/wk SC)

RHemoglobin ≤8.5 g/dL:

Secondary Strategy (EPO, RBV DR, transfusion)

R = randomization

DR, dose reduction; EPO, erythropoietin; PEG-IFN, peginterferon; RBV, ribavirin; SC, subcutaneously.

Results – Primary and Key Efficacy End Points

Patie

nts,

%

205/251203/249 19/196 19/197178/249 178/251

(95% CI)–0.7% (– 8.6 , 7.2)*

End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms

CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin;SVR, sustained virologic response.*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort.

Patie

nts,

%

Secondary Anemia Intervention

Results – SVR by Secondary Anemia Intervention (cont)

DR, dose reduction; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response.

Anemia Management Recommendations With TVR or BOC-based Therapy

Start with a lower dose of RBV : round down CBC pretreatment, every 2 weeks until treatment week 8,

then monthly Primary strategy: RBV dose reduction EARLY and OFTEN!

• BOC—Hgb < 10 g/dL: decrease in dosage or interruption of RBV is recommended

• TVR—If anemia occurs, reduce RBV right to 600 mg ;order EPO, if inadequate, consider D/C TVR

Hgb < 8.5 g/dL: discontinue all therapy or transfuse If RBV is permanently D/C, BOC or TVR also must be D/C Do not reduce PI dose to manage anemia

Peginterferon alfa-2a Solution for Subcutaneous Injection [package insert]. South San Francisco, CA: Genentech, Inc.; 2011. Peginterferon alfa-2b Injection, Powder for Solution for Subcutaneous Use [package insert]. Kenilworth, NJ: Schering Corporation; 2011. Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011. Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Anemia Management Recommendations After PI Is Complete

Receiving just PEG-IFN/RBV• CBC should continue to be monitored monthly after week 12

1Peginterferon alfa-2a Solution for Subcutaneous Injection [package insert]. South San Francisco, CA: Genentech, Inc.; 2011.2Peginterferon alfa-2b Injection, Powder for Solution for Subcutaneous Use [package insert]. Kenilworth, NJ: Schering Corporation; 2011.

Agents Hgb Value ActionPeginterferon alfa-2a/ RBV1

<10 g/dL in patients with no cardiac disease

Reduce RBV dose to 600 mg/day≥2 g/dL decrease in Hgb during any 4-week period treatment

<8.5 g/dL D/C PEG-IFN/RBV<12 g/dL despite 4 weeks

at reduced dose

Peginterferon alfa-2b/ RBV2

< 10 g/dL PEG-IFN: For patients with cardiac disease, reduce by 50%RBV: 1st dose reduction is by 200 mg/day, except in patients receiving 1400-mg dose—it is by 400 mg/day; 2nd dose reduction (if needed) is by an additional 200 mg/day

< 8.5 g/dL D/C PEG-IFN/RBV

Summary

Both telaprevir and boceprevir added to PR improve SVR rates

Now at least half of individuals can be treated for 6 months

Telaprevir: Rash , GI side effects, anemia Boceprevir: Anemia, dysguesia Careful monitoring, especially in those with advanced

fibrosis Identify consultants prior to initiating therapy

• Dermatologist Drug-Drug interactions must be assessed

• virtually all interactions can be addressed

30

French Cupic • Prospective trial • GT 1 Chronic HCV • CP A Compensated Cirrhotics 

• Interim Analysis  16 wks on PI

Mt Sinai • Retrospective trial• GT 1 Chronic HCV• All comers • Interim analysis 

Baseline, wk 4 and wk 12 data included 

Synopsis of Real Life Treatment Experiences: French ATU/Cupic/ Mt. Sinai 

Baseline Demographic

NYC – Mt. Sinai

French

CUPIC

ATU

N= 98 (TVR) N= 296 (TVR)

Median Age (IQR) 57 (51-61)Mean

57 56 (22-89)

Sex- males (% of total) 70 (71%) 68% 70.6%Previous treatment history – n (% of total)

Naive 19 (19%) N/A N/ARelapser 24 (24%) 40% 42.7%

Non-responder (Part. Resp. , Null Resp., Breakthrough) 48 (49%) Null

8%Breakthrough

3.6%

CUPIC Prior partial 52% 53.5%

Intolerant 7 (7%) N/A N/APts w/ phase 3 exclusion criteria N/A 34%

Baseline demographics continued 

NYC Mt. Sinai French Cupic

ATU

N = 98 TVR N=296

TVR = 333

Advanced fibrosis or cirrhosis –n (% of total)

33/91 (36%) 296/296100% 100%

Median baseline log10 HCV viral load 6.4

Mean

6.56.05 (1.04-

7.84)Median Hemoglobin (IQR) [g/dL]

14.4 (13.4-15.4)

Mean

14.414.7

(8.7-19 g/dL)Median platelets (IQR) [count/uL] 157 (111-194)

Mean

150,000141,000 (32-

409)**

**ATU ‐ 20% had platelets <90000/mm3, with 11 patients (3.9%) having a platelet count between 25000 and 50000/mm3

Mt. Sinai NYC Data (TVR Treated patients)

Cupic Alternate

definitionsCupic ATU

Characteristic (units)Median (IQR) Week 4 Week 12 TVR

Wk 16

Hemoglobin (g/dL)

11.1 (9.8-12.6)

10.5 (9.2-11.5)

Anemia (n) <13.5 men; <12 g/dL women 85% (73) 98% (65)

Anemia Grade 2 (8-<10 g/dL)

(%)19.6% 99/330

(30%)

Severe anemia (n) <9g/dL or ↓ ≥ 4.5g/dL 23% (20) 38% (25) Grade ¾ (<8

g/dL) 10.1% 19/330(5.8%)

Transfusion rate 25% 15% 38/333 (11%)

Epo Use 57% 163/333 (49%)

RBV dose reduction 2% 22/333 (6.6%)

Platelet (count/uL)

104 (74-144)

93 (62-121)

Virologic Responses

Mt. Sinai French CUPIC ATU

Week 12 Wk 16 TVR

RVR 39/89 (44%) 51% ITT 157/223(70.4%)

cEVR 55/77 (71%)

Extended rapid virological response (eRVR)

26/68 (38%) N/A** 84/122

(68.9%) Cumulative undetectability 86%

Mt. Sinai CupicTVR ATU

Early D/C due to Secondary side effects Wk 12 6/77 (8%) 14.5%

SAE 48.6% 40.2%

Death 6 (2%) 3 (1%)

Anemia Overall

0

20

40

60

80

100

120

Anemia * Anemia SAE **

Mt. SinaiC‐TVRATU

*Mt. Sinai Anemia (n) <13.5 men; <12 g/dL womenCupic /ATU Anemia Grade 2 (8-<10 g/dL) (%)

**Mt. Sinai SAE Anemia <9g/dL or ↓ ≥ 4.5g/dLCupic/ATU Anemia Grade ¾ (<8 g/dL)

98

19.630

38

10.1 5.8

Percentage of p

atients w

ith Ane

mia 

Conclusions: Real Life Treatment

This is a very difficult population,desperately in need of treatment, and careful monitoring is needed.

Patients were quite ill and a large portion would not have qualified for Phase 3 trials

– One third of TVR patients would have not qualified for REALIZE

– The platelet cut off was 50,000

MSSM HIV HCV CohortBaseline characteristics

Co-infected(N = 20)

Mono-infected(N = 63) P-value

Median age (IQR) 57 (52-58) 58 (53-63) 0.21*Male (% of total) 16 (80%) 46 (73%) 0.77**Race (% of total)

CaucasianAfrican AmericanOther

11 (55%)5 (25%)4 (20%)

40 (63%)7 (11%)

16 (25%)

0.59**

Previous treatment (% of total)NaiveRelapserNon responderIntolerant

1 (5%)4 (20%)11 (55%)4 (20%)

17 (28%)12 (18%)30 (48%)

4 (6%)

0.08***

Bridging fibrosis/cirrhosis(% of total) 6 (30%) 23 (40%) 0.79**

Baseline HCV viral loadlog10 IU/mL (IQR)

6.17(5.80-6.74)

6.40(5.97-6.72) 0.34*

* Two-tailed t-test , ** Fisher’s exact test, ***

HIV baseline characteristics

Co-infected (n = 20)

Median CD4 countcells/μL (IQR)

499(346-640)

HIV VL (% of total)Undetectable/< 20 copies/mL< 1000 copies/mL

14/18 (78%)17/18 (94%)

ART regimen (% of total)TDF/FTC + ATZ/rTDF/FTC + EFVTDF/FTC + RALTDF/FTC + RAL + ATZ/rABC/3TC + ATZ/r

10 (50%)5 (25%)2 (10%)2 (10%)1 (5%)

ART regimen switch required before treatment (% of total) 10 (50%)

Virological responses

Virological responses are lower in co-infected patients, but the difference is not statistically

significant

Co-infected Mono-infected P-valueWeek 4 (% of total)

Undetectable (RVR)< 4343-1000> 1000

N = 166 (38%)7 (44%)2 (13%)1 (6%)

N = 6025 (42%)22 (37%)6 (10%)7 (12%)

0.99*

Week 12 (% of total)Undetectable (EVR)< 4343-1000> 1000

N = 149 (64%)2 (14%)0 (0%)

3 (21%)

N = 6346 (73%)

4 (6%)4 (6%)

9 (14%)

0.53*

eRVR (% of total) N = 103 (30%)

N = 6025 (42%) 0.35*

* Fisher’s exact test (comparaison “undetectable” vs “detectable)

More frequent discontinuation for adverse events (NS) but similar rates of anemia

HIV/HCV co-infected patients

HCV mono-infected patients

P-value

Discontinuation due to side effects (% of total)

Weeks 0-4Weeks 0-12

0/16 (0%)3/14 (21%)†

2/60 (3%)4/63 (6%)

0.99*0.11*

Anemia (% of total)

Week 4Week 12

11/15 (73%)9/9 (100%)

48/55 (87%)55/56 (98%)

0.23*0.99*

Severe anemia (% of total)

Week 4Week 12

2/15 (13%)4/9 (44%)

17/54 (31%)22/55 (40%)

0.21*0.99*

†2 of the 3 patients stopped telaprevir only ; * Fisher’s exact test

Conclusion

Early on-treatment responses:• Lower in HIV/HCV co-infected patients than in HCV

mono-infected patients

• Not statistically significant in this small study

• Previously presented study was for naive patientsimpossible to compare

• SVR data are needed to determine clinicaleffectiveness

Conclusion (2)

Higher rate of discontinuation in the co-infectedpatients, but the difference was not statisticallysignificant.

50% of patients changed their antiretroviral regimenprior to starting triple therapy out of concern aboutpossible drug-drug interactions.

The number of patients is currently too low to recommend one antiretroviral regimen over another based on RVR, EVR, eRVR rates or treatment failure.