Slide 1 of 66 Case 4: Management of the HIV/HCV Coinfected Patient · PDF file · 2017-07-19Management of the HIV/HCV Coinfected Patient IAS–USA Betty J. Dong, ... – risk severe

B. J. Dong, PharmD

April 23, 2013IAS–USA

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Slide 1 of 66

Case 4:Management of the HIV/HCV

Coinfected Patient

IAS–USA

Betty J. Dong, PharmDProfessor of Clinical Pharmacy

University of California San FranciscoSchool of Pharmacy

AU EDITED: 04-19-13

Slide 2 of 66

Learning Objectives

• Identify the advantages of using HCV DAA in the treatment of the HIV/HCV co infected

After attending this presentation, learners will be able to:

in the treatment of the HIV/HCV co-infected patient.

• Describe interactions between ARVs and HCV DAA

• Discuss HCV DAA specific side effects and recommendations for management

Slide 5 of 66

HIV/HCV Co‐Infection• Liver disease is the leading cause of non‐AIDS related death; 66% deaths due to HCV.

• Effects of HIV on HCV infection:

– risk severe liver/cirrhosis (RR 2.07‐2.92), decompensated liver disease (RR 6 14) and HCCdecompensated liver disease (RR 6.14), and HCC

– cirrhosis/fibrosis CD4 < 350 c/mm3 (RR 1.72 ART)

– Associated with 2 fold risk for HCV death

– Potential risk of hepatotoxicity with ART

• Effects of HCV on HIV infection are less clear

JAIDS 2008;47:221; Clin Infect Dis 2008;47:1468; Ann Intern Med 2012;308:370AIDS 2008;22:1979; J Viral Hepat 2010;17:400; EuroSIDA, 13th EACS 2011, abst PS7/3

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Fibrosis Stage Predicts Clinical Outcomes in Those with HIV/HCV

RRAll

RRLiver

Limketkai BN. JAMA 2012.

F4 3.6 16.8

CD4>350

0.21 0.52

OnART

0.27 0.34

638 co-infected subjects followed for a mean of 5.8 years

Slide 7 of 66

HCV cure is associated with survival in HIV/HCV coinfected patients

JAMA. July 25, 2012,308(4):370-378

Slide 8 of 66

Current Status of HCV Treatment in HIV/HCV Co‐Infection

• Direct acting HCV PI (telaprevir and boceprevir) not FDA approved but recommended by DHHS HIV and AASLD

• Only PEG‐IFN alfa 2a FDA approved for HIV/HCV+

– Either preparation effective

• Use WT based ribavirin for ALL HCV GT

– 1000 mg (<75kg)

– 1200 mg (>75kg)

• Treatment duration 48 weeks for all genotypes

• Co‐infection affects ARVs, ADRs, HCV tx duration, SVR

AIDS 2007;12:1073; DHHS ARV guidelines http:www.aidsinfo.nih.gov; HRSA guidelines for HIV/HCV co-infection http://hab.hrsa.gov/; Rallon NI et al AIDS 2011 May 15;25(8):1025-33.

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HCV PI Treatment Concerns During Management of HIV/HCV Co‐infected Patients

• Limited data in co‐infected patients:

– Interim TVR and BOC data presented to date

– Ongoing outcome and drug interaction studies

O l i t i iti f ARV /HCV DAA• Overlapping toxicities of ARVs/HCV DAA

• Drug‐drug interactions b/t ARVs/HCV DAA

• adherence: complex drug regimen, high pill burden, dietary requirements, longer treatment duration

• Potential for drug resistance

Slide 10 of 66

Case Study

• RC is a 58 yr old AA male co‐infected with HIV/HCV on tenofovir/emtricitabine/efavirenz

• PMH: HCV1a, depression, COPD, dyslipidemia, HIV+ d/t hemophilia, HTN, BPH, CKD Stage II

• Habits: + MJ: denies tobacco, EtOH, illicit drug use

All i NKA• Allergies: NKA

• PE: nonictericBP 125/70 P 70 Wt 158 lbs BDI 5/63COR: S1, S2, no extra heart soundslungs: clear A & Pno hepatomegaly/splenomegalyno peripheral edema

Slide 11 of 66

Laboratory Laboratory findings:findings:

•• HCV RNA HCV RNA 2 mu 2 mu IU/mLIU/mL•• AST/ALT 158/161AST/ALT 158/161•• TbilTbil 1.21.2•• Albumin 4.0Albumin 4.0

•• WBC 5.0, ANC 5.0WBC 5.0, ANC 5.0•• HgbHgb/HCT=15/45gm/HCT=15/45gm•• MCV 98 MCV 98 •• Platelet 350KPlatelet 350K

•• INR 1.2INR 1.2•• Liver U/S: no discrete Liver U/S: no discrete lesions, +corkscrewing lesions, +corkscrewing c/w cirrhosisc/w cirrhosis

•• HepHep A and B immuneA and B immune

•• BUN/BUN/SCrSCr 20/20/ScrScr 1.81.8•• CrCLCrCL: 50cc/min: 50cc/min•• CD4 390 cells/mm3CD4 390 cells/mm3•• HIV RNA 100K c/mlHIV RNA 100K c/ml•• HIV GT: no mutationsHIV GT: no mutations

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What would you treat first, HIV or HCV?

1.HIV

2.HCV

3.Does not matter

4.Don’t know

Slide 13 of 66

HIV or HCV Treatment First?

• Timing of the initiation of HCV and ART

–ART first to CD4 count (CD4 with HCV tx) and achieve undetectable HIV VL

–ART X 6‐12 mo if CD4 <200 cells/mm3:

– SVR if CD4 > 350

– HIV RNA by ART may also HCV RNA and SVR

Slide 14 of 66

What would you tell RC about the SVR reported with a HCV DAA/PEGIFN/RBV

regimen for a patient such as him

1. 35‐45%

2 46 55%2. 46‐55%

3. 56‐64%

4. 65‐80%

5. 81‐90%

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Slide 15 of 66

Efficacy of PegIFN + RBV in HCV/HIV‐Coinfected Patients

44-49.6

(%)

All patients

GT1 HIV/HCV co-infected patients

60

100

80

1.Torriani F, et al. N Engl J Med. 2004;351:438-450. (Apricot) 2. Chung R, et al. N Engl J Med. 2004;351:451-459.(ACTG) 3. Carrat F, et al. JAMA. 2004;292:2839-2848. (RIBAVIC) 4. Laguno M, et al.AIDS. 2004;18:F27-F36 (BARCELONA). Nunez M et al. AIDS Hum Res Retroviruses 2007;23:972-(PRESCO)

PegIFN alfa-2a +RBV 800[1]

PegIFN alfa-2a +RBV 600-1000[2]

PegIFN alfa-2b + RBV 800[3]

Peg IFN alfa-2b +Wt based RBV 800-1200[4-5]

40

29 27

14

27

17

38-35SV

R

0

20

40

Slide 16 of 66

Telaprevir/PR for Treatment Naïve HCV GT 1 HIV negative and positive patients (SVR12)

75 74

44 45

60

80

0

20

40

HIV negative HIV positive

HCV PI + PR

PR48

.Sulkowski et al JID 2013;207 (S1):S26; Jacobson et al. New Eng J Med 2011

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Boceprevir/PR for Treatment Naïve HCV GT1 HIV negative and positive patients (SVR 12)

6662

60

80

38

29

0

20

40

HIV negative HIV positive

HCV PI + PR

PR48

.Sulkowski et al JID 2013;207 (S1):S26; Poordad et al. New Eng J Med 2011

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On treatment responses to TVR based HCV treatment similar in HIV/HCV co‐infected and HCV mono‐infected

• N=33 co‐infected and 117 mono‐infected

• Median CD4 489, 81% (25/310 HIV VL<LLQ/D)

• Undetectable HCV VL (co‐infected vs. mono‐infx)

– Wk 4 42.4% vs. 43.6% (p=1.00)

– Wk 12 72.7% vs 65.8% (p=0.532)

– Wk 24 72.7% vs 58.1% (p=0.16)

– EOT 63.6% vs 51.2% (p=0.24)

Martel-Laferriere et al. CROI 2013, abst 679

Slide 19 of 66

ANRS: TVR/IFN/RBV in HIV/HCV Co‐infection with Prior PR Failures (n=69)

%

80%

100%

Overall

Fibrosis 3‐ 4

Null Responders with Cirrhosis Excluded

Cotte, et al. CROI 2013, Abstract 36;

0%

20%

40%

60%

EVR16

prior null

partial

Relapse

Breakthrough

TDF/FTC +ATV/r 49%EFV 19%RAL 17%

Slide 20 of 66

ANRS: BOC/IFN/RBV in HIV/HCV Co‐infection with Prior PR Failures (n=64)

• Null responders with cirrhosis excluded• PR failures: relapse 31.3%; breakthrough 7.8%; partial response 28.1%, null response 32.8%

• TDF or ABC + FTC/3TC + ATV/r or RAL

Poizot-Martin, et al. CROI 2013, Abst 37

0

20

40

60

80

100

EVR 16 (%)

6373

38

53

70

All

F4 (N=11)

Prior null resp (N=21)

ATV/r

RAL

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Which HCV DAA is Associated with Higher SVR for HIV/HCV Co‐infected Patients?

1. Telaprevir

2. Boceprevir

3. Both are reported to be equivalent

4. No head to head comparison data to determine this

Slide 22 of 66

Telaprevir Outperformed Boceprevir in Retrospective Analysis

• No head‐to‐head trials of TVR vs BOC

• Retrospective analysis of all treated patients at 3 clinics, n = 106

TVR i t d ith hi h RVR BOC• TVR associated with higher RVR vs. BOC

– Irrespective of HIV status

• Reduced BOC response particularly in patients with prior IFN experience and GT1a

Benito, et al Abstract 676, CROI 2013

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Triple Combination TVR HCV Therapy Exhibits Higher Early Antiviral Potency than

with BOC Regardless HIV Status

• N=274 (68 BOC, 206 TVR) international sites– 29% vs 23% IL28B CC

– 95% advanced liver cirrhosis vs 66% (p< 0.001)

– HIV co‐infection (12 vs 18%)

• Results: RVR 84% TVR vs 60% BOC– TVR strongest predictor RVR (OR 5.3) p < 0.0001

– Baseline HCV RNA 0.44 p=0.03

– GT 1b OR 2.3 (p=0.05)

– No effect from HIV infection

Benito JM et al CROI 2013, Abst 676

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In our HIV+ pt receiving efavirenz/TDF/FTC, which telaprevir

dose would you recommend?

1. 750 mg q 8hr

2. 750 mg q 12hr

3. 1125 mg q 12hr

4. 1125 mg q 8hr

5. 1500 mg q 8hr

Slide 25 of 66

Telaprevir and EFV

1000

2000

3000

4000

TVR 750 mg q8h (n=20, reference)

TVR 1500 mg q12h + E/T (n=16)TVR 1125 mg q8h

+ E/T (n=15)

TV

R c

once

ntra

tion

(ng/

mL)

TVR doseEffect of EFV/TDF on TVR

Cmin Cmax AUC8h

750 mg q8h 0.53 0.80

1125 mg q8h 0.75 (0.66–0.86) 0.86 (0.76–0.97) 0.82 (0.73–0.92)

1500 mg q12h 0.52 (0.42–0.64) 0.97 (0.88–1.06) 0.80 (0.73–0.88)*

Van Heeswijk R. ICAAC 2008. Van Heeswijk R. CROI 2011.

0

0 2 4 6 8 10 12

+ E/T (n=15)

Time (hours)

*Average steady state plasma concentration (Cssaverage)

Slide 26 of 66

Effect of Nonnucleosides on Telaprevir (TVR) Pharmacokinetics

% Change in TVR PK TVR Cmin

TVR Cmax

TVR AUC*

ff f

• TVR to 1125 mg q 8hr minimized efavirenz intx• No significant changes in TVR PK with ETR or RPV

CROI 2011, Abst 119; CROI 2011 Abst 629;

Effect of ART on Telaprevir 750 mg tid exposures

EFV with 1125 mg q 8hr TVR ‐25 ‐14 ‐18

EFV 600 mg daily ‐47 ‐9 ‐26

ETR 200 mg bid ‐25 ‐10 ‐16

RPV 25 mg daily ‐13 ‐5 ‐8

Kakuda TN et al Abstr O-18; Barcelona 2012

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Slide 27 of 66

Effect of Telaprevir (TVR) on NNRTI Levels

% Change in NNRTI PK Parameter

NNRTI Cmin

NNRTI Cmax

NNRTI AUC*

Eff t f T l i 750 8h

• No significant reduction in ETR levels • RPV levels (risk QTc prolongation?)

Van Heeswijk R et al, CROI 2011, Abst 119; Garg V et al, CROI 2011 Abst 629;

Effect of Telaprevir 750 mg q8hr on NNRTI exposuresEFV ‐2 ‐16 ‐7

EFV with 1125 mg Q 8hr TVR ‐10 ‐24 ‐18

ETR 200 mg bid ‐3 ‐7 ‐6

RPV 25 mg daily +93 +49 +78

Kakuda TN et al Abstract O-18; Barcelona, Spain 2012

Slide 28 of 66Telaprevir (TVR) Administration (TVR) and Missed Dosages

• TVR: 375 mg tablets: total 6 tabs/day

– 750 mg Q 8 hr (2 tabs/dose q 8hr)

– 1125 mg (3 tabs/dose) bid

• (OPTIMIZE): comparable SVR12 73% (q 8r) vs 74% (q 12 hr)

– 1125 mg q 8hr with efavirenz

– Within 20‐30 minutes of 20 gm fat meal

– What to do about missed doses

• If miss within 4 hr of missed dose, take ASAP w/ food.

• If > 4 hrs, do not take missed dose, resume dosing

Slide 29 of 66

OPTIMIZE: BID Dosing Noninferior to TID Dosing of TVR in Tx‐Naive GT1

Patients

73 7478 81

59 58

TVR q8hr + pegIFN/RBVTVR BID + pegIFN/RBV

2 (

%)

100

80

60

• Adverse events similar between treatment arms

Buti M, et al. AASLD 2012. Abstract LB-8.

270/371

274/369

209/268

213/264

61/103

61/105

n/N =

Bridging Fibrosisor Cirrhosis

No, Minimal, orPortal Fibrosis

Overall

SV

R1

2

40

20

0

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In our HIV+ pt receiving efavirenz/TDF/FTC, what happens if boceprevir is used instead?

1. Better choice since no interaction

2. EFV toxicity d/t EFV levels

3. BOC failure d/t BOC levels

4. Risk of both EFV and BOC failure

5. Unclear, since data not available

Slide 31 of 66Boceprevir (BOC) and NNRTIs• Avoid with EFV; Cmin BOC

• Can co‐administer with ETR and RPV.

• Monitor for RPV induced QT

% Change in BOC PK Cmax AUC Cmin

Efavirenz ‐8 ‐19 ‐44

Rilpivirine ‐2 ‐6 +4

Hammond KP et al. J Acquir Immumn Defic Syndro 2013; 62:67-73; Kasserra C, et al. CROI 2011. Abstr 118.

p

Etravirine +10 +10 ‐12

Effect of boceprevir on NNRTI exposure

Tenofovir +32 +5 No data

Efavirenz +11 +20 No data

Etravirine 200 mg bid ‐24 ‐23 ‐29

Rilpivirine 25 mg daily +15 +39 +51

Slide 32 of 66

Pharmacokinetic Interaction Between Boceprevir and Etravirine in HIV/HCV SeronegativeVolunteers.Hammond, Kyle;

lf lWolfe, Pamela; Burton, James; Predhomme, Julie; RN, MS; Ellis, Christine; Ray, Michelle; Bushman, Lane; Kiser, JenniferJAIDS 62(1):67‐73, January 1, 2013.

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Slide 33 of 66

Summary of NNRTI and TVR/BOC Interactions

• Telaprevir

–TVR to 1125mg Q8 with efavirenz

– TVR 750 mg q 8hr with etravirine and rilpivirine

• Boceprevirp

–Avoid co‐administration with efavirenz

– Standard doses with etravirine and rilpivirine

–Potential for virologic failure with etravirine if used with LPV/r, SQV/r, DRV/r

–Risk RPV QT if used with other QT agentsVan Heeswijk R. ICAAC 2008. Van Heeswijk R. CROI 2011. Kasserra C. CROI 2011.

Slide 34 of 66

Case Presentation

• RC develops a severe rash to tenofovir/emtricitabine/efavirenz and is changed to abacavir/lamivudine + darunavir 800 mg/ritonavir 100 mg once daily800 mg/ritonavir 100 mg once daily

• His HCV therapy was held while the rash resolved from the tenofovir/emtricitabine/efavirenz.

• He is now ready to start HCV therapy

Slide 35 of 66

What would you recommend for his abacavir/lamivudine component

before starting HCV PI based tx?

1. Change to ZDV/3TC

2. Change to NRTI free regimen

3. Change to TDF/FTC

4. No changes necessary

B. J. Dong, PharmD


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Slide 36 of 66

Abacavir Reducing Efficacy of HCV Treatment

• Inhibitory competition b/t ABC and RBV (guanosine analogues)

Retrospective Abacavir Non‐ABC P‐values

SVR rates SVR rates

n=256 29% 45% 0.02

• Conclusions:

– Retrospective analysis of small data sets

– ABC did not SVR w/ wt‐based RBV

– ABC appropriate to use if benefits > risks

Antivir Ther. 2008;13(3):429-37, J Antimicrob Chemother 2008;62:1365.;

RBV >13.2 mg/kg/day 31% 38% 0.4

RBV<13.2 mg/kg/day 20% 52% 0.03

n=244 46.2% 46.7% <0.05

Slide 37 of 66

Adriana A et al CROI 2013, abstr 538

Conclusions:• ABC did not alter RBV or

RBV=TP concentrations.• ABC can be co-

administered safely to HIV/HCV co-infected pts

Slide 38 of 66

What would you recommend for the ritonavir boosted darunavir component

before starting a telaprevir based treatment

1. Increase DRV/r to 600/100 mg BID.

2 Ch DRV/ t RAL 800 d il2. Change DRV/r to RAL 800 mg daily.

3. Change DRV/r to ATV/r

4. Stop all ART during the HCV PI treatment.

5. Continue his once daily DRV/r.

B. J. Dong, PharmD


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Slide 39 of 66Effects of HIV Protease Inhibitors on Telaprevir (TVR) Pharmacokinetics

%Change in TVR PK Parameter TVR Cmin

TVR Cmax

TVR AUC*

• Atazanavir/r had minimal effect on TVR PK• Avoid co-administration w/ other HIV PI: TVR levels

CROI 2011, Abst 119; CROI 2011 Abst 629;

ATV/RTV ‐15 ‐21 ‐20

DRV/RTV ‐32 ‐36 ‐35

FPV/RTV ‐30 ‐33 ‐32

LPV/RTV ‐52 ‐53 ‐54

RTV 100 mg bid ‐32 ‐15 ‐24

Kakuda TN et al Abstract O-18; Barcelona 2012

Slide 40 of 66

Mean TVR PK Profiles

TVR alone

n=14 n=17 n=16 n=20

3000

on

(n

g/m

L)

LPV ATV DRV fAPV

0 2 4 6 8 0 2 4 6 8

van Heeswijk R. CROI 2011.AUC = area under the curve

AUC 54% AUC 20% AUC 32%AUC 35%

TVR + ARV

n=12 n=14 n=11 n=18

Time (hours)

0

1000

2000

TV

R c

on

cen

trat

i

0 2 4 6 8 0 2 4 6 8

42% 15%

32% 30%

Slide 41 of 66

Effect of Telaprevir (TVR) on HIV PI

%Change in ARV PKParameters

ARV Cmin

ARV Cmax

ARV AUC*

•ATV/r w/ potential for bilirubin• DRV/r, FPV/r, LPV/r: avoid co-administration

Van Heeswijk R et al, CROI 2011, Abst 119; Garg V et al, CROI 2011 Abst 629;

ATV/RTV +85 ‐15 +17

DRV/RTV ‐42 ‐40 ‐40

FPV/RTV ‐56 ‐35 ‐47

LPV/RTV +14 ‐4 +6

Kakuda TN et al Abstract O-18; Barcelona, Spain 2012

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Slide 42 of 66

Impact of telaprevir on HIV PIsLPV/r ATV/r

AUC AUC 17%

n=19

n=11

n=12 n=7

4000

8000

12000

LP

V c

on

cen

tra

tio

n (

ng

/mL

)

AT

V c

on

cen

trat

ion

(n

g/m

L)

4000

3000

2000

1000

PI alonePI + TVR

PI alonePI + TVR

82%14%

van Heeswijk R. CROI 2011.

0 2 4 6 8 10 12 0 2 4 6 8 10 12

DRV/r fAPV/r

AUC 47%AUC 40%

n=20n=16

n=11n=18

Time (hours)

00 2 4 6 8 10 12 0 6 12 18 24

Time (hours)

0

Time (hours)

DR

V c

on

cen

tra

tio

n (

ng

/mL

)

6000

4000

2000

0

AP

V c

on

cen

tra

tio

n (

ng

/mL

)

Time (hours)

4000

3000

2000

1000

0

PI alonePI + TVR

PI alonePI + TVR

42% 56%

Slide 43 of 66

Effects of Raltegravir on Telaprevir PK

RAL AUC 31% and Cmin 78%

van Heeswijk et al., ICAAC, Chicago, Sept. 17-20, 2011

Slide 44 of 66Drug‐Drug Interactions: Boceprevir (BOC) and HIV PIs

• HIV protease inhibitors: avoid co‐administration% Change in BOC PK BOC Cmax BOC AUC BOC Cmin

Atazanavir/r ‐7 ‐5 ‐18

Darunavir/r ‐25 ‐32 ‐35

L i i / 50 45 57

Hammond KP et al. J Acquir Immun Defic Syndro 2013; 62:67-73; Hulskotte EGJ et al CID 2013;56:718-26

Lopinavir/r ‐50 ‐45 ‐57

% Change in ARV PK ARV Cmax ARV AUC ARV Cmin

Atazanavir/ritonavir ‐36 ‐44 ‐59

RTV100 mg daily ‐27 ‐36 ‐45

Darunavir/ritonavir ‐36 ‐44 ‐59

RTV 100 mg BID ‐13 ‐27 ‐45

Lopinavir/ritonavir ‐30 ‐34 ‐43

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Slide 45 of 66

ATV 59%

Hulskotte EGJ et al. PK Interactions between HCV PI Boceprevir and Ritonavir boosted ATV/r, DRV/r, and LPV/r. Clin Infect Dis. (2013) 56(5): 718-726 first published online November 15, 2012 doi:10.1093/cid/cis968

LPV 43%

DRV 59%

Slide 46 of 66

Lack of a Clinically Significant Interaction Between BOC and RAL

de Kanter, CTMM et al. CID 2013:56 (15 January); :300–6

Slide 47 of 66

Administering Boceprevir (BOC) in HIV/ HCV Co‐Infection

• Avoid with boosted HIV protease inhibitors

• Avoid with efavirenz

• Raltegravir, etravirine, rilpivirine okay based on PK

• Dosage: 800 mg (4 tabs/dose) Q 8 hr with food

– 200 mg tablets for total of 12 tablets/day

• What to do about missed doses?

– If miss < 2hr before next dose, skip missed dose

– If >2hr before next dose, take missed dose

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Slide 48 of 66

Side Effects to HCV Direct Acting Agents: Telaprevir and Boceprevir in HIV/HCV Co‐infected Persons/ o ec ed e so s

Slide 49 of 66

Which might be most problematic in our patient taking abacavir/lamivudine +

atazanavir/r plus telaprevir/PEGIFN/ribavirin?

1. Dysgeusia

2 A t l t2. Anorectal symptoms

3. Renal failure

4. Neutropenia

5. Hypersensitivity reaction

Slide 50 of 66

TVR based HCV treatment ADRs in HIV/HCV co‐infected and HCV

mono‐infected Patients

• ADR: co‐infected mono‐infected

– Stopped 18.2% 13.7% (p=0.58)

– Severe anemia 33.3% 37.6% (p=0.69)

– Rash 15.2% 34.1% (p=0.05)

– Rectal sx 12.1% 43.6% (p=0.001)

Martel-Laferriere V, Brinkley S, Bichoupan K, Posner S, Stivalas A, Perumalswami P, Schiano T, Sulkowski M, Dieterich D, Branch A . CROI 2013, abst 679

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Slide 51 of 66

In our patient taking TVR, PEG‐IFN/RBV, what would you do for an itchy maculo‐

papular rash involving both arms

1. Start oral steroids

2. Start topical steroids

3. Stop telaprevir only

4. Stop PEG and RBV

5. Stop PEG/RBV/TVR

Slide 52 of 66

Telaprevir and Cutaneous ReactionsCutaneous

Reactions

Phase 2 Studies

(PROVE‐1,2,3)

Phase 3 Studies

(Illuminate/Advance/Realize)

Rash and/or pruritus 47‐59% 51‐60% (56%)

Grade 3 skin (severe) 4‐7% 4‐5%

Onset (days) 7‐28 16‐20

Discontinuation Rate 5‐7% 6‐6.5%

• Mechanism unclear

• Antihistamines, topical steroids for symptomatic relief

• Systemic steroids not recommended

• Close monitoring for rash progression/systemic reactions → D/C

• If no improvement within 7 days of stopping TVR, stop PEG-IFN/RBV

Dermatology 2010; 221: 303-5; NEJM 2010;362:1292; Gastro 2010;139:1412

Slide 53 of 66

Telaprevir‐Associated Rash

FDA Antiviral Drugs Advisory Committee Meeting, May 2011.

STOPTelaprevir

MonitorClosely

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Slide 54 of 66

Pre‐Treatment Considerations for Telaprevir‐Associated Rash and Rectal

Symptoms • Good skin hygiene

– Emollient creams and lipid‐rich lotions

– Sunscreen avoid prolonged sun exposureSunscreen, avoid prolonged sun exposure

– Avoid hot showers and drying soaps (eg. Ivory)

• Anal itching

– Enough fat with TVR

– Sitz bath

– Tucks1. Telaprevir [package insert]. October 2012. 2. Cacoub P, et al. J Heptol. 2012;56:455-463.

Slide 55 of 66

Case Discussion

• A 32‐year‐old Ukranian female with genotype 1b HCV infection and cirrhosis (corkscrew) on ultrasounds comes for F/U after starting peginterferon alfa‐2a and ribavirin 1000 mg/day with boceprevir 800ribavirin 1000 mg/day, with boceprevir 800 mg 3 times daily after a 4‐week lead‐in.

• After one week of boceprevir, ANC is 670 cells/mm3 with no signs of infection. Platelets are down to 118K from her baseline of 250K.

Slide 56 of 66

What would you do at this time?

1. Start eltrombopag to increase her platelet count

2. Start filgrastim to reduce risk of infection

3 Start eltrombopag and filgrastim immediately3. Start eltrombopag and filgrastim immediately

4. Start prophylactic antibiotics to prevent infection

5. Reduce PEGIFN dose to 135 mcg/week and start filgrastim

6. Do nothing

B. J. Dong, PharmD


19

Slide 57 of 66

Eltrombopag

• FDA approved in Nov 2012 for thrombocytopenia in HCV to allow the initiation and maintenance of IFN

• Risks: hepatotoxicity, hepatic decompensation, thrombotic/ thromboembolic events

• Should not be used to normalize platelet counts; not thoroughly evaluated for safety or efficacy with protease inhibitor–based HCV therapy

• Consider if plt <20‐30K

• Must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements

Slide 58 of 66

ENABLE 1: Eltrombopag as Adjunct Therapy for Thrombocytopenia in HCV

• Regimen: pegIFN/RBV

• In patients with baseline platelets < 75,000/mm3, 95% were eligible to start antiviral therapy with pegIFN following open‐label eltrombopag

• Eltrombopag: significantly improved response rates to HCV p g g y p ptherapy

Afdhal N, et al. AASLD 2011. Abstract LB-3.

100

80

60

40

20

0

Pat

ien

ts (

%)

RVR

17

Virologic Response (ITT)PlaceboEltrombopag

EVR cEVR ETR SVR

16

50

66

26

4237

48

14

23

P = .0064

P = .008P < .0001

P < .0001

P = .7495

Slide 59 of 66

Crystal Ball into

What Does the Future Hold?

B. J. Dong, PharmD


20

Slide 60 of 66

SVR12 in HIV/HCV Coinfection Treated with Simeprevir/IFN/RBV

40%

60%

80%

100%

77% 75% 80%

All

Naïve

Relapse10/13

RGT patients ONLYDoes not include cirrhotics/nulls(64% of nulls still

0%

20%

SVR 12

Relapse

Dieterich, et al. CROI 2013, Abstr154LB

(Excludes cirrhotics)

10/13 6/84/5

5% hyperbilirubinemia27% neutropenia21% anemia

responding at wk 24)

Slide 61 of 66

Faldaprevir/IFN/RBV in HIV/HCV Coinfection: EVR

80%

100%

60%

74%

82%

91% 78% naïve22% relapseF4 4%96% on ART

Dieterich, et al. CROI 2013; Abstr 40LB; Sabo Abst 35

0%

20%

40%

60%

Naïve (n=239) Relapser (n=69)

WEEK 4

WEEK 12

Slide 62 of 66

Faldaprevir Drug Interactions

• DRv/r 800/100 mg

– FDV AUC 129% and Cmin 283%

– No clinically relevant interaction on DRV/r levels

– FDV 120 mg daily with DRV/r

Ef i• Efavirenz


– FDV 240 mg bid being with EFV

– No significant effects on EFV

• TDF


Sabo Abst 35 CROI 2013

B. J. Dong, PharmD


21

Slide 63 of 66

Conclusions

• Treatments for HIV/HCV patients are evolving

• HCV DAA data suggest SVR in HIV/HCV similar to mono‐infected

• Interferon free agents under investigation but• Interferon free agents under investigation but several years before approval in HIV/HCV co‐infected

• Be mindful of HCV/HIV drug‐drug interactions and overlapping toxicities

Slide 66 of 66

Acknowledgements

Special thanks for slides:

Jennifer Kiser, PharmD, U ColoradoCharles Flexner, MD, Johns HopkinsChip Schooley, MD, Univ San Diego

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