1

Dr Andy WilliamsBarts and The London NHS Trust

18-20 April 2012, The International Convention Centre, Birmingham

18th Annual Conference of the

British HIV Association (BHIVA)

A direct hit

Difficult Pharmacology Case Presentation

BHIVA Conference April 2012

Dr Andy Williams

Barts and the London NHS Trust

2

Anne

� 54 year old White British ♀

� Cleaner, dog breeder, avid jogger

� HIV positive (1984)

� Hepatitis C positive (1993) G1

� MoA: Previous IDU (last use ’85)

� Alcohol : “hardly ever”

� Arrived East London in 1998 1998

CD4 467

Viral Load 42000

Newham 2000

� LRTI

� Started CBV/EFV

� “Terrible” CNS toxicity

� Then…..

ALT 110AST 108Alb 27INR 1.0

HCV IgG +ve

HBV cAb +ve

sAg –ve

eAg –ve

eAb +ve

Other liver screen normal

HBV DNA undetectable

HCV RNA not routine in 2000

CD4 180

VL 223,000

3

Liver biopsy result 2000

�� Metavir: Stage:1/4

� HAI: grade:4/18

� No other pathologies noted, consistent with

viral hepatitis

0

100

200

300

400

500

600

700

Jan-

00

Feb-0

1

Jan-

02

Jan-

03

Jan-

04

Feb-0

5

Jul-0

6

Aug-0

7

Jun-

08

Jul-0

9

0

50000

100000

150000

200000

250000

CD4

VL•Switched to CBV/Nelfinavir•LFTs still abnormal•Switched again to AZT/3TC/ABC•Continued 2000-2009•No IDU•Uses methadone – ‘buying from friend’-’hates the DDU’•Husband unwell•Not ready to discuss HCV Rx

4

Her views on Hep C Rx explored

� ‘Toxic’

� Low chance of clearance

� Primary carer for partner – severe

cardiopulmonary disease awaiting heart

transplant

2009

CD4 512

Viral Load 0

QUESTION 1

The median time from HCV infection to cirrhosis

is 32yrs for HCV mono infection. How long is it

for HCV-HIV co-infection?

1. 3 years

2. 13 years

3. 23 years

4. 33 years

5. 43 years

5

It’s been 10 years…

�� Partner died

� Time to re-evaluate

Con Meds:

� Milk thistle

� Garlic

� Chinese herbal meds ?which

� Decision to biopsy liver again Dec’10

Liver biopsy result 2010

� Metavir 4/4; 5/18

� No decompensation

� Signs of CLD – spider naevi

� Now considering Hep C treatment

� Seen by psych: started citalopram

� Continues on AZT/3TC/ABC

6

� Referred to Tertiary centre for

consideration of Hep C Rx

� Other concomitant meds reviewed

� Now buying buprenorphine (subutex)

instead of methadone

� Referred to DDU by nurse to discuss

opioid substitution therapy options

DI concern -picked up by DDU

�� Subutex can cause AST and ALT rises1

� DDU suggested ?difficult to monitor

advanced liver patients on subutex

� DDU - switched back to Methadone 30mls

od

� Weaning regime

� 1. PETRY et al (2000) American Journal on Addictions, 9, 265 -269

7

Hepatitis C Treatment

PIFNRBV

BI 1335Herbals

PIFNRBVBOC

None

PIFNRBV

DAATMC435

PIFNRBVTPV

8

Question 2

What treatment would you give for

her Hepatitis C?

1. Nothing

2. PIFN/RBV

3. PIFN/RBV/BOC

4. PIFN/RBV/TPV

5. PIFN/RBV + other DAA

6. Absolutely no idea

Efficacy

9

Summary of Sustained Virologic Response in

HIV/HCV-Coinfected PatientsSustained Virologic Response at Week 72 (%)

Overall Genotype 1 Genotype 2/3

AACTG 50711

IFN/RBV (n=67) 12 6 33

Peg-IFN/RBV (n=66) 27 14 73

APRICOT2

IFN/RBV (n=285) 12 7 20

Peg-IFN/RBV (n=289) 40 29 62

Peg-IFN (n=286) 20 14 36

RIBAVIC3

IFN/RBV (n=207) 20 6 43

Peg-IFN/RBV (n=205) 27 17 44

AACTG 5071 ribavirin dose: 600, 800, and 1000 mg/day for weeks 1-2, 4-8, and 8-72, respectively.Ribavirin dose was fixed at 800 mg/day for APRICOT and RIBAVIC.

1Chung R, et al. N Engl J Med. 2004;351:451-459.2Torriani FJ, et al. N Engl J Med. 2004;351:438-450.3Carrat R, et al. JAMA. 2004;292:2839-2848.

Triple therapy works in Advanced fibrosisADVANCE (telaprevir): SVR rates by fibrosis stage

SV

R (

%)

PR48

134/288n/N=

ADVANCE1

1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A;

T12PR

226/290

PR48

24/73

T12PR

45/73

No, minimal or portal fibrosis

Bridging fibrosisor cirrhosis

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SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone

BOC RGT

233/368

BOC RGT

233/368

BOC44/PR48

242/366

BOC44/PR48

242/366

PR48

137/363

PR48

137/363

Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402AFor non-Black patients, p<0.0001 for both boceprevir arms versus PR48; for Black patients, p=0.044 and p=0.004 for BOC RGT and BOC44/PR48, respectively, versus PR48

Options

� PIFN/RBV/BOC

� PIFN/RBV/TPV

� TMC 435

� BI 1335

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• Bocepravir and Telaprevir

(1st gen A/E ++)

BI 1335 TMC 435

• Drug screen• Methadone contraindicated for BI

• Bocepravir and Telaprevir

(1st gen A/E ++)

BI 1335 TMC 435

• Drug screen• Methadone contraindicated for BI

12

• Switched to Truvada/Raltegravir

OPERA-1 (Cohorts 1 and 2): response to treatment at Day 28

• 6/9 patients in the 25 mg arm, 9/9 patients in the 75 mg arm and 10/10 patientsin the 200 mg arm of Panel B had HCV RNA <10 IU/mL at Week 12 (4-weeks TMC435 + SoC, 8-weeks SoC only)

Patients(%)

Placebo 25 mg 75 mg 200 mg

Panel A

Placebo 25 mg 75 mg 200 mg

Panel B

TMC435 QDTMC435 QD

n=8 n=9 n=9 n=8 n=9 n=9 n=9 n=10

_

Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoCPanel B: 4 weeks of TMC435 combined with SoC

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Disallowed Concomitant Medications with TMC 435

Any approved or investigational ant-HCV drug other than study meds

Interleukins, cyclosporin

Any herbal products for HCV

Carbamazepine, phenytoin, phenobarbital

Rifabutin, Rifampicin

Dexamethasone

St John’s Wort

Ketoconazole, itraconazole

Clarithromycin, erythromycin

Amiodarone, flecainide, systemic lidocaine, quinidine

Cispride

Amitiptyline, theophylline

Simvastatin, rosuvastatin, atorvastatin, pravastatin, fluvastatin

� Screened and baselined for TMC435-C212

� Fibroscan: F4 Fibrosis METAVIR score (22.3KPA)

� Wt = 58 Kg

� Stopped herbal products

� Started Rx 3/1/12: TMC 435 150mg od X3/12

� PIFN 180mcg weekly X 1 year, RBV 1000mg per day (split dose) x 1 yr

2012 pre DAA

CD4 543 HCV 2,000,000

Viral Load <40 Hb 13.8 Neuts 1.99 Plt 115

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Treatment schedule

DAA

Day 0 12/52 48/52

PIFN/RBV

24 weeks overall if all 3 criteria apply: Treatment-naïve or RelapserHCV RNA < 25 IU/mL (detectable or undetectable) Week 4HCV RNA < 25 IU/mL (undetectable) Week 12

48 weeks overall if any of 3 criteria apply: Previous Nonresponder (partial, null)Cirrhosis (Metavir F4, …)Not meeting both virologic response criteria

Day 0 3/7 1/52

January 2012

DAA/PIFN/RBV

Directly pre HCV treatment

CD4 457 HCV 2,000,000

Viral Load <40 Hb 13.8 Neut 1.99 Plt 115

HCV RNA 423 HCV RNA 227

Hb 12.3

Neut 0.75

Plts 83

HCV RNA 67

Hb 10.6

Neut 0.74

Plts 87

2/52

HCV RNA <25

Hb 9.8

Neut 0.68

Plts 81

4/52

Hb Neut Plts HCV RNA

Week 8 9.5 0.7 71 Not detd

Week 12 9.2 0.7 73 Not Detd

TMC 435

stopped 27/3/12

as per protocol

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Symptom review 27/3/12

� Tired� Bit weaker than before treatment� Mood up and down, “bit fed up”, “I’m ok” � Cleaning houses� Dog walking� Exercise bike – 4miles x4 per week

Challenges managing A/E’s within

limits of protocol

� No GCSF

� No Elthrombopag

� No EPO

� Allowed dose reductions. (But important to try to keep RBV full dose to 8/52)

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Learning Points

1. Timing is everything

2. 10 years has seen her progress fibrosis 1

through 4

3. New drugs are now available that may halt

the progression of her liver disease

4. Scrupulous attention to detail on lab

parameters and drugs needed

5. www.hep-druginteractions.org

Acknowledgements

� Dr Chloe Orkin – Consultant HIV

Physician, Royal London Hospital

� Mr Carl De Souza – Research Charge

Nurse, Royal London Hospital

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� Any questions?