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Slide 1
Pharmacological Challenges in Treating HIV-HCV Co-infected Patients
David Back University of Liverpool UK
David Back University of Liverpool
May 2013
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ARV Co-
med
Reduced Efficacy
Toxicity
This is the ‘simple example’! What about combination ARV and multiple co-meds?
Drug-Drug Interactions
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HIV Infection
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The Magnitude of the Problem
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Slide 5 Risk for ‘clinically significant’ interactions
Marzolini et al. AVT 2010;15:413 Evans-Jones et al. CID 2010;50:1419
Kigen et al. Plos One 2010 Patel Ann Pharmacother 2011;45
Miller et al Pharmacother 2007;27:1379 De Maat et al. Clin Pharmacokinet 2003;42:223
Shah et al. CROI 2007, Abstr 573. 2007
Study Year Setting N CSDI Screening Tool VL Effect
de Maat 2004 Netherlands (hospital)
115 26% Liverpool website N/A
Shah et al 2007 USA (Medicaid)
571 30% Liverpool website; Micromedex
No VL impact
Miller et al 2007 USA (hospital)
153 41% DHHS; PI; Micromedex
N/A
Kigen et al 2009 Kenya (hospital)
996 34% Liverpool website N/A
Marzolini et al
2009 Switzerland (SHCS)
1497 40% Liverpool website No VL impact
Evans-Jones et al
2009 UK (hospital)
159 27% Liverpool website N/A
Patel et al 2011 USA 190 34% Lex-interact N/A
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(N = 3674)
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The Mechanisms Involved
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1 2 3 4 5 6 7 8 9 10 11 12
Drug
Con
c.
Days
Interacting Drug
Why an increase in steady state of a drug?
Possible reasons for increased exposure? GI Tract Hepatic Renal
Back D Unpublished
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Increase in pH
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The breakdown of raltegravir 400 mg tablets at pH 1 to 8
Tablet breakdown rate increased at higher pH
0
0,5
1
1,5
2
2,5
3
1 2 3 4 5 6 7 8
Tabl
et d
isso
lutio
n ra
te
(% o
f tab
let m
in-1
)
pH
Moss D & Back DJ – Unpublished observation
Dissolution of Raltegravir at different pH
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Effect of lopinavir/r on digoxin exposure: transporter mediated
Absorption
Efflux
Digoxin AUC ↑1.8- fold
Wyen C et al Clin Pharm Ther; 2008; 84: 75-82
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Effect of Boosted PI on intestinal & hepatic CYP3A4
MDZ AUC ↑3-fold MDZ AUC ↑10-fold
I.V. Midazolam Oral Midazolam
Dumond JB et al., Clin Pharmacol Ther. 2010; 87: 735–742.
Hepatic Interaction Intestinal + Hepatic Interaction
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A major cause of drug-drug interaction:
inhibition of CYP3A4 enzyme
CYP 3A isozymes are involved in the metabolism
of majority of drugs
CYP 3A isozymes are the most abundant in the liver
Proportion of drugs that are substrates for major CYP enzymes
CYP 3A4
CYP 1A2 CYP 2A6
CYP 2B6 CYP 2C8
CYP 2C9 CYP 2C19
CYP 2D6
CYP 2E1
Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009
CYP: cytochrome P450 All percentages are approximate. For illustrative purposes, hepatic CYP enzymes present at <5% are all represented as 3.3%
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Kiser JJ et al., JAIDS 2008; 15: 570-578
Effect of lopinavir/r on rosuvastatin exposure: hepatic transporter mediated
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EACS Guidelines 2012
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Drug
Con
c.
Days 1 2 3 4 5 6 7 8 9 10 11 12
Interacting Drug
Key Mechanisms of Drug Interactions: Why a decrease in steady state of a drug
Reasons for decreased exposure? Gut Liver
Back D Unpublished
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Effect of Omeprazole on plasma levels of Rilpivirine
Van Heeswijk et al. 4th IAS Conference, Sydney, Australia, 22–25 July 2007, abstract TUPDB01
Co-administration of OMEPRAZOLE 20 mg reduced rilpivirine exposure by 40% Combination of rilpivirine (25 mg) with PPIs is contraindicated
Effect of H2-blockers can be circumvented with separate intake (12h before, or 4h after)
Crauwels et al. 9th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 9–13 November 2008.
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Enyzme Induction • Antimycobacterial drugs
– Rifampicin (CYP3A, 2C9/19, UGT), – Rifabutin (CYP3A) – Isoniazid (2E1)
• Anticonvulsant drugs – Carbamazepine, Phenytoin, Phenobarbital (CYP3A)
• Herbals – St John’s wort (CYP3A)
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Rifampicin Induction and Lopinavir/r
LPV/r 400/100 mg bid
LPV/r 400/100 mg bid + RMP
Dose adjustment LPV/r
800/200 mg BID
400/400 mg BID
-90%
La Porte CJ et al., AAC 2004; 48: 1553-1560.
Not Recommended
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“If Sustiva is coadministered with rifampin to
patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended.”
Food and Drug Administration - January 6, 2012
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CDC 2012 Update
http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf
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Slide 22
• ‘Efavirenz-based antiretroviral therapy and rifampin-containing TB treatment at standard doses is the preferred treatment for HIV-related tuberculosis in adults’. We consider that data are insufficient to support a definitive statement regarding the need to increase the dose in persons over 50 kg.
http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf
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Artemether Lumefantrine
J Antimicrob Chemother 2012; 67: 1217-1223
Beware – the unexpected!
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What Constitutes a Clinically Relevant Drug-Drug Interaction? 20%, 30%, 50%, 70% decrease in PK OR
0.5-fold, 2-fold, 3-fold increase in PK?
Can be confusing! Depends on the individual drug and the exposure –
response relationship
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Are we only concerned about interactions with oral drugs?
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Corticosteroid metabolism and formulations
Drug Oral Inhaled Topical Eye/ear drops
Injection Rectal
Budesonide CYP3A4
Dexamethasone CYP3A4
Fludrocortisone CYP3A4
Fluticasone CYP3A4
Hydrocortisone CYP3A4
Prednisolone CYP3A4
Beclomethasone Esterase to active met
Triamcinolone CYP3A4
Mometasone CYP3A4
Created from SmPCs for all included drugs. Available at: http://www.medicines.org.uk/emc/.
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HCV Infection
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The Magnitude of the Problem
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0 10 20 30 40
2003
2005
2007
2009
2011
Drug-drug interactions in Hepatitis C (No of publications)
2012 – 30 publications 2013 - ??
DDIs – an emerging ‘hot topic’ in Hepatitis C
Maasoumy B et al Clinical significance of drug-drug interactions in the era of direct acting antiviral agents against hepatitits C – a real
world experience. EASL 2013, Abs 856
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The Mechanisms Involved
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Small Intestines Liver
Adapted from Bailey DG, et al. Br J Clin Pharmacol. 1998:46:101–10
CYPs
Efflux
CYPs, UGTs
Telaprevir and Boceprevir interfere with the way the body handles other drugs
DRUG
DRUG
Efflux
Influx
Influx
Efflux
CYP3A4 important!
May be involvement of other enzymes
and transporters
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HCV med
Co-med
Reduced Efficacy
Toxicity
Whereas the major effect of DAAs is to increase concentrations of co-med they may also decrease AND co-meds can interact with DAA
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Clinical case: patient characteristics at time of treatment
BMI: body mass index; Hb: haemoglobin; HCV: hepatitis C virus; HDL: high-density lipoprotein
54-year-old male Smoker and no alcohol abuse Treatment naïve
Description
Genotype: HCV G1a Fibrosis stage: F3
HCV disease characteristics
BMI: 28 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) – Total
Chol: 1.70 g/L; HDL: 0.42 g/L Hypertension (taking propranolol) Suffering from mild depression (receiving behavioural therapy) Hb level: 14 g/dL
Other medical information
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DDIs: patient’s medications
Telaprevir
Atorvastatin
PR
Metformin
Propranolol
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Which medications are a concern with telaprevir?
ED: erectile dysfunction http://www.hep-druginteractions.org
Renal excretion – no interaction expected
Not anticipated to cause a problem when combined with DAAs
Metabolised by CYP2D6 (major) – no interaction expected
Metformin
Propranolol
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Treatment decision
Because of interactions Atorvastatin was temporarily stopped for
12 weeks after consultation with the cardiologist No changes were made to the
metformin and propranolol prescriptions
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Week 2–8 visits: results
Patient health Patient develops an upper
respiratory tract infection (deemed unrelated to treatment) He develops mild rash His depression worsens
(becomes moderate)
Telaprevir + PR
HCV RNA levels
0
2
4
6
0 4 8 12
HCV
RNA
(log 10
IU/m
L)
Weeks
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Management of the patient’s upper respiratory tract infection
Clarithromycin
CYP 3A inhibitor & substrate Concern about increase in
telaprevir exposure Also concern of increase in
CLA – this may warrant ECG monitoring due to the possible risk of QT prolongation
A 5-day course of azithromycin was chosen due its reduced likelihood of interactions
Azithromycin
Not a CYP 3A inhibitor or substrate Drug interactions unlikely
http://www.hep-druginteractions.org ECG: electrocardiogram
Choose carefully
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Management of mild rash: which corticosteroid?
• Not recommended with telaprevir and boceprevir • Prednisone and methylprednisolone are CYP3A substrates;
levels may significantly increase and lead to side effects
Systemic cortico-steroids
• OK to use concomitantly with HCV PIs • Although not expected to cause significant systemic
absorption – be watchful (lessons form HIV)
Topically applied steroids
http://www.hep-druginteractions.org; Cacoub P, et al. J Hepatol 2012;56:455–463
In this patient, a topically applied corticosteroid (betamethasone) was initiated
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Interaction is unlikely*
Venlafaxine
Paroxetine Fluoxetine
Antidepressants and telaprevir
Interaction is likely, caution is advised
Sertraline
Trazodone Mirtazapine
http://www.hep-druginteractions.org
Some Antidepressants are metabolized by CYP 3A4
Some Antidepressants metabolized primarily by non CYP 3A4
* Caution – note escitalopram
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0
2
4
6
0 12 24 36
HC
V R
NA
(log 1
0 IU
/mL)
Weeks
Treatment outcome: summary
Telaprevir + PR PR
SVR12
Rash disappeared; topical steroid stopped
Depression symptoms improved
Morphine and midazolam IV
Betamethasone Fluoxetine Restart statin
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Drug Interaction Resources
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Management of Hep Drug-Drug Interactions
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HCV med
HIVmed
Reduced Efficacy
Toxicity
In a co-infected patient we now need to manage the interactions between the HCV and HIV medication as well as other co-meds
Co- med
ATV/r DRV/r LPV/r Efavirenz Rilpivirine Raltegravir Maraviroc NRTIs
Telaprevir Boceprevir Ribavirin Drugs in pipeline