Drug Interactions in TB / HIV Co-infected...

Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, Boston USA

Drug Interactions in TB / HIV Co-infected Patients

Saye KhooHIV Pharmacology Group

University of Liverpool / Biomedical Research Centre in Microbial Diseases



HIV and TB ‐ prevalence



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• HIV‐TB drug interactions

• What we know and don’t know

• Inter‐individual differences in DDIs

• Management of DDIs in different healthcare settings


Potential to be affected Potential to affect other drugs

ADME Potential Mechanism Potential

NRTIs

NNRTIs CYP2B6, CYP3A4 P450 inducer

PIs CYP3A4, transporters

Inhibits P450Induces UGT

Integrases UGT1A1

maraviroc CYP3A4

T20

ARV and TB drugs have great potential for interactions – comprising some of the most ‘therapeutically risky’ drugs for DDIs


Potential to be affected Potential to affect other drugsADME Potential Mechanism Potential

Rifampicin* CYP3A4, SLCO1B Induce CYPs, transporters Isoniazid* Acetylation Pyrazinamide* POA; renal Ethambutol renal (75%) Streptomycin renal Rifabutin CYP P450 Rifapentine esterase Induces 3A4, 2C8/9 Moxifloxacin Phase II Gatifloxacin Renal (77%) Capreomycin renal Ethionamide* SulphoxidePAS Renal (>80%) Linezolid Renal MAO inhibitor Cycloserine Renal (65%)

TMC207 CYP3A4 PA824 SQ109 CYP2D6, 2C19 OPC67683 LL3858 ? ?


- 86%

- 35%

- 89%

- 82%

- 82%

- 73%

- 63%

- 80%

- 72%

Change (%) in AUC of ARVs when given with rifampicin

www.hiv-druginteractions.org accessed Sept 2010

- 40%

- 26%

- 40%

• No significant interactions – NRTIs and T20• Steady‐state RIF, single or multiple doses HIV drugs• Patients and healthy volunteers• No data on intermittent or high dose RIF regimens

ND ND


+53%+4 fold

+2 fold+11 fold

+3 fold+2 fold

+17%- 38%

-17% RBT AUC

Change (%) in AUC of ARVs when given with rifabutin

www.hiv-druginteractions.org accessed Sept 2010

• Studies done in healthy volunteers• HIV/TB patients – RBT exposure with intermittent RBT + LPVr• No data for RPT


www.hiv-druginteractions. org

Rif INH PZA Eth Strep RBT RPT Mox Ethio Cyclo Capreo TMC 207

PA 824

OPC 67683

SQ 109

SQV/r RTV IDV

NFV FPV/r LPV/r ATV/r TPV/r DRV/r

NVP EFV ETR ZDV 3TC ddI

d4T ABC ddC FTC TDF ENF MVC RAL

TB-HIV drug interactions


What we know What we need to know

ARVs do not completely eliminate TB risk

No substitute for rifamycin in intensive or continuation phases

Interaction potential Rif>RPT>RBT

Plasma exposure of Rif, INH, ethambutol reduced in TB, and HIV patients compared with healthy volunteers

Induction potential with different dosing of Rif

Large datasets of RBT safety and efficacy in HIV+TB coinfection

Optimal RBT dose with bPI

Interaction data for new drugs & RPT

Shorter regimens with greater sterilisation

HIV‐TB Treatment interactionsTB drugs

McIlleron et al AAC 2006;50:1170-77Perlman et al 2005; 41:1638–47Tappero et al. CID 2005;41:461-9Sahai et al. AIM 1997;127:289–293O’Reilly. AIM 1974;81:337

Lawn et al AIDS 2009, 23:1717–1725Jindani et al. Lancet 2004;364:1244Burman et al. CPK 2001;40:327Boulanger CID 2009; 49:1305–11


Effect of disease on PKEffect on ARVsPIs‐ ATV, others less clear

Effect on TB drugsR, H, E concentrations altered in TB vs healthy volunteersAdditional impact of HIV on Rif & INH ?

RBT PK in HIV/TB co‐infection (n = 10; USA)Cmax targets >0.30 g/mL

TBTC Study 23A: Cmin 0.45 g/mL, AUC >5.2 g.h/mL(<3.2 for ARR)1 patient relapsed with ARR

No below Cmax target

RBT 300mg od 5 / 10

RBT 150mg 3x/w + LPVr 7 / 10

Boulanger CID 2009; 49:1305–11



ARVs do not completely eliminate TB risk

No substitute for rifamycin in intensive or continuation phases

Interaction potential Rif>RPT>RBT

Plasma exposure of Rif, INH, ethambutol reduced in TB, and HIV patients compared with healthy volunteers

Induction potential with different dosing of Rif

Large datasets of RBT safety and efficacy in HIV+TB coinfection

Interaction data for new drugs & RPT

Shorter regimens with greater sterilisation

HIV‐TB treatment interactionsTB drugs

McIlleron et al AAC 2006;50:1170-77Perlman et al 2005; 41:1638–47Tappero et al. CID 2005;41:461-9Sahai et al. AIM 1997;127:289–293O’Reilly. AIM 1974;81:337

Lawn et al AIDS 2009, 23:1717–1725Jindani et al. Lancet 2004;364:1244Burman et al. CPK 2001;40:327Boulanger CID 2009; 49:1305–11



Integrate ART into TB therapy

NNRTIs preferred: observational data suggest efficacy and safety of EFV > NVP if started during TB therapy

No dose modification of EFV in Africans and Thais

2nd line choices are difficult

How and when to start

NNRTIs‐ prospective trials

How to use NVP ?

Pharmacogenetics – CYP2B6 ?

Safety of bPIs with Rif

LPVr ‘superboosting’ ?

Raltegravir efficacy data

NRTI only regimens ?

Alternatives to a rifamycin ?

HIV‐TB treatment interactionsHIV drugs

Schmidt et al. Arch Drug Info 2009;2:8–16Nijland et al AIDS 2008:22:931;Acosta AAC 2007;51:3104Burger et al. AAC 2006;50:3336Haas CROI 2008 Abst 766bAbdool Karim et al. NEJM 2010;362:697-706Boulle et al. JAMA 2008;300:530-39Stohr. AVT 2008;13:675


Outcomes in a “smear negative” cohort treated for TB

Hargreaves N, et al, INT J TUBERC LUNG DIS 2001 5(9):847–854

• mortality in smear-positives ~23% [Harries IJTLD 2001]

• higher mortality in smear-negative, HIV-positive

• can early introduction of ARVs modulate this ?



SAPIT

Abdool Karim et al. NEJM 2010;362:697

HIV‐positive, CD4 <500new TB infection


Early integrated (IP)Early integrated (IP) Late Integrated (CP)

Late Integrated (CP)

N = 642

Sequential (> 6m)N = 213


Combined IntegratedN = 429


HIV+ , TB infection in S Africa

CD4 count ≤ 500

Randomised open label

• Early Integrated : intensive phase (within 4w) • Late Integrated: continuation phase (within 4w of completing IP)

• Sequential : within 4w of completing TB therapy

ddI + 3TC + EFV (600mg)


SAPIT

Abdool Karim et al. NEJM 2010;362:697



Early integrated (IP)Early integrated (IP) Late Integrated (CP)

Late Integrated (CP)

N = 642






CAMELIAANRS1295/1260‐ CIPRA KHOO1/10425

• HIV+ , TB infection in Cambodia

• low CD4 count (median 25)

• Randomised to early (2w) vs late (8w) ART

• d4T + 3TC + EFV(600mg)

• superiority trial• Primary endpoint: survival

• Secondary endpoints: IRIS, virological & immunological response



Early ART (2w)N = 332


Late ART (8w)N = 329


N = 661

Blanc et al. IAS 2010 Vienna THLBB106


Camelia HIV‐positive, CD4 <200new TB infection






N = 661

Blanc et al. IAS 2010 Vienna THLBB106


EFV vs NVP

Khayelitsha observational data (N=2035) suggest inferior outcomes with NVP in patients with concurrent, but not incident TB

Blantyre data (n = 27) suggest 59% NVP ‘plasma levels’ subtherapeutic during lead‐in, vs 14% at weeks 4 & 8

Thai RCT (N2R Study)Prospective RCT (N = 142) EFV (600) vs NVP (400, standard lead‐in)

At w12, C12h < MEC in EFV (3.1%) vs NVP (21.3%)No difference in CD4 & VL responseVariability EFV >> NVP (CV 107% vs 47%)

Boulle et al. JAMA 2008;300:530-39Van Osterhout et al 2008;300:530-39Manosuthi et al CID 2009:48:1752


NVP 400 vs 600 mg / day

Thai patients (N = 32) on Rif for 2-6 weeks

Randomised to• NVP 400mg/day: 200mg/day lead-in• NVP 600mg/day: 400mg/day lead-in

PK of NVPProportion C12 below 3.1mg/L at w2NVP400 (79%) vs NVP600 (19%) (P = 0.002)

NVP hypersensitivityNVP600 (4/16) 2 during lead-inNVP400 (1/16)3 /4 were female

Proportion C12 <3.1mg/L

Avihinghasanon et al AVT 2008;13:529

Indian patients (N = 13)• NVP Cmax and Ctrough sampled before & 1 week after Rif• Ctrough <MEC in 8/13 patients• Dose increment to 300mg bd restored NVP troughs to therapeutic

range in 7/7 patientsRamachandran JAIDS 2006, 41:36-41


NVP 400mg vs 600mg/day

Elsherbiny et al EJCP 2009;65:71

• S African HIV+ patients taking NVP‐based regimen

• with (n=27) and without (n=26) concurrent TB treatment

• Population PK models: Cl/F by 37.4%

• Simulations suggest 300mg NVP bid achieves adequate concentrations

Predicted NVP 200mg bid

Predicted NVP 300mg bid


CARINEMO HIV‐positive, CD4 <250new TB infection


EFVEFV NVPNVP

N = 570

• HIV+ , TB infection in Mozambique

• Randomised to EFV versus NVP‐based ART

• started 4‐6w after TB treatment

• no lead‐in dosing of NVP (i.e. starting at 200mg bid)

• PK data presented in 20 patients M:F 11:9

Median weight 52.7 kg

Bonnet et al WAC Cape Town 2009


CARINEMO HIV‐positive, CD4 <250new TB infection


EFVEFV NVPNVP

N = 570

Bonnet et al WAC Cape Town 2009


Incident TB on ART

Komati et al AIDS 2010, 24:1849–1855

ART reduces, but does not eliminate TB in high prevalence settings

Different treatment scenario• No lead-in dosing issues• Risk of HSR lower • Induction is taking place over 10-14 days• ? Increase NVP dose• ? If so, when ?

Lawn et al AIDS 2009, 23:1717–1725

PHIDISA Cohort (n = 1771) Gugulethu Cohort (n = 1480)


NevRif (Malawi)

• developing incident TB following >4w of NVP-containing ART• N = 20 (M:F 10:10), Mean BMI 19.4• mean 1.5 months on NVP

• AUC0-8h 22% over 2 weeks • Day 3 gave the greatest mean drop in NVP levels of 21.3 %• 30% patients had NVP troughs below MEC

Chaponda et al IWCPHT 2010 Sorrento

Incident TB on ART


Incident TB

New HIV Diagnosis Not on ARVs

Receiving ARVs(assumes virologically suppressed)

HIV resistance testNNRTI‐ susceptible?

EFV‐containing regimen

Known Drug Interactions ?No

YesContinue regimenNRTI onlyENF containingManageable Interaction ?

Yes‐ EFV or RAL

No / difficult‐ PI, NVP, MVC Continue, dose

modify if appropriate– EFV or RAL‐ containingCan be safely switched to EFV ?

No Yes

Modify TB treatmentSubstitute Rif with RBT+ current regimen

or

Yes No

Modify TB treatmentSubstitute Rif with RBT+ bPI‐containing ART

or Modify ARVs‐ RAL regimen if possible

Less preferable‐ bPI – ‘super‐boosted ‘LPVr‐ RTV at full dose‐ Double dose MVC‐ Switch to ENF‐ NRTI‐only regimen

Modify ARVs‐ RAL regimen if possible

Less preferable‐ bPI – ‘super‐boosted ‘LPVr‐ RTV at full dose‐ Double dose MVC‐ Switch to ENF‐ NRTI‐only regimen

Concurrent TB


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Can Rif – EFV interaction differ between people?

Rif tends to increase rather than decrease variability 5 ‐ 55 fold in oral AUC of S‐verapamil, midazolam and theophyllineCV of EFV was 58% without, vs 157% with Rif (n = 19)

Inter‐individual differences in EFV – Rif interaction ?Ethnicity and CYP2B6 PM more than compensates for Rif effect

Non‐genetic factorssmoking (CYP P450 induction), diet, etc

Genetic factorsRif + S‐mephenytoin induction in CYP2C19 EMs, but not PMsRif + Propafenone induction in CYP2D6 PMs, but not EMs

Friedland JAC 2006;58:1299Di Iulio et al Pharmacogenet Genom 2009;19:300Ren et al. JAIDS 2009;50:439Ramachandran AAC 2009;53:863Uttayamakul AIDS Res Ther 2010;7:8Uttayamakul IAS 2010 Vienna WEPE0104

Lin. Ann Rev Pharm Toxicol 2001:41:535Fromm BJCP 1998;45:247Backman CPT 1996;59:7Robson BJCP 1984;18:445Zhou. BJCP 1990;30:471Dilger. Pharmacogenetics 1999;9:551


TB coinfection – to dose increase or not ?

020406080

100

020406080

100

white black white black


600mg 800mg 600mg 800mg 600mg 800mg 600mg 800mg


50kg 60kg

70kg 80kg

EFV < 1000ng/ml EFV 1000-4000ng/ml EFV > 4000ng/ml

%Multivariable regression model: predicted trough (C24h )

Male, aged 41y, on EFV for 12 months, taking TB treatment

Stohr. AVT 2008;13:675


020406080

100

020406080

100





50kg 60kg

70kg 80kg

EFV < 1000ng/ml EFV 1000-4000ng/ml EFV > 4000ng/ml

%

TB coinfection – to dose increase or not ?Multivariable regression model: predicted trough (C24h )

Male, aged 41y, on EFV for 12 months, taking TB treatment

Stohr. AVT 2008;13:675


• 26 TB+ HIV patients from Ghana• Concomitant Rif + EFV (600mg)• CYP2B6 516G>T + haplotypes• Rif did not reverse effects of poor

metaboliser genotype

CYP 2B6 PolymorphismsN=26 Ghanians given EFV + RIF

Kwara et al. JCP 2008;48:1032Kwara BJCP 2009;67:427

• 65 patients from Ghana on EFV• 19 received comitant Rif + EFV (600mg)• CYP2B6 and CYP2A6 PM genotypes

accounted for 36% and 12% population variance

• No significant effect of Rif use


Variability in Rif – EFV interaction

CYP2B6 PM more than compensates for Rif effect

• S Indian patients (n = 57) receiving EFV + Rif• Full PK with genotyping in n = 19• sparse PK in n = 38• CYP2B6 G516T but not Rif significantly influenced EFV PK

• Thai patients (n = 124) receiving EFV (600mg) + Rif• CYP 2B6 516 GG (38.5%), GT (47.7%) and TT (13.9%) affect C12h concentrations• small effect of Rif on EFV PK in comparison

Ramachandran et al. AAC 2009;53:863Uttayamakul et al. AIDS Res Ther 2010;7:8


CYP2B6

CYP2A6

Hom-LOF 2B6 & 2A63A4 _rs46464337

Hom-LOF 2B6Het 3A4 _rs46464337

Di Iulio et al Pharmacogenet Genom 2009;19:300Arab Almeddine et al. CPT 2009;85:485

X X


0

5000

10000

15000

20000

25000

on RIF off Rif

EFV

conc

entr

atio

n (n

g/m

L)

CV 157% CV 58%

0

5000

10000

15000

20000

25000

on RIF off Rif

EFV

conc

entr

atio

n (n

g/m

L)

CV 157% CV 58%

Adults (n=19) Durban Children (n=15) Cape Town

Ren et al. JAIDS 2009;50:439Friedland et al JAC 2006;58:1299

Variability in Rif – EFV interaction

• Thai patients (n = 124) receiving EFV (600mg) + Rif• CYP 2B6 516 GG (38.5%), GT (47.7%) and TT (13.9%)• C12h concentrations• small effect of Rif on EFV PK in comparison

Ramachandran et al. AAC 2009;53:863Uttayamakul et al. AIDS Res Ther 2010;7:8


Overlapping Syndromes

Syndrome Causes

Febrile, generally unwell IRIS, paradoxical reactions, MDR TB

Abnormal LFTs TB drugs, HIV drugs, paradoxical reactions, hepatitis virus ‘flares’

neuropathy d4T, ddI, 3TC, HIV, isoniazid, ethionamide, linezolid

Eye problems Ethambutol, rifabutin, linezolid, ethionamide

CNS Efavirenz, cycloserine

Cardiac PIs, quinolones

Arthropathies HIV, pyrazinamide, quinolones, PAS


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Risk for clinically significant interactions

Study

Year Setting N CSDI lower Screening Tool Adverse Notes

de Maat et al

2004 Netherlands (hospital)

115

105

26%

23%

N/A Liverpool website

N/A Pharmacy screening effective, further pharmacy input not

Shah et al

2007 USA (Medicaid)

571

(689)

30%

(15%)

8%

(4%)

Liverpool websiteMicromedex

no VL impact

Audit, and re-audit.

Miller et al 2007 USA (hospital)

153 41% N/A DHHS SPC / PI Micromedex

N/A Age >42y (OR 2.9) >3 conditions (OR 3.0) >3 ARVs (OR 2.4) PI use (OR 11.5)

Kigen et al

2009 Kenya (hospital)

996 34%* 12% Liverpool website

N/A

Marzolini et al

2009 Switzerland(hospital)

1497 40% 4% Liverpool website

no CD4 or VL impact

Antiviral Ther 2010

Evans-Jones et al

2009 UK (hospital)


N/A CID 2010Only 36% CSDIs correctly identified

* excludes ARV-ARV interactions


How common are HIV Drug Interactions ?

Kenya [Kigen et al. HIV8, 2008 Abstract O121; manuscript in preparation]

• 996 consecutive patients receiving ARVs• Moderate / Major drug interactions identified in 34%• 12% (1:3 CSDIs) could have lowered ARV concentrations• Rifampicin > Azoles > Steroids > Antimalarials > PPIs


Risk for clinically significant interactionsStudy

Year Setting N CSDI lower Screening Tool Adverse Notes

de Maat et al

2004 Netherlands (hospital)

115

105

26%

23%

N/A Liverpool website

N/A Pharmacy screening effective, further pharmacy input not

Shah et al

2007 USA (Medicaid)

571

(689)

30%

(15%)

8%

(4%)

Liverpool websiteMicromedex

no VL impact

Audit, and re-audit.

Miller et al 2007 USA (hospital)

153 41% N/A DHHS SPC / PI Micromedex

N/A Age >42y (OR 2.9) >3 conditions (OR 3.0) >3 ARVs (OR 2.4) PI use (OR 11.5)

Kigen et al

2009 Kenya (hospital)

996 34%* 12% Liverpool website

N/A (in preparation)

Marzolini et al

2009 Switzerland(hospital)


no CD4 or VL impact

(submitted)

Evans-Jones et al

2009 UK (hospital)

159 27% Liverpool website

N/A Only 36% CSDIs correctly identified

* excludes ARV-ARV interactions

Evan Jones et al CID 2010;50:1419


Interventions which work• Prescriber education

• Pharmacist input [1-2]

• Drug interactions databaseswww.hiv-druginteractions.org, www.clinicalcareoptions.com, etcConcordance is variable [3]

Tendency to over-call – ‘Alert fatigue’ !

• ‘Active vs passive’ identification of interactionsDecision support software for dispensaries / electronic prescribers

Interaction datasheets for patients or prescribers

• Therapeutic Drug Monitoringto manage interactions, or else to discount them

1 Hanlon Am J Med 1996;100;428. 2 de Maat J Clin Pharm Ther 2004;29:1213 Pham. CPT 2008;83:396


Resource‐limited settings

A Public Health approach to managing DDIs

• Training to improve quality of prescribing

• Regional Drug Information Centres – e.g. ATIC

• Programmatic approach – Integrated, rather than vertical programmes

• Instituting systems for pharmacovigilance

• Incorporate monitoring for serious DDIs within ARV Programmes

• Audit quality of prescribing


Liverpool HIV Drug Interactions website


Acknowledgements

www.hiv-druginteractions.orgReceives sponsorship from GSK, Abbott, Merck, BMS, Tibotec, Roche, Gilead, Pfizer, Elton John AIDS Foundation, British HIV Association, Glasgow HIV conference.

Editorial content remains independent.

Declaration of Interests

David BackGerry DaviesAndrew OwenSara GibbonsKay Seden

Wolfgang StoehrDavid DunnGabriel KigenLawrence LeeCeppie Merry

… and many others….

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