Drug Interactions in TB / HIV Co-infected Patients

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1 Drug Interactions in TB / HIV Co-infected Patients Saye Khoo HIV Pharmacology Group University of Liverpool / Biomedical Research Centre in Microbial Diseases

2 HIV and TB prevalence

3 Menu HIV TB drug interactions What we know and don t know Inter individual differences in DDIs Management of DDIs in different healthcare settings

4 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 drugs ADME Potential Mechanism Potential NRTIs NNRTIs CYP2B6, CYP3A4 P450 inducer PIs CYP3A4, transporters Inhibits P450 Induces UGT Integrases UGT1A1 maraviroc CYP3A4 T20

5 Potential to be affected Potential to affect other drugs ADME 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* Sulphoxide PAS Renal (>80%) Linezolid Renal MAO inhibitor Cycloserine Renal (65%) TMC207 CYP3A4 PA824 SQ109 CYP2D6, 2C19 OPC67683 LL3858??

state RIF, single or multiple doses HIV drugs Patients and healthy volunteers No data

6 Change (%) in AUC of ARVs when given with rifampicin -86% -89% -82% -72% -26% -63% -35% -82% -73% -40% -80% -40% ND ND No significant interactions NRTIsand T20 Steady state RIF, single or multiple doses HIV drugs Patients and healthy volunteers No data on intermittent or high dose RIF regimens accessed Sept 2010

healthy volunteers HIV/TB patients RBT exposure with intermittent RBT

7 Change (%) in AUC of ARVs when given with rifabutin +53% +4 fold +2 fold +11 fold +3 fold +2 fold +17% -17% RBT AUC -38% Studies done in healthy volunteers HIV/TB patients RBT exposure with intermittent RBT + LPVr No data for RPT accessed Sept 2010

8 TB-HIV drug interactions Rif INH PZA Eth Strep RBT RPT Mox Ethio Cyclo Capreo TMC 207 PA 824 OPC 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 org

9 HIV TB Treatment interactions TB drugs 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 Lawn et al AIDS 2009, 23: Jindani et al. Lancet 2004;364:1244 Burman et al. CPK 2001;40:327 Boulanger CID 2009; 49: McIlleron et al AAC 2006;50: Perlman et al 2005; 41: Tappero et al. CID 2005;41:461-9 Sahai et al. AIM 1997;127: O Reilly. AIM 1974;81:337

10 Effect of disease on PK Effect on ARVs PIs ATV, others less clear Effect on TB drugs R, H, E concentrations altered in TB vs healthy volunteers Additional impact of HIV on Rif & INH? RBT PK in HIV/TB co infection (n = 10; USA) Cmax targets >0.30 g/ml No below Cmax target RBT 300mg od 5 / 10 RBT 150mg 3x/w + LPVr 7 / 10 TBTC Study 23A: Cmin 0.45 g/ml, AUC >5.2 g.h/ml(<3.2 for ARR) 1 patient relapsed with ARR Boulanger CID 2009; 49:

11 HIV TB treatment interactions TB drugs 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 Interaction data for new drugs & RPT Shorter regimens with greater sterilisation Lawn et al AIDS 2009, 23: Jindani et al. Lancet 2004;364:1244 Burman et al. CPK 2001;40:327 Boulanger CID 2009; 49: McIlleron et al AAC 2006;50: Perlman et al 2005; 41: Tappero et al. CID 2005;41:461-9 Sahai et al. AIM 1997;127: O Reilly. AIM 1974;81:337

12 HIV drugs HIV TB treatment interactions What we know What we need to know 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 2 nd line choices are difficult Schmidt et al. Arch Drug Info 2009;2:8 16 Nijland et al AIDS 2008:22:931; Acosta AAC 2007;51:3104 Burger et al. AAC 2006;50:3336 Haas CROI 2008 Abst 766b Abdool Karim et al. NEJM 2010;362: Boulle et al. JAMA 2008;300: Stohr. AVT 2008;13:675 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?

13 Outcomes in a smear negative cohort treated for TB mortality in smear-positives ~23% [Harries IJTLD 2001] higher mortality in smear-negative, HIV-positive can early introduction of ARVs modulate this? Hargreaves N, et al, INT J TUBERC LUNG DIS (9):

14 SAPIT HIV positive, CD4 <500 new TB infection N = 642 Early integrated (IP) Late Integrated (CP) Combined Integrated Sequential (> 6m) N = 429 N = 213 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) Abdool Karim et al. NEJM 2010;362:697

15 SAPIT HIV positive, CD4 <500 new TB infection N = 642 Early integrated (IP) Late Integrated (CP) Combined Integrated Sequential (> 6m) N = 429 N = 213 Abdool Karim et al. NEJM 2010;362:697

16 CAMELIA ANRS1295/1260 CIPRA KHOO1/10425 HIV positive, CD4 <200 new TB infection N = 661 Early ART (2w) N = 332 Late ART (8w) N = 329 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 Blanc et al. IAS 2010 Vienna THLBB106

17 Camelia HIV positive, CD4 <200 new TB infection N = 661 Early ART (2w) N = 332 Late ART (8w) N = 329 Blanc et al. IAS 2010 Vienna THLBB106

18 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 response Variability EFV >> NVP (CV 107% vs 47%) Boulle et al. JAMA 2008;300: Van Osterhout et al 2008;300: Manosuthi et al CID 2009:48:1752

19 NVP 400 vs 600 mg / day Indian patients (N = 13) NVP Cmax and Ctrough sampled before & 1 week after Rif C trough <MEC in 8/13 patients Dose increment to 300mg bd restored NVP troughs to therapeutic range in 7/7 patients Ramachandran JAIDS 2006, 41:36-41 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 Proportion C12 <3.1mg/L PK of NVP Proportion C12 below 3.1mg/L at w2 NVP400 (79%) vs NVP600 (19%) (P = 0.002) NVP hypersensitivity NVP600 (4/16) 2 during lead-in NVP400 (1/16) 3 /4 were female Avihinghasanon et al AVT 2008;13:529

20 NVP 400mg vs 600mg/day Predicted NVP 200mg bid Predicted NVP 300mg bid 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 Elsherbiny et al EJCP 2009;65:71

21 CARINEMO HIV positive, CD4 <250 new TB infection N = 570 EFV NVP 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

22 CARINEMO HIV positive, CD4 <250 new TB infection N = 570 EFV NVP Bonnet et al WAC Cape Town 2009

23 Incident TB on ART PHIDISA Cohort (n = 1771) Gugulethu Cohort (n = 1480) 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 days? Increase NVP dose? If so, when? Komati et al AIDS 2010, 24: Lawn et al AIDS 2009, 23:

24 Incident TB on ART 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 AUC 0-8h 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

25 New HIV Diagnosis Not on ARVs Concurrent TB Receiving ARVs (assumes virologically suppressed) Incident TB Yes HIV resistance test NNRTI susceptible? No Known Drug Interactions? Yes Manageable Interaction? No Continue regimen NRTI only ENF containing EFV containing regimen No / difficult Yes PI, NVP, MVC Continue, dose EFV or RAL modify if appropriate Can be safely switched to EFV? EFV or RAL containing No Yes Modify TB treatment Substitute 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 TB treatment Substitute Rif with RBT + current regimen 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

26 Menu HIV TB drug interactions What we know and don t know Inter individual differences in DDIs Management of DDIs in different healthcare settings

27 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 theophylline CV 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 factors smoking (CYP P450 induction), diet, etc Genetic factors Rif + S mephenytoin induction in CYP2C19 EMs, but not PMs Rif + Propafenone induction in CYP2D6 PMs, but not EMs Lin. Ann Rev Pharm Toxicol 2001:41:535 Fromm BJCP 1998;45:247 Backman CPT 1996;59:7 Robson BJCP 1984;18:445 Zhou. BJCP 1990;30:471 Dilger. Pharmacogenetics 1999;9:551 Friedland JAC 2006;58:1299 Di Iulio et al Pharmacogenet Genom 2009;19:300 Ren et al. JAIDS 2009;50:439 Ramachandran AAC 2009;53:863 Uttayamakul AIDS Res Ther 2010;7:8 Uttayamakul IAS 2010 Vienna WEPE0104

28 TB coinfection to dose increase or not? Multivariable regression model: predicted trough (C 24h ) Male, aged 41y, on EFV for 12 months, taking TB treatment % kg 60kg 600mg 800mg 600mg 800mg 600mg 800mg 600mg 800mg white black white black 70kg 80kg 600mg 800mg 600mg 800mg 600mg 800mg 600mg 800mg white black white black EFV < 1000ng/ml EFV ng/ml EFV > 4000ng/ml Stohr. AVT 2008;13:675

29 TB coinfection to dose increase or not? Multivariable regression model: predicted trough (C 24h ) Male, aged 41y, on EFV for 12 months, taking TB treatment % kg 60kg 600mg 800mg 600mg 800mg 600mg 800mg 600mg 800mg white black white black 70kg 80kg 600mg 800mg 600mg 800mg 600mg 800mg 600mg 800mg white black white black EFV < 1000ng/ml EFV ng/ml EFV > 4000ng/ml Stohr. AVT 2008;13:675

30 CYP 2B6 Polymorphisms 26 TB+ HIV patients from Ghana Concomitant Rif + EFV (600mg) CYP2B6 516G>T + haplotypes Rif did not reverse effects of poor metaboliser genotype N=26 Ghanians given EFV + RIF 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 Kwara et al. JCP 2008;48:1032 Kwara BJCP 2009;67:427

31 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;53:863 Uttayamakul et al. AIDS Res Ther 2010;7:8

32 CYP2B6 X CYP2A6 X Di Iulio et al Pharmacogenet Genom 2009;19:300 Arab Almeddine et al. CPT 2009;85:485 Hom-LOF 2B6 & 2A6 3A4 _rs Hom-LOF 2B6 Het 3A4 _rs

33 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;53:863 Uttayamakul et al. AIDS Res Ther 2010;7:8 EFV concentration (ng/ml) Adults (n=19) Durban CV 157% CV 58% on RIF off Rif Ren et al. JAIDS 2009;50:439 Friedland et al JAC 2006;58:1299 Children (n=15) Cape Town

34 Overlapping Syndromes Syndrome Febrile, generally unwell Abnormal LFTs neuropathy Eye problems Causes IRIS, paradoxical reactions, MDR TB TB drugs, HIV drugs, paradoxical reactions, hepatitis virus flares d4t, ddi, 3TC, HIV, isoniazid, ethionamide, linezolid Ethambutol, rifabutin, linezolid, ethionamide CNS Cardiac Arthropathies Efavirenz, cycloserine PIs, quinolones HIV, pyrazinamide, quinolones, PAS

35 Menu HIV TB drug interactions What we know and don t know Inter individual differences in DDIs Management of DDIs in different healthcare settings

36 Risk for clinically significant interactions Study Year Setting N CSDI lower Screening Tool Adverse Notes de Maat et al 2004 Netherlands (hospital) % 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 website Micromedex no VL impact Audit, and re-audit. Miller et al 2007 USA (hospital) % 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) Marzolini et al 2009 Switzerland (hospital) %* 12% Liverpool website N/A % 4% Liverpool website no CD4 or VL impact Antiviral Ther 2010 Evans-Jones et al 2009 UK (hospital) % 15% Liverpool website N/A CID 2010 Only 36% CSDIs correctly identified * excludes ARV-ARV interactions

37 Risk for clinically significant interactions Study Year Setting N CSDI lower Screening Tool Adverse Notes de Maat et al 2004 Netherlands (hospital) % 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 website Micromedex no VL impact Audit, and re-audit. Miller et al 2007 USA (hospital) % 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) Marzolini et al 2009 Switzerland (hospital) %* 12% Liverpool website N/A % 4% Liverpool website no CD4 or VL impact Antiviral Ther 2010 Evans-Jones et al 2009 UK (hospital) % 15% Liverpool website N/A CID 2010 Only 36% CSDIs correctly identified * excludes ARV-ARV interactions

38 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

39 Risk for clinically significant interactions Study Year Setting N CSDI lower Screening Tool Adverse Notes de Maat et al 2004 Netherlands (hospital) % 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 website Micromedex no VL impact Audit, and re-audit. Miller et al 2007 USA (hospital) % 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) %* 12% Liverpool website N/A (in preparation) Marzolini et al 2009 Switzerland (hospital) % 4% Liverpool website no CD4 or VL impact (submitted) Evans-Jones et al 2009 UK (hospital) % Liverpool website N/A Only 36% CSDIs correctly identified * excludes ARV-ARV interactions Evan Jones et al CID 2010;50:1419

40 Interventions which work Prescriber education Pharmacist input [1-2] Drug interactions databases etc Concordance is variable [3] Tendency to over-call Alert fatigue! Active vs passive identification of interactions Decision support software for dispensaries / electronic prescribers Interaction datasheets for patients or prescribers Therapeutic Drug Monitoring to manage interactions, or else to discount them 1 Hanlon Am J Med 1996;100; de Maat J Clin Pharm Ther 2004;29:121 3 Pham. CPT 2008;83:396

41 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

42 Liverpool HIV Drug Interactions website

43 Acknowledgements David Back Gerry Davies Andrew Owen Sara Gibbons Kay Seden Wolfgang Stoehr David Dunn Gabriel Kigen Lawrence Lee Ceppie Merry and many others. Declaration of Interests Receives sponsorship from GSK, Abbott, Merck, BMS, Tibotec, Roche, Gilead, Pfizer, Elton John AIDS Foundation, British HIV Association, Glasgow HIV conference. Editorial content remains independent.

HIV and TB coinfection: Updates. Awewura Kwara, MD, MPH &TM Associate Professor, Alpert Medical School of Brown University

HIV and TB coinfection: Updates Awewura Kwara, MD, MPH &TM Associate Professor, Alpert Medical School of Brown University Learning objectives Identify the optimal timing of antiretroviral therapy in patients