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THE UNIVERSITY of LIVERPOOL

THE UNIVERSITY of LIVERPOOL. HIV & TB Drug Interactions Research Priorities. S. H. Khoo University of Liverpool. Interactions between HIV and TB Drugs. Pharmacology Effects of TB drugs on HIV treatment Effects of ARVs on TB treatment Therapeutics

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THE UNIVERSITY of LIVERPOOL

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  1. THE UNIVERSITY of LIVERPOOL HIV & TB Drug Interactions Research Priorities S. H. Khoo University of Liverpool

  2. Interactions between HIV and TB Drugs • Pharmacology Effects of TB drugs on HIV treatment Effects of ARVs on TB treatment • Therapeutics Drug toxicities & overlapping syndromes Effect on mortality Adherence

  3. Anti-retroviral therapy NNRTI nevirapine efavirenz delavirdine PI saquinavir ritonavir indinavir nelfinavir lopinavir amprenavir atazanavir fosamprenavir (tipranavir) NRTI zidovudine lamivudine didanosine zalcitabine stavudine abacavir emtricitabine tenofovir • Toxicity • Adherence • Prescribing issues for developing countries

  4. How much adherence is enough ? Paterson 2000

  5. Prescribing issues for developing countries • Effect of gender, body weight, ethnicity • Interactions with other medications (TB, antibiotics, OCP, herbals, etc) • Need to be dosed with food • Once-daily for DOTS • Pediatric formulations of FDCs • Drug quality • Shelf life & storage • Monitoring • The need for second line ARVs – role for protease inhibitors ? • Access to information / knowledge

  6. PK of ARVs • Large intra-individual variability • Significant proportion of individuals with low / high levels

  7. PK of ARVs Effect of ethnicity, gender and body weight Ethnicity  EFV in Africans (? 2B6 polymorphism) () NVP in Africans  IDV peaks in Thais Different toxicity profile (lipo, hypersensitivity) Gender  Levels in women (NVP/ EFV/ ?LPV) • ZDV/3TC triphosphates in women • Toxicity (lipo, hepatitis) Body weight Differences for PIs & NNRTIs ?

  8. Dutch TDM Liverpool TDM Nevirapine Efavirenz LaPorte et al, 2003 LHPG data, 2004

  9. STOP Study • 10 patients stopping therapy (EFV-containing regimen) • EFV concentrations measured over 3 w • Nucleoside backbone continued 1w after stopping EFV 5 had EFV T½ 40-50 h 5 had EFV T½ >100 h 4 / 5 Black African women 3 had EFV levels in the ‘therapeutic’ range at 2 w

  10. Rif Clearance of HIV Drugs PI / NNRTI Hepatoxicity Chronic Hepatitis Alcohol Other toxins

  11. TB / HIV drug Interactions • Rifampicin lowers HIV NNRTI levels • NVP – 30-60% • EFV – 20-25% • Rifampicin lowers HIV PIs by ~ 90% • partially restored by high dose RTV - cost, toxicity, pill burden • HIV drugs may affect rifamycins • increase RBT dose with NNRTIs • decrease RBT dose with Pis

  12. IDV SQV Grub EJCP 2001 Jutesen CID 2004 LPV La Porte et al. Antimicrob Agents Chemother. 2004;48:1553-1560.

  13. Distribution of plasma EFV levels between EFV 600 and 800 mg groups Manosuthi et al. XV AIDS Conference Bangkok 2004

  14. START Study Prospective pilot HAART + TB (DOT) n = 20 19 remained in study; ddI+3TC+EFV Jack et al. JAIDS 2004;36:929-35 EFV TB treatment post-TB treatment Repeatedly high 40(4/4 normalised) Repeatedly low 62(4/6 normalised) Low / normal 61 (4/5 normalised) Consistently normal 2

  15. Complex Clinical Syndromes Liver toxicity • Liver toxicity of HIV drugs 8-13% [2NN 2003] • Liver toxicity of TB drugs 2- 4% [Aquinas BMJ 1972] • Liver toxicity TB + HIV drugs > TB drugs [Patel JAIDS 2004] • Background chronic hepatitis B • Immune reconstitution with ARVs Paradoxical reactions • TB (7%) vs TB / HIV (36%) [Narita AJRCCM 1998] Impact on Mortality

  16. 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 2001 5(9):847–854

  17. Alternatives to RIF ? • Sterilising phase • RH (95%) > EH (87.4%) IUTLD Study A Jindani Paris 2003 • What other (short course) regimens would allow ARVs ? • induction: rifampicin > rifapentine > rifabutin • Study 22: Rifapentine + INAH once weekly • Rifamycin monoresistance in 4/30 (13%) TB+HIV patients • Vernon et al Lancet 1999;353:1843 • Study 23: Rifabutin + INAH twice weekly • Rifamycin monoresistance in 5/147 (3.4%) TB+HIV patients • MMWR March 15 2002/ 51 (10);214 • Quinolones ?

  18. Disseminating ‘Knowledge’ to support prescribing Knowledge • Dosing • Interactions • Identifying toxicities • Gender, ethnicity, weight • Adherence interventions • etc Need to : Gather & synthesise existing information identify gaps in knowledge Address these in a co-ordinated manner Access and training

  19. Research Priorities • Problem with rifampicin RPT / RBT/ quinolones • When / how to give ARVs ? effect of ARVs on early mortality use of rifampicin in sterilising phase lead-in dosing for NVP dose modifications vs FDC • Toxicity & resistance pharmacovigilance networks surveillance networks

  20. Research Priorities • How to support adherence ? What are the barriers? DOTs alternatives ? • How do we disseminate knowledge ? Co-ordinate research activities Gather available evidence Enable access Support training

  21. Patients with EFV level < 1 mg/L Number of patients 25 20 Plasma EFV 15 10 5 p = 0.274 0 EFV 600 mg EFV 800 mg

  22. Inadequate drug levels may result in resistance Drug level Periodically inadequate drug levels Mutant selected with reduced susceptibility Rebound with highly resistant organism

  23. Rifabutin & Ritonavir Mean Rifabutin Plasma Concentrations Mean 25-O-Desacetylrifabutin Plasma Concentrations AUC (ng.h.ml-1) 1843 ± 392 8362 ± 2229 AUC (ng.h.ml-1) 165 ± 79 6289 ± 840 Cato et al, 1998

  24. La Ribera et al. JAIDS 2001

  25. Unboosted PI Boosted PI NNRTI Adherence - resistance relationship Risk of resistance 20 40 60 80 100 Adherence (%) Bangsberg, Moss & Deeks. JAC 2004

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