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TB and HIV Management

TB and HIV Management. Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK. TB Epidemiology. TB incident cases in 2007 9.27 million incident cases in 2007 Asia: 55% Africa 31% East Med 6% East Euro 5% Americas 3% TB incident cases has been on the increase since 1990s

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TB and HIV Management

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  1. TBandHIVManagement Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

  2. TB Epidemiology TB incident cases in 2007 • 9.27 million incident cases in 2007 • Asia: 55% • Africa 31% • East Med 6% • East Euro 5% • Americas 3% TB incident cases has been on the increase since 1990s • 9.27 million (2007) • 9.24 million (2006) • 8.30 million (2000) • 6.60 million (1990)

  3. Tb epidemiology • TB incidence rate has been falling since 2004 • 137 cases per 100,000 (2007) • 142 cases per 100,000 (2004) • The rate of decline is less than 1% a year (generally) • TB Incident rates are falling in all regions except Eastern Europe • Of the total 9. 3 million new TB cases in 2007, 1.4 million also had HIV (TB/HIV cases) • 15% of all TB cases in 2007 were co-infected with HIV • 85% of all TB cases in 2007 were not co-infected with HIV • Out of the 15% TB cases co-infected with HIV: • Africa (79%) • South East Asia (11%) • Other regions (10%)

  4. TB epidemiology • Case detection rate reached 63% in 2007 • Americas (73%) • Western Pacific (77%) • South East Asia (69%) • Eastern Med. (60%) • Eastern Euro (51%) • Africa (47%) • Treatment success rate reached 85% in 2006 • TB remains the leading cause of death among PLHIV • PLHIV are 20 – 30 times more likely to acquire TB than people without HIV • PLHIV with TB are highly vulnerable to MDR-TB and XDR-TB

  5. TB/HIVMany Challenges When to start Antiretroviral Therapy (ART) What ART to start Drug interactions

  6. Issues in initiating antiretroviral therapy in HIV patients with TB

  7. HAART in TB-HIV: Early or late? Adapted from J Acquir Immune Defic Syndr 2007; 46: S9-S18.

  8. When to Start ART: in TB Immediately? TB TREATMENT 1 2 6 TB, HIV+ CD4<350 Or ?<200 Months ANTIRETROVIRAL THERAPY-WHEN?

  9. Don’t Wait till it’s too lateFurther AIDS 27/188 TB/HIV patients developed further AIDS On HAART =3 Not on HAART= 24 median CD4 70 cells 90% had median CD4 <100 4 months post TB 16 died only 4 on HAART (3 short term) Dean et al AIDS 2001

  10. Mortality among patients with prevalent active TB (n=73) initiating ART a) 1.00 0.90 0.80 Survival probability 0.70 ART 0.60 Awaiting ART 0.50 0 30 60 90 120 150 180 Days from TB diagnosis No difference in CD4 count or Stage 4 disease between those starting and not starting Lawn S et al. CROI 2007;Abstract 81

  11. 313 HIV-infected patients with ≥ 1 TB episode andwho initiated HAART after TB diagnosis Mortality significantly lower at end of follow-up for patients with simultaneous <8W HAART/TB treatment vs delayed HAART *P = .011 vs patients who received simultaneous HAART/TB treatment. Velasco M, et al. JAIDS. 2009;50:148-152

  12. SAPIT Study: Study design and intervention Open-label randomised controlled trial 3-arm randomisation: ART initiated ASAP after diagnosis during intensivephase of TB treatment ART initiated after intensive phase ART initiated after TB treatment completed TB treatment standard regimen Co-trimoxazole prophylaxis given to all patients ART was ddI/3TC/EFV given OD with TB-DOT Integrated arm Karim SA et al. CROI 2009. Abstract 36a

  13. SAPIT Study: Mortality rates per CD4 count Reduction in mortality rates is present in patients with CD4 counts above and below 200 cells/mm3 Karim SA et al. CROI 2009. Abstract 36a

  14. SAPIT Study: Mortality in sequential arm occurred late Kaplan-Meier Survival Curve 1.00 0.95 Integrated Arm 0.90 Survival 0.85 Sequential Arm 0.80 Intensive Phase of TB treatment Continuation Phase of TB treatment Post –TB Treatment 0.75 0.70 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months After Randomization Karim SA et al. CROI 2009. Abstract 36a.

  15. However not all TB is the same!!Randomised Controlled Trial ofImmediate Versus Deferred Antiretroviral Therapyin HIV-Associated Tuberculous Meningitis Torok ME et al ICAAC 2009 Presentation H-1224

  16. Study design • Randomised, double blind • Placebo controlled • Patients • n=253 • ≥15 years • HIV-1+ • 90% male, mostly IDU • Clinically suspected TBM • Randomisation stratified by • TBM grade Immediate ART (n=127) AZT/3TC+EFV for 12 months Deferred ART (n=126) Placebo for 2 months followed by AZT/3TC+EFV for 10 months Anti tuberculous TX: RHZE 3 months RH 6 months + Corticosteroids Co-trimoxazole for PCP prophylaxis If CD4<200 Torok ME et al. ICAAC 2009. Abstract H-1224

  17. Overall survival (Kaplan Meier curves) 1.0 0.8 0.6 Placebo 0.4 ARV 0.2 0 0 3 6 9 12 Months since randomisation Torok ME et al. ICAAC 2009. Abstract H-1224

  18. Severe AEs Torok ME et al. ICAAC 2009. Abstract H-1224

  19. Conclusions Immediate ART appears not to improve outcomes in HIV-associated TBM patients Significantly more severe AEs in the first two months in the immediate ARM These data support delayed initiation of ART in HIV-associated TBM Torok ME et al. ICAAC 2009. Abstract H-1224

  20. Impact on Survival of Early vs. Late Initiation of HAART In HIV-infected Adults with Newly Diagnosed Tuberculosis • Methods: CAMELIA (CAMbodian Early vs. Late Introduction of ART) • An open-labelled randomized clinical trial to compare the impact upon mortality of early (2 weeks) vs. late (8 weeks) HAART initiation after TB treatment onset in treatment-naïve adults with newly diagnosed acid-fast bacilli (AFB) positive TB and CD4+ cell count <200 cells/mm3. • Patients received standard 6-month TB treatment plus stavudine, lamivudine and efavirenz and were followed through 50 weeks after the last patient was enrolled. • 661 patients (early, n=332; late, n=329) were enrolled. • CD4+ cell count 25 cells/mm3and viral load 5.64 log copies/ml. Kaplan-Meier Survival Estimates 1.00 Probability of Survival 0.75 0.50 P=0.042 0.25 0.00 0 50 100 150 200 Weeks After Randomization Late Early Blanc F, et al. 18th IAC; Vienna, July 18-23, 2010; Abst. THLBB106.

  21. IRIS significantly more frequent in the early arm * expressed in person-months ** per 100 person-months Time after TB treatment initiation (weeks) ANRS 1295/12160 - CIPRA KH001/10425 study

  22. When to start HAART BHIVA TB-coinfection Guidelines, consultation Draft 2010

  23. Treatment of drug sensitive TB • 90% of MTB dead in 2 days when regimen includes INH • 99% of MTB dead in 14 days when regimen also includes RIfampicin • If INH and RIF and PZA given in first 2 months then total course of TB treatment is 6 months • Debate whether HIV + should be treated for longer • ? Quinolones will shorten to 4 months

  24. If we are treating both HIV and TB.. • Have we enough evidence to give clear treatment recommendations for HIV and TB coinfection? • What are the major drug issues for clinicians • 1. NNRTIs and rifampicin • 2. Pis and rifampicin and rifabutin

  25. Rifampicin • The major problem is the use of rifampicin with HAART • But at present it is an essential part of the solution for TB

  26. CYP3A4 Regulation • PXR: pregnane X receptor; RXR: retinoid X receptor • In vitro models now exist for identifying drugs that bind PXR Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002

  27. Rifampicin • Induces: CYP1A2, CYP2C8, CYP2C9, CYP2E1, 2C19, 3A4 • Induces P-gp activity • Induces phase II metabolism (transferase enzymes) • … rifampin brings broad changes in the pattern of gene expression, rather than increased expression of a small N of metabolic enzymes. Clinicians and researchers who use and study rifampin and other drugs that induce drug metabolism should be alert to the possibility of multiple effects Rae et al. 2001

  28. Drug-drug interactions TB/HIV Absorption Rifampicin ↑CYP3A4 Metabolism PIs NNRTIs Metabolism Elimination

  29. Rifampin Effects on “older” HIV Drugs • Protease inhibitors • Boosted PIs should not be used with concomitant rifampicin-PK or safety or can they? • Nonnucleoside reverse transcriptase inhibitors (NNRTI) • Nevirapine 37 % decrease what dose? • Efavirenz 26 % decrease what dose? • Reverse transcriptase inhibitors • No significant effect Enfurvitide - No effect

  30. NVP and Rifampicin Distributions of plasma nevirapine (NVP) levels at week 8 and week 12 of therapy Manosuthi 2006;CID 43:253–5

  31. 24-Week Efficacy and safety of Nevirapine: 400 mg versus 600 mg based HAART in HIV-infected Patients with Active Tuberculosis Receiving Rifampicin Clin Infect Dis. 2009 Jun 15;48(12):1752-9. Arm 1: NVP 400 mg/day ( GPOvir Z 1 tab po BID) Lead in 14 days with NVP 200 QD N=32, ARV naïve, TB/HIV, smear pos, CD4<200, RIF 2-6 weeks Arm 2: NVP 600 mg/day( GPOvir Z 1 tab po BID+ NVP 1tab QD) Lead in 14 days with NVP 200 BID All patients received AZT+3TC as a backbone 24weeks interim analysis 48 weeks 2-6 weeks of TB treatment 14 days 12 weeks 2 weeks 4 weeks Assessments: + + + TDM of NVP + 12 hr of NVP Prospective, randomized, multicenter, open-label, 2-arm study

  32. Summary of adverse events * ** * disseminated MAC, bloody pleural effusion and liver mass ** cardiomyopathy and heart failure Table 4. Summary of adverse events

  33. Efavirenz • PK data • Standard dose? • Increased dose?

  34. Population PK modeling in HIV-pts with TB treated with EFV and rifampicin • EFV dose 30% increase (from 600 to 800) adequate • Body weight important determinant on CL Soy et al. 2005 PK of EFV 800 mg plus rifampicin similar to those of EFV 600 mg without rifampicin Lopez-Cortes et al. 2002

  35. EFV levels in HIV-infected Thai patients with TB 60 50 40 % of patients 30 20 10 0 < 1 1-4 > 4 600mg 800mg Manisuthi et al. 2005

  36. Nevirapine and Efavirenz • What is also important is • Clinical outcome • Toxicity

  37. 18 month outcomes • 1,283 started ART while on rifampicin: • 209 people on nevirapine and 1,074 on efavirenz. • Those starting NVP with TB rx had a OR(CI) of 2.9(1.8-4.7) of virological failure <400 copies compared with those on EFV or not on TB RX Boulle JAMA. 2008 Aug 6;300(5):530-9.

  38. Now add this into the mix!! • P450 2B6 genes-Patients with a TT genotype 20% of the black population cf. 3% of white individuals have an extended clearance of EFV and are at risk of toxicity Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 microg x h/mL, P< .0001) J Clin Pharmacol. 2008 Sep;48(9):1032-40. • Pregnancy • Chronic Hepatitis • Stopping rifampicin

  39. Nevirapine and Efavirenz • Quote “Clinical outcome studies to date do not support dose adjustment of EFV or NVP” WHO • I would say they don’t support not adjusting the dose too!! • Need good clinical trials matching Pk and outcomes • Is the Cmin the right parameter? • Is The accepted Cmin for efficacy set too high?

  40. Boosted PIs and Rifampin Interaction Lopinavir/rit Saquinavir/rit • Ritonavir 400 bid required • GI toxicity and lipid perturbation • High rates of elevated transaminase1 (5/7 dropouts) 1/10 low trough concentrations • plusrecent Pk study2 • -LFT problems • Early studies from SA suggested could be used • SQV 1000/rit100 BID • 39% hepatitis • Transaminase elevations 20x upper normal2 Arch Drug Inf. 2009 Mar;2(1):8-16. 1La Porte, AAC, 2004 BergerAIDS. 2008 May 11;22(8):931-5.

  41. TB Treatment RegimensRIFAMPICIN / HAART HAART Dose TB Dose therapy 4NRTI No change RIF No change nevirapine 200 mg bd RIF 600 mg od efavirenz* 6-800 mg od RIF 600 mg od *Dose adjusted?

  42. Rifabutin • As “potent” as rifampicin but no long-term data for comparison CYP3A4 CYP3A4 Rifabutin Active metabolites (i.e. 25-O-desacetyl, 31-hydroxy) • CYP3A4 inhibitors increase rifabutin levels

  43. What about Rifabutin? Can be administered With PIs Given at a dose of 150mg 3xWK Benefits Limitations • Expensive! Cost of 4 days of rifabutin = cost of an entire rifampin regimen • Toxicity: marrow suppression, arthralgias, uveitis • Dosing: Dose adjustments of ART regimens ? Dose with boosted PIs

  44. TB Treatment RegimensRifabutin HAART Dose TB Dose therapy 4NRTI No change RBT No change Boosted PI No change RBT 150? mg 2-3/7 nevirapine 200 mg bd RBT 300 mg od efavirenz 600 mg od RBT 450 mg od

  45. Newer HIV drugs

  46. TB/HIVMany Challenges When to start Antiretroviral Therapy (ART) What ART to start Drug interactions

  47. TBandHIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

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