1. TB and HIV Management Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

2. TB incident cases in 2007 –9.27 million incident cases in 2007 Asia:55% Africa31% East Med6% East Euro5% Americas3% 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) TB Epidemiology

3. 3.TB incidence rate has been falling since 2004 –137 cases per 100,000 (2007) –142 cases per 100,000 (2004) 4.The rate of decline is less than 1% a year (generally) 5.TB Incident rates are falling in all regions except Eastern Europe 6.Of the total 9. 3 million new TB cases in 2007, 1.4 million also had HIV (TB/HIV cases) 7.15% of all TB cases in 2007 were co-infected with HIV 8.85% of all TB cases in 2007 were not co-infected with HIV 9.Out of the 15% TB cases co-infected with HIV: –Africa (79%) –South East Asia (11%) –Other regions (10%) Tb epidemiology

4. 10.Case detection rate reached 63% in 2007 –Americas (73%) –Western Pacific (77%) –South East Asia (69%) –Eastern Med. (60%) –Eastern Euro (51%) –Africa (47%) 11.Treatment success rate reached 85% in 2006 12.TB remains the leading cause of death among PLHIV 13.PLHIV are 20 – 30 times more likely to acquire TB than people without HIV 14.PLHIV with TB are highly vulnerable to MDR-TB and XDR-TB TB epidemiology

5. TB/HIV Many 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. START TB TREATMENT AND HAART SIMULTANEOUSLY START TB TREATMENT FIRST AND DELAY HAART PROS Lower risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm 3 ) Avoid overlapping side effects Avoid PK interactions Lower pill burden Lower risk of IRIS CONS Overlapping side effects PK interactions Higher pill burden Risk of immune reconstitution disease Higher risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm 3 ) Adapted from J Acquir Immune Defic Syndr 2007; 46: S9-S18. HAART in TB-HIV: Early or late?

8. When to Start ART: in TB Immediately? TB, HIV+ CD4<350 Or ?<200 TB TREATMENT ANTIRETROVIRAL THERAPY-WHEN? Months 126

9. Dont Wait till its too late Further 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. a) Awaiting ART ART 0.50 0.60 0.70 0.80 0.90 1.00 0306090120150180 Days from TB diagnosis Survival probability No difference in CD4 count or Stage 4 disease between those starting and not starting Mortality among patients with prevalent active TB (n=73) initiating ART Lawn S et al. CROI 2007;Abstract 81

11. 313 HIV-infected patients with 1 TB episode and who initiated HAART after TB diagnosis Mortality significantly lower at end of follow-up for patients with simultaneous <8W HAART/TB treatment vs delayed HAART Outcome at End of Follow-up Simultaneous HAART/TB (n = 140) Delayed HAART (n = 173) Mortality, %9.319.7* Other AIDS-defining conditions, %16.413.9 Median HIV-1 RNA, log10 copies/mL (IQR) 3.8 (2.0-4.6)2.8 (2.0-4.5) Median CD4+ cell count, cells/mm3 (IQR) 325 (136-482)321 (173-468) Velasco M, et al. JAIDS. 2009;50:148-152 *P =.011 vs patients who received simultaneous HAART/TB treatment.

12. SAPIT Study: Study design and intervention Open-label randomised controlled trial 3-arm randomisation: –ART initiated ASAP after diagnosis during intensive phase 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/mm 3 CD4 count 200 cells/mm 3 >200 cells/mm 3 Integrated arm # dead/ py (n) Mortality rate 23/281 (273) 8.2 (5.2–12.3) 2/185 (156) 1.1 (0.1–3.9) Sequential arm # dead/ py (n) Mortality rate 21/137 (138) 15.3 (9.57–23.5) 6/86 (75) 7.0 (2.6–15.3) Hazard ratio Cox regression 0.54 (0.34–0.98) p=0.04 0.16 (0.03–0.79) p=0.02 Karim SA et al. CROI 2009. Abstract 36a

14. SAPIT Study: Mortality in sequential arm occurred late Months After Randomization Survival 1.00 0.90 0.70 0.80 0.95 0.85 0.75 0123456789101112131415161718192021222324 Post –TB Treatment Continuation Phase of TB treatment Intensive Phase of TB treatment Sequential Arm Integrated Arm Kaplan-Meier Survival Curve Karim SA et al. CROI 2009. Abstract 36a.

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

16. Study design 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 Randomised, double blind Placebo controlled Patients n=253 15 years HIV-1+ 90% male, mostly IDU Clinically suspected TBM Randomisation stratified by TBM grade 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) 0 1.0 0.8 0.6 0.4 0.2 039126 Months since randomisation Placebo ARV Torok ME et al. ICAAC 2009. Abstract H-1224

18. Severe AEs Immediate ART (n=127) Deferred ART (n=126) P Grade 3 & 4 AE114 (89.8%)112 (88.9%)0.84 Grade 3 & 4 AEs 2 mths109 (85.8%)95 (75.4%)0.04 Grade 4 AE102 (80.3%)87 (69.1%)0.04 Grade 4 AEs 2 mths77 (60.6%)59 (46.8%)0.03 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/mm 3. 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/mm 3 and viral load 5.64 log copies/ml. Kaplan-Meier Survival Estimates Early Late Weeks After Randomization Probability of Survival 1.00 0.75 0.50 0.25 0.00 050100150200 Blanc F, et al. 18th IAC; Vienna, July 18-23, 2010; Abst. THLBB106. P=0.042

21. NPR/IRI S Follow-up time* Incidence** (95% CI) p Early arm3321102 728.54.03 (3.34 – 4.86) <0.0001 Late arm329483 333.51.44 (1.09 – 1.91) IRIS significantly more frequent in the early arm ANRS 1295/12160 - CIPRA KH001/10425 study * expressed in person-months ** per 100 person-months Time after TB treatment initiation (weeks)

22. When to start HAART BHIVA TB-coinfection Guidelines, consultation Draft 2010 CD4 count, cells/μLWhen to start HAART <100 As soon as practical 100–350 As soon as practical, but can wait until after completing 2 months TB treatment especially when there are difficulties with drug interactions, adherence and toxicities >350 At physician discretion 1

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

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 Metabolism Absorption Elimination Metabolism Rifampicin CYP3A4 PIs NNRTIs

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) –Nevirapine37 % decrease what dose? –Efavirenz26 % 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. N=32, ARV naïve, TB/HIV, smear pos, CD4<200, RIF 2-6 weeks 2 weeks4 weeks 12 weeks Prospective, randomized, multicenter, open-label, 2-arm study TDM of NVP 12 hr of NVP + Assessments: + + + 48 weeks 14 days 2-6 weeks of TB treatment 24weeks interim analysis ( GPOvir Z 1 tab po BID) Arm 1 : NVP 400 mg/day ( GPOvir Z 1 tab po BID) Lead in 14 days with NVP 200 QD ( GPOvir Z 1 tab po BID+ NVP 1tab QD) 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 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.

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

33. Efavirenz PK data Standard dose? Increased dose?

34. Population PK modeling in HIV-pts with TB treated with EFV and rifampicin Soy et al. 2005 EFV dose 30% increase (from 600 to 800) adequate Body weight important determinant on CL 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 % of patients 0 10 20 30 40 50 60 < 11-4> 4 Manisuthi et al. 2005 600mg800mg

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):1032-40.1032-40 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 dont 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 Ritonavir 400 bid required GI toxicity and lipid perturbation High rates of elevated transaminase 1 ( 5/7 dropouts) 1/10 low trough concentrations plus recent Pk study 2 -LFT problems Saquinavir/rit 1 La Porte, AAC, 2004 Berger AIDS. 2008 May 11;22(8):931-5. Early studies from SA suggested could be used SQV 1000/rit100 BID 39% hepatitis Transaminase elevations 20x upper normal 2 Arch Drug Inf. 2009 Mar;2(1):8-16.

41. PIRifampicinRifabutinComment ATV ATV C min by 93% (300/100), 80%(300/200), 60% (400/200) rifabutin AUC (205%) 1) Avoid co-adm. with rifampicin 2) Reduce rifabutin dose** FPV APV AUC by 82% rifabutin AUC (193%) 1) Avoid co-adm. with rifampicin 2) rifabutin dose*** or ** if boosted DRVNo Data do not use RBT and metabolite increase 1.5X and increase in DRV57% 1) Avoid co-adm. with rifampicin 2) rifabutin dose*** LPV/r LPV AUC by 75%; increased doses to 400/400 or 800/200 bid compensate rifabutin AUC (303%), 1) > toxicity during co-administration of rifampicin and increased dose of LPV/r 2) rifabutin dose** NFV NFV AUC by 82% NFV AUC by 32%; rifabutin AUC (207%) 1) Avoid co-adm. with rifampicin 2) TDM of NFV; rifabutin dose** SQV SQV AUC by 84%; induction partly compensate by SQV/r 400/400 mg bid SQV AUC by 43%; compensated by r 1) Hepatotoxicity during co- administration of rifampicin and SQV/r 2) rifabutin dose in presence of r** TPV/r TPV by 80% TPV; rifabutin AUC (190%), C max (70%), and C min (114%) 1) Avoid co-adm. with rifampicin 2) rifabutin dose** *25-O-desacetyl-rifabutin **150 mg every other day or 150 mg 3 times per week *** 150 mg every other day or 300 mg 3 times per week r = ritonavir; AUC = area under the curve; C max and C min = maximum and minimum concentrations; TDM = therapeutic drug monitoring

42. HAART Dose TB Dose therapy 4NRTINo change RIF No change nevirapine 200 mg bd RIF600 mg od efavirenz*6-800 mg od RIF 600 mg od TB Treatment Regimens RIFAMPICIN / HAART *Dose adjusted?

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

44. Can be administered With PIs Given at a dose of 150mg 3xWK 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 BenefitsLimitations What about Rifabutin?

45. TB Treatment Regimens Rifabutin HAART Dose TB Dose therapy 4NRTI No change RBT No change Boosted PI No changeRBT 150? mg 2-3/7 nevirapine 200 mg bdRBT 300 mg od efavirenz 600 mg odRBT450 mg od

46. PIRifampicinRifabutinComment TMC 125 No data Small decreases etravirine rifabutin 25-Odesacetylrifabutin use normal doses unless given with PI when 125 levels may be decreased significantly TMC 278 APV AUC by 82%AUC, Cmax and Cmin decr by 80/69/89%; Cmin by 49% Avoid co-adm. with rifampicin\ ?double dose 278 with rbt Ralte gravir reduced the Cmin AUC and C max of MK-0518 by 61%, 40% and 38% respectively no dose adjustment ?Avoid co-adm. with rifampicin-use with caution Elvite gravir Levels of EVR do not use Not done MRV6.6-fold increase in CYP3A4 induction with rifampin no dose adjustment Double dose of maraviroc may compensate DRVNot doneIncrease DRV (57%) Increase AUC of 25-O-da- rifabutin 881% increase AEs T20 No change Can use r = ritonavir; AUC = area under the curve; C max and C min = maximum and minimum concentrations; TDM = therapeutic drug monitoring Newer HIV drugs

47. TB/HIV Many Challenges When to start Antiretroviral Therapy (ART) What ART to start Drug interactions

48. TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK