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TB-HIV Co-infection Treatment

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Published on February 18, 2014

Author: HopkinsCFAR

Source: slideshare.net

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Gary Maartens

December 7, 2013
Main Session, Inter-CFAR Sub-Saharan Africa Biannual Meeting
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TB-HIV co-infection treatment Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD

ART in patients with TB co-infection: current evidence Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD

TB in patients starting ART Khayelitsha, Cape Town 45 40 35 30 % 25 20 15 10 5 0 2001/2 2003 2004 2005 2006 2007 Boulle AIDS 2010;24:563

High incidence of TB on ART, Cape Town PLoS ONE 2012;7(3):e34156

ARV-TB drug interactions

Rifampicin induction Enzyme/transporter ARV substrate CYP3A4 (55.1-fold) CYP2B6 (8.8-fold) PIs, NVP EFV, NVP P glycoprotein PIs UGT1A1 Raltegravir Dolutegravir J Pharmacol Exp Ther 2001;299:849

st 1 line regimen: Rifampicin-based Rx & NNRTIs

Impact of TB Rx on nevirapine PK Cohen K JAC 2008;61:389

TB Rx effect on EFV PK • Package insert says AUC reduced 26% (n=12, healthy volunteers, only rifampicin, no P value) – FDA recommend increase dose to 800 mg • PK studies in patients with TB show no significant effect: – – – – Spain South African adults (2 studies) & children India STRIDE study Clin Pharmacokinet 2002;41:681 JAC 2006;58:1299 Antivir Ther 2009;14;687 JAIDS 2009;50:439 AAC 2009;53:863 Clin Infect Dis. 2013;57(4):586

“Unexpectedly, concomitant rifampicincontaining tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure.”

EFV increases during TB Rx: pharmacogenomics • PK study in children – Genetic slow metabolisers in 20% – EFV concentrations increased 49% during TB Rx in slow metabolisers – Likely due to inhibition by INH of CYP2A6 • STRIDE: Cmin trend higher on TB therapy, significantly higher in blacks – Pharmacogenomic study underway Clin Infect Dis. 2013;57(4):586-93 AIDS. 2013 Jul 31;27(12):1933-40.

EFV vs NVP in TB patients • Cohort study in patients with/without TB showed EFV equal efficacy, but NVP outcomes worse • CARINEMO study RCT of EFV vs NVP in TB – CD4 <250 – ART naive – Non-inferiority – NVP lead-in dose omitted Boulle JAMA 2008;300:53 Lancet Infect Dis 2013;13: 303

Probability of suppressed viral load (<50cp/mL) Non-inferiority margin of 10% exceeded

2nd line regimen: Rifampicin & boosted PIs

Rifampicin decreases AUC of all protease inhibitors PI Rifampicin Saquinavir 84% Atazanavir 95% Indinavir 89% Amprenavir 81% Lopinavir/ritonavir 75% CDC 2008

Adjusted dose PIs & rifampicin: healthy volunteers • Very high rates of hepatitis reported in 3 healthy volunteer studies (Saquinavir, Atazanavir, Lopinavir); all stopped early due to toxicity • ?relevant to HIV+ patients – rif + PZA for LTBI well tolerated in HIV+, but not HIVArch Drug Inf. 2009 Mar;2(1):8-16 AIDS 2008;22:931-5 JAIDS 2009;50:290-3 CID 2004;39:561

Double dose LPV/r with rifampicin: HIV+ adults on 2nd line ART, VL <400 18 Study day 22 16 Double dose Referent: Study day 1 Lopinavir (mg/L) 14 12 10 8 6 4 2 Recommended trough in ART-naive 0 0 2 4 6 8 10 12 Time (hours) 2/21 asymptomatic grade 3/4 ALT 0/18 grade 3/4 ALT in TB patients Need to evaluate darunavir-r interaction with rif Decloedt AAC 2011;55:3195 Decloedt PLoS ONE 7(3): e32173

Adjusted dose LPV/r in kids with TB • “Super boosting”(RTV:LPV = 1:1) resulted in similar LPV trough concentrations to controls • Double dose PLV/r failed: 60% of children with TB were sub-therapeutic – Study stopped early by DSMB • Studies of other dosing strategies needed McIlleron Anitivir Ther 2011;16:417 JAIDS 2008;47:566

Rifabutin dose with PIs RBT does not induce PI metabolism, but PIs inhibit RBT Dose-related toxicity (uveitis, neutropenia) 2 PK studies of RBT: 150 mg/d vs 150 mg 3 × a week on LPV-r Compared with RBT 300 mg daily without PI 150 mg daily 150 mg 3 × week South Africa AUC0-48 AUC0-48 Viet Nam Steady state 32% 52% 45% Steady state 30% 25-O-desacetyl-RBT metabolite (active against TB) ACTG RCT rifampicin vs RBT (3 × a week) with LPV-r in TB patients underway Naiker CROI 2012 Huy Dung IAS 2013

Raltegravir & rifampicin Wenning AAC 2009

ANRS REFLATE: EFV- vs RAL in TB • Multicenter, randomized, open-label phase II trial – Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24 Wk 244 Primary endpoint Wk 4848 Raltegravir 400 mg BID + Tenofovir + Lamivudine (n = 51) Antiretroviral-naive pts initiating rifampincontaining therapy* for TB coinfection (N = 154) Raltegravir 800 mg BID + Tenofovir + Lamivudine (n = 51) Raltegravir 400 mg BID + Tenofovir + Lamivudine Efavirenz + Tenofovir + Lamivudine (n = 52) *Rifampin-containing therapy initiated before ART and consisted of rifampin, isoniazid, pyrazinamide, and ethambutol for 2 mos, followed by rifampin and isoniazid for 4 mos. Grinsztejn B, et al. AIDS 2012. Abstract THLBB01.

Virologic Suppression at Wk 24 Pts with VL < 50 c/mL (%) 100 RAL 400 mg RAL 800 mg EFV 80 78 76 67 60 ITT; M = F, D/C = F 40 Virologic Failure at Wk 24 0 0 2 4 8 RAL 400 (n = 51) RAL 800 (n = 51) EFV (n = 51) VL > 50 c/mL, n (%) 20 12 (24) 4 (8) 15 (29) 12 16 20 24 Wks Grinsztejn B, et al. AIDS 2012. Abstract THLBB01. Clinical Care Optrions.

Dolutegravir-rifampicin DTG 50 mg 12 hourly + rif DTG 50 mg daily AUC0-24 DTG 50 mg/d 32.1 DTG 50 mg 12 hly + rif 42.6 JAIDS 2013;62:21

Bedaquiline ARV interactions • Extremely long T1/2 (almost 6 months) • No clear relationship between plasma concentrations & effect/toxicity • Healthy volunteer studies data modelled to estimate steady state show: – EFV reduces BDQ 48% – NVP no significant effect – LPV/r increases BDQ 286% • Urgent need for data in patients AAC 2013;57:2780. Svensson et al. 2013, Int Workshop Clin Pharmacol TB drugs, abstract 28

When to start ART in TB? Earlier ART Deferred ART Risk of IRIS Risk of HIV disease progression

ART timing in TB: RCT’s primary endpoints Death p=0.006 Death/AIDS p=0.45 Death/AIDS p=0.73 Median CD4 25 N Engl J Med 2011;365:1471 N Engl J Med 2011;365:1482 N Engl J Med 2011;365:1492

AIDS/death by CD4 CD4 counts Early ART Later ART Comparison (95%CI) SAPiT <50 8.5/100 py 26.3/100 py IRR 0.32 (0.07, 1.13) ≥50 6.6/100 py 4.4/100 py IRR 1.51 (0.61, 3.95) STRIDE <50 15.5% 26.6% +11.15 (1.5, 20.5) ≥50 11.5% 10.3% -1.2 (-6.7, 4.3)

TB-IRIS by ART timing Study Early ART Later ART Comparison SAPiT 19.5/100 py 7.5/100 py IRR 2.6 (1.5 to 4.8) CAMELIA 58.2/100 py 20.4/100 py P<0.0001 STRIDE 11% 5% P=0.02 STRIDE: “IRIS management required ≥ 1 invasive procedures in 34.4%, hospitalization in 31.1% and corticosteroids in 54.1%.” SAPiT: IRIS milder & of shorter duration in later ART group Ann Intern Med. 2012;157:313 AIDS 2013, 27:2577 N Engl J Med 2011;365:1482 Luetkemeyer JAIDS in press

ART & TB: what lies ahead? • More data needed on PI use with rifampicin • New TB drug-ARV interactions need to be established • If RCTs to prevent TB-IRIS (NSAIDs, low dose steroids) are successful, this may allow safe earlier ART use • New TB drug regimens likely to clear antigens faster, which should IRIS risk, and earlier ART initiation may be safer

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