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TB-HIV co-infection treatment Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
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TB-HIV Co-infection Treatment

Dec 05, 2014

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HopkinsCFAR

Gary Maartens

December 7, 2013
Main Session, Inter-CFAR Sub-Saharan Africa Biannual Meeting
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Page 1: TB-HIV Co-infection Treatment

TB-HIV co-infection treatment

Gary Maartens

Division of Clinical PharmacologyUNIVERSITY OF CAPE TOWNIYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD

Page 2: TB-HIV Co-infection Treatment

ART in patients with TB co-infection:

current evidence

Gary Maartens

Division of Clinical PharmacologyUNIVERSITY OF CAPE TOWNIYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD

Page 3: TB-HIV Co-infection Treatment

TB in patients starting ARTKhayelitsha, Cape Town

2001/2 2003 2004 2005 2006 20070

5

10

15

20

25

30

35

40

45

Boulle AIDS 2010;24:563

%

Page 4: TB-HIV Co-infection Treatment

High incidence of TB on ART, Cape Town

PLoS ONE 2012;7(3):e34156

Page 5: TB-HIV Co-infection Treatment

ARV-TB drug interactions

Page 6: TB-HIV Co-infection Treatment

Rifampicin induction

Enzyme/transporter ARV substrate

CYP3A4 (55.1-fold)CYP2B6 (8.8-fold)

PIs, NVPEFV, NVP

P glycoprotein PIs

UGT1A1 RaltegravirDolutegravir

J Pharmacol Exp Ther 2001;299:849

Page 7: TB-HIV Co-infection Treatment

1st line regimen:

Rifampicin-based Rx & NNRTIs

Page 8: TB-HIV Co-infection Treatment

Impact of TB Rx on nevirapine PK

Cohen K JAC 2008;61:389

Page 9: TB-HIV Co-infection Treatment

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;41:681JAC 2006;58:1299Antivir Ther 2009;14;687JAIDS 2009;50:439AAC 2009;53:863Clin Infect Dis. 2013;57(4):586

Page 10: TB-HIV Co-infection Treatment

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

Page 11: TB-HIV Co-infection Treatment

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):586-93AIDS. 2013 Jul 31;27(12):1933-40.

Page 12: TB-HIV Co-infection Treatment

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;300:53Lancet Infect Dis 2013;13: 303

Page 13: TB-HIV Co-infection Treatment

Probability of suppressed viral load (<50cp/mL)

Non-inferiority margin of 10% exceeded

Page 14: TB-HIV Co-infection Treatment

2nd line regimen:

Rifampicin & boosted PIs

Page 15: TB-HIV Co-infection Treatment

Rifampicin decreases AUCof all protease inhibitors

RifampicinPI

Saquinavir

Atazanavir

Indinavir

Amprenavir

Lopinavir/ritonavir

84%

95%

89%

81%

75%

CDC 2008

Page 16: TB-HIV Co-infection Treatment

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 HIV-

Arch Drug Inf. 2009 Mar;2(1):8-16AIDS 2008;22:931-5JAIDS 2009;50:290-3CID 2004;39:561

Page 17: TB-HIV Co-infection Treatment

Decloedt AAC 2011;55:3195Decloedt PLoS ONE 7(3): e32173

Double dose LPV/r with rifampicin: HIV+ adults on 2nd line ART, VL <400

2/21 asymptomatic grade 3/4 ALT0/18 grade 3/4 ALT in TB patients Need to evaluate darunavir-r interaction with rif

0

2

4

6

8

10

12

14

16

18

0 2 4 6 8 10 12

Lopi

navi

r (m

g/L)

Time (hours)

Study day 22

Referent: Study day 1

Recommended trough in ART-naive

Double dose

Page 18: TB-HIV Co-infection Treatment

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;16:417JAIDS 2008;47:566

Page 19: TB-HIV Co-infection Treatment

Rifabutin dose with PIsRBT 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

25-O-desacetyl-RBT metabolite (active against TB)

ACTG RCT rifampicin vs RBT (3 × a week) with LPV-r in TB patients underway

150 mg daily 150 mg 3 × week

South Africa AUC0-48 52% AUC0-48 45%

Viet Nam Steady state 32%

Steady state 30%

Naiker CROI 2012Huy Dung IAS 2013

Page 20: TB-HIV Co-infection Treatment

Raltegravir & rifampicin

Wenning AAC 2009

Page 21: TB-HIV Co-infection Treatment

• Multicenter, randomized, open-label phase II trial– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

Antiretroviral-naive pts initiating rifampin-

containing therapy* for TB coinfection

(N = 154)

Raltegravir 400 mg BID +Tenofovir + Lamivudine

(n = 51)

Raltegravir 800 mg BID +Tenofovir + Lamivudine

(n = 51)

Efavirenz +Tenofovir + Lamivudine

(n = 52)

Wk 244Primary endpoint

Wk 4848

Raltegravir 400 mg BID +Tenofovir + Lamivudine

*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.

ANRS REFLATE: EFV- vs RAL in TB

Grinsztejn B, et al. AIDS 2012. Abstract THLBB01.

Page 22: TB-HIV Co-infection Treatment

Virologic Failure at Wk 24

RAL 400 (n = 51)

RAL 800(n = 51)

EFV(n = 51)

VL > 50 c/mL, n (%) 12 (24) 4 (8) 15 (29)

Virologic Suppression at Wk 24

Grinsztejn B, et al. AIDS 2012. Abstract THLBB01. Clinical Care Optrions.

RAL 400 mgRAL 800 mg

EFV

100

80

60

40

20

0

Pts

wit

h V

L <

50

c/m

L (

%)

240 2 4 8 12 16 20

Wks

ITT; M = F, D/C = F

7876

67

Page 23: TB-HIV Co-infection Treatment

Dolutegravir-rifampicin

JAIDS 2013;62:21

DTG 50 mg 12 hourly + rif

DTG 50 mg daily

AUC0-24 DTG 50 mg/d 32.1DTG 50 mg 12 hly + rif 42.6

Page 24: TB-HIV Co-infection Treatment

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

Page 25: TB-HIV Co-infection Treatment

When to start ART in TB?

Risk of IRIS

Risk of HIV disease progression

EarlierART

DeferredART

Page 26: TB-HIV Co-infection Treatment

ART timing in TB:RCT’s primary endpoints

Death/AIDSp=0.45 Death/AIDS

p=0.73

Deathp=0.006

MedianCD4 25

N Engl J Med 2011;365:1471N Engl J Med 2011;365:1482N Engl J Med 2011;365:1492

Page 27: TB-HIV Co-infection Treatment

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)

Page 28: TB-HIV Co-infection Treatment

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

Ann Intern Med. 2012;157:313AIDS 2013, 27:2577N Engl J Med 2011;365:1482Luetkemeyer JAIDS in press

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

Page 29: TB-HIV Co-infection Treatment

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