TB-HIV co-infection treatment Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
TB-HIV co-infection treatment
Gary Maartens
Division of Clinical PharmacologyUNIVERSITY OF CAPE TOWNIYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
ART in patients with TB co-infection:
current evidence
Gary Maartens
Division of Clinical PharmacologyUNIVERSITY OF CAPE TOWNIYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
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
%
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, NVPEFV, NVP
P glycoprotein PIs
UGT1A1 RaltegravirDolutegravir
J Pharmacol Exp Ther 2001;299:849
1st 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;41:681JAC 2006;58:1299Antivir Ther 2009;14;687JAIDS 2009;50:439AAC 2009;53:863Clin Infect Dis. 2013;57(4):586
“Unexpectedly, concomitant rifampicin-containing 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):586-93AIDS. 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;300:53Lancet 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 AUCof all protease inhibitors
RifampicinPI
Saquinavir
Atazanavir
Indinavir
Amprenavir
Lopinavir/ritonavir
84%
95%
89%
81%
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 HIV-
Arch Drug Inf. 2009 Mar;2(1):8-16AIDS 2008;22:931-5JAIDS 2009;50:290-3CID 2004;39:561
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
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
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
Raltegravir & rifampicin
Wenning AAC 2009
• 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.
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
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
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?
Risk of IRIS
Risk of HIV disease progression
EarlierART
DeferredART
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
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
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
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