Gary Maartens December 7, 2013 Main Session, Inter-CFAR Sub-Saharan Africa Biannual Meeting

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

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

3. 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

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

5. ARV-TB drug interactions

6. 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

7. st
1
line regimen:
Rifampicin-based Rx & NNRTIs

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

9. 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

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

11. 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.

12. 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

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

14. 2nd line regimen:
Rifampicin & boosted PIs

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

16. 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

17. 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

18. 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

19. 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

20. Raltegravir & rifampicin
Wenning AAC 2009

21. 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.

22. 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.

23. 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

24. 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

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

26. 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

27. 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)

28. 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

29. 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