TB-HIV co-infection treatment

Gary Maartens

Division of Clinical Pharmacology

UNIVERSITY OF CAPE TOWN
IYUNIVESITHI YASE...
ART in patients with TB co-infection:
current evidence

Gary Maartens

Division of Clinical Pharmacology

UNIVERSITY OF CA...
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

B...
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 glycoprot...
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...
“Unexpectedly, concomitant rifampicincontaining tuberculosis treatment reduced
apparent EFV clearance with a
corresponding...
EFV increases during TB Rx:
pharmacogenomics
• PK study in children
– Genetic slow metabolisers in 20%
– EFV concentration...
EFV vs NVP in TB patients
• Cohort study in patients with/without TB showed
EFV equal efficacy, but NVP outcomes worse
• C...
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%

Ampr...
Adjusted dose PIs & rifampicin:
healthy volunteers
• Very high rates of hepatitis reported in 3 healthy
volunteer studies ...
Double dose LPV/r with rifampicin:
HIV+ adults on 2nd line ART, VL <400
18
Study day 22

16

Double dose

Referent: Study ...
Adjusted dose LPV/r in kids with TB
• “Super boosting”(RTV:LPV = 1:1) resulted
in similar LPV trough concentrations to
con...
Rifabutin dose with PIs
RBT does not induce PI metabolism, but PIs inhibit RBT
Dose-related toxicity (uveitis, neutropenia...
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 co...
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/...
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
J...
Bedaquiline ARV interactions
• Extremely long T1/2 (almost 6 months)
• No clear relationship between plasma
concentrations...
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...
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...
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)

CAMEL...
ART & TB: what lies ahead?
• More data needed on PI use with rifampicin
• New TB drug-ARV interactions need to be
establis...
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TB-HIV Co-infection Treatment

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Gary Maartens

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

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  • This study was done in HIV+ volunteers (not with TB, subsequent study of 18 in PLOS One was in TB patients) Double dose LPV overcame effects of rif on LPV concentrationsNeed for more clinical data to assess tolerability of double dose LPV with TB therapyPharmaceutical companies won’t do PI-rif interactions following bad experience with HNVs
  • 150 mg daily results in higher concentration – risk of uveitis &amp; neutropenia (both dose related). 150 mg 3 × a week results in lower concentrations – risk of developing rifamycin resistance. Other doses need to be studied.
  • ART, antiretroviral therapy; BID, twice daily; EFV, efavirenz; RAL, raltegravir; TB, tuberculosis. Ian M. Sanne, MBBCH, FCP (SA): The REFLATE study, supported by the ANRS and conducted predominantly in Brazil, has been much awaited. This phase II trial evaluated alternative antiretroviral treatment options in combination with rifampicin-based tuberculosis treatment in patients with HIV/tuberculosis coinfection. A total of 154 patients were randomly assigned to receive the standard dose of raltegravir (400 mg twice daily), an escalated dose of raltegravir (800 mg twice daily), or standard care with efavirenz, all in combination with tenofovir, lamivudine, and a rifampicin-containing tuberculosis regimen.For more information about this study, go online to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/AIDS%202012/Tracks/Highlights%20From%20AIDS%202012/Capsules/THLBB01.aspx
  • ART, antiretroviral therapy; D/C = F, discontinuation equals failure; EFV, efavirenz; ITT, intent to treat; M = F, missing equals failure; RAL, raltegravir; VL, viral load. Ian M. Sanne, MBBCH, FCP (SA): Overall, the study results were similar in the 2 raltegravir-containing arms. Although no statistics were provided and the sample size is too small for statistical analysis, there was a numerical benefit in the proportion of patients with virologic suppression at 24 weeks for the raltegravir arms. In addition, the shorter time to HIV-1 RNA suppression with the integrase inhibitor regimens that we discussed earlier was again demonstrated in this study. What was not discussed was whether this influenced tuberculosis outcomes, which the investigators will be analyzing in the future. For example, it would be interesting to see whether an integrase-containing HIV regimen would affect the time to sputum conversion in patients with tuberculosis. The standard dose and the escalated dose of raltegravir provided similar results, which elicits the question of whether the lowest possible dose for therapeutic raltegravir activity has been identified. The pharmacokinetic data for this study were not presented, and we await those results with anticipation.For more information about this study, go online to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/AIDS%202012/Tracks/Highlights%20From%20AIDS%202012/Capsules/THLBB01.aspx
  • TB-HIV Co-infection Treatment

    1. 1. TB-HIV co-infection treatment Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
    2. 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. 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. 4. High incidence of TB on ART, Cape Town PLoS ONE 2012;7(3):e34156
    5. 5. ARV-TB drug interactions
    6. 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. 7. st 1 line regimen: Rifampicin-based Rx & NNRTIs
    8. 8. Impact of TB Rx on nevirapine PK Cohen K JAC 2008;61:389
    9. 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. 10. “Unexpectedly, concomitant rifampicincontaining tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure.”
    11. 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. 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. 13. Probability of suppressed viral load (<50cp/mL) Non-inferiority margin of 10% exceeded
    14. 14. 2nd line regimen: Rifampicin & boosted PIs
    15. 15. Rifampicin decreases AUC of all protease inhibitors PI Rifampicin Saquinavir 84% Atazanavir 95% Indinavir 89% Amprenavir 81% Lopinavir/ritonavir 75% CDC 2008
    16. 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. 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. 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. 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. 20. Raltegravir & rifampicin Wenning AAC 2009
    21. 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. 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. 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. 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. 25. When to start ART in TB? Earlier ART Deferred ART Risk of IRIS Risk of HIV disease progression
    26. 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. 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. 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. 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
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