tb - diagnosis, treatment & controversies in paediatric...

Presented at the 2nd International Workshop on HIV Pediatrics16-17 July 2010, Vienna Austria

TB TB -- diagnosis, treatment & diagnosis, treatment & controversies in paediatric HIV controversies in paediatric HIV

infectioninfection

Brian EleyPaediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital

School of Child and Adolescent Health

University of Cape Town


TB risk in HIVTB risk in HIV--infected childreninfected children

Hesseling A, et al. Clin Infect Dis 2009;48:108-114


HIV prevalence in patients with TBHIV prevalence in patients with TB

http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdfMadhi SA, et al. Int J Tuberc Lung Dis 2000;4(5):448-454Kiwanuka J, et al. Ann Trop Paediatr 2001;21:5-14Jeena P, et al. Int Tub ercJ Lung Dis 2002;6(8):672-678Schaaf HS, et al. BMC Infect Dis 2007;7:140

Paediatric studies: HIV prevalence in TBMadhi S, et al. (2000): 68/161 [42%]Kiwanuka, et al. (2001): 72/102 [70.6%]Jeena P, et al. (2002): 57/118 [48%]Schaaf S, et al: (2007): 133/414 [32.1%]


Effect of Effect of cARTcART on TB riskon TB risk

Ref Design TB incidence rate / TB risk

1 Cohort(n=1132)

SA

Pre-cART: 21.1 / 100 py vs on cART: 6.4 / 100 py a crude reduction of 70%

2 Cohort(n=6535)

DRC

On cART: 7.2 / 100 py vs not on-cART: 22.2 / 1– py; IRR for cART = 0.32 [0.26-0.40]Adjusted for other factors, cART was associated with marked reduction in TB risk; AHR: 0.15 [0.12-0.20]

3 Cohort (n=364)Kenya

On-cART: 10.2 / 100 py vs not on-cART: 20.4 / 100 pyModel-estimated TB Hazard ratio for cART: 0.51 [0.27-0.94]

• Reconstitution of specific antimycobacterial immunityKampmann B, et al. AIDS 2006; 20:1011-1018Tena-Coki N, et al. Am J Respir Crit Care Med 2010 Mar 11. [Epub ahead of print]

1 Martinson NA, et al. Int J Tuberc Lung Dis 2009;13(7):862-867; 2 Braitstein P et al. P Infect dis J 2009;28:626-6323 Edmonds A, et al. Int J Epidemiol 2009;38:1612-1621


Approach to TB diagnosis Approach to TB diagnosis

• History (Contact, symptoms consistent with TB)• Clinical examination (including growth

assessment)• Tuberculin skin testing• Bacteriological confirmation whenever possible• Investigations relevant for suspected PTB and

EPTB• Scoring systems• HIV testing (in high prevalence areas)

WHO, WHO/HTM/TB/2006.361, 2006


Impact of HIV on TB diagnosisImpact of HIV on TB diagnosis

History including contact history NB because of poor sensitivity of TSTSymptoms consistent with TB Lower specificity due to overlap between

symptoms of TB & HIVHigh proportion of patients with short duration of symptoms

Examination including growth Lower specificity because malnutrition common in TB & HIV

Tuberculin skin testing Lower sensitivity; TST positivity with immunosuppression

Bacteriological confirmation Important but beyond capabilities of many cliniciansLacks sensitivity

Investigations relevant for suspected PTB and EPTB

Wide range of diagnostic possibilities because of other HIV-related disease

Chest radiograph findings Lower specificity: overlap with HIV-related disease

Adapted from: WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)


CultureCulture--confirmed TB confirmed TB


InterferonInterferon-- release assays (release assays (IGRAsIGRAs))Reference Results

Liebeschuetz(2004)

HIV-infected with confirmed/probable TB:HIV-: 88/103 [85%] ELISPOT+ vs 64/91 [70%] TST+

HIV+: 22/30 [73%] ELISPOT+ vs 9/25 [36%] TST+

Davies (2009) HIV-infected with confirmed/probable TB:HIV+: 25/39 [64%] ELISPOT+ vs 10/34 [29%] TST+

Limitations•Expense•ELISPOT & Quantiferon assays produce discordant results•In the absence of clinical & radiological signs IGRAs do not distinguishbetween latent TB infection and active disease

•Discordance between TST and In vitro assays suggest that these are complementary measures of antimycobacterial immunity

•Minimal study of the kinetics of IGRA responses in HIV-infected childrenLiebeschuetz S, et al. Lancet 2004;364:2196Davies M, et al. AIDS 2009;23:961-969Mandalakas AM, et al. Int J Tuberc Lung Dis 2008;12;417-423

Gallant CJ, et al. Chest 2010;137:1071-1077Connell TG, et al. BMC Infect Dis 2010;10:138


Newer (potential) diagnostic testsNewer (potential) diagnostic testsMicroscopic visualisation of bacteria: FM, LED & Bleach microscopy

Automated liquid culture systems: BACTEC MIGIT 960, ALERT 3D

Microscopic-observation drug-susceptibility (MODS) assay

Nucleic acid amplification tests (NAAT): loop-medicated isothermal amplification (TB-LAMP), test, GenoType MTBDRplus assay, Geno Type MTBDRsl, Inno-LiPA Rif TB Line probe assay, GeneXpert MTB

Antigen detection tests: LAM ELISA urinary antigen test

Antibody detection (serological) assays

Experimental approaches: host proteomic & gene expression signatures, TB protein arrays

Perkins MD, et al. J Infect Dis 2007;196(Supp 1):S15-S27Pai M, et al. Sem Respir Crit Care med 2008;29:560-568Swaminthan S et al. Clin Infect Dis 2010;50(S3):S184-S194

Wallis RS, et al. Lancet 2010;375:1920-1937Lawn , et al. AIDS 2009;23:1875-1880


HIV testing rates in TB patientsHIV testing rates in TB patients

http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf


WHO Recommendations, 2010WHO Recommendations, 2010Isoniazid (INH) Preventive Therapy (IPT) Strength of

recommendationQuality of evidence

All HIV-infected infants & children exposed to TB through household contacts, but with no evidence of active disease, should begin IPT

Strong Very low

Children living with HIV (>12 months of age and including those previously treated for TB) who are not likely to have active TB, and are not known to be exposed to TB should receive 6 months of IPT as part of a comprehensive package of care

Strong Moderate

Infants living with HIV who are unlikely to have active TB and are not known to be exposed, should not receive IPT as part of a comprehensive package of care

Conditional Very low

The recommended dose of INH for preventive therapy in HIV co-infection is 10 mg/kg/daily for 6 months (maximum 300 mg/day)

WHO, ART guidelines, 2010 revision


IPT in HIVIPT in HIV--infected childreninfected children• Exposure through household contact

– Missed opportunities: 117/182 (64.3%) of children who developed culture-confirmed TB did not receive IPT1

– IPT & drug-resistant contacts2

• No routine IPT for infants– Phase II/III trial [PACTG 1041]:INH 10-20mg/kg/day vs placebo – n=452 infants enrolled at 3-4 months of age, 266 / group– 28% were on ART at baseline, and 66% at the interim analysis– After median follow-up of 36 wks, 39 (17.3%) and 32 (14.2%) in

INH and placebo groups respectively had developed TB or died, p=0.34

– Conclusion: IPT did not improve disease-free survival in infants enrolled at 3-4 months of age3

1 Schaaf HS, et al. BMC Infect Dis 2007;7:1402 Sneag DB, et al. Pediatr Infect Dis J 2007;26:1142-11463 Madhi SA, et al. 48th ICAAC, October 2008, abstract G2-1346a


IPT in HIVIPT in HIV--infected children (2)infected children (2)• Routine IPT for children > 12 months

– RCT (INH [10mg/kg/day] vs placebo)1

• n=263 > 8 wks of age [median age: 24.7 months]; 9% on ART • median follow-up: 5.7 mo [IQR: 2.0-9.7]• All-cause mortality was lower in INH arm (8% vs 16%, HR=0.46, CI:0.22-

0.95, p=0.015)• Incidence of TB was lower in INH arm (3.8% vs 9.9%, HR=0.28, CI:0.1-0.78,

p=0.005) – Efficacy of IPT in children on ART not known, although synergy has

been demonstrated in adult studies2,3

– Operational concerns: (1) Exclusion of active TB, (2) Optimal duration of prophylaxis unkown (3) INH-related hepatic failure4

• INH dose for IPT [10 mg/kg/day]– At dose of 8-12 mg/kg/day an acceptable Cmax of > 3 mg/L is achieved5

1 Zar H, et al. Br Med J 2007;334:136-1422 Golub JE, et al. AIDS 2007;21:1441-14483 Golub JE, et al. AIDS 2009;23:631-636

4 Wu SS, et al. Transplantation 2007;84:173-1795 Mcilleron H, et al. Clin Infect Dis 2009;48:1547-1553


WHO Recommendations, 2010 (2)WHO Recommendations, 2010 (2)Infants and children diagnosed with TB & HIV Strength of

recommendationQuality of evidence

Any child with active TB disease should begin TB treatment immediately, and start ART as soon as tolerated in the first 8 weeks of TB therapy, irrespective of CD4 count and clinical stage

Strong Very low

The preferred first-line ART regimen for infants & children < 3 years of age who are taking a rifampicin-containing regimen for TB is 2 NRTIs + NVP or a triple nucleoside regimen


The preferred first-line ART regimen for children > 3 years of age who are taking a rifampicin-containing regimen for TB is 2 NRTIs + EFV


The preferred first-line ART regimen for infants < 2 years of age who have been exposed to NVP and are taking a rifampicin-containing regimen for TB is a triple NRTI regimen


HIV-infected infants & children who develop TB on ART

For all children, anti-TB therapy should be started immediately upon the diagnosis of TB; ART should continue


Make adjustments to ART regimens as needed to decrease the potential for toxicities and dug interactions;•If on a regimen of 2 NRTIs + NVP, substitute EFV for NVP if child is ≥ 3 years•If on a regimen of 2 NRTIs + NVP and substitution with EFV is not possible, increase NVP to maximum dose•If on a regimen containing LPV/r, consider adding RTV to 1:1 ratio LPV:RVT to achieve full therapeutic dose

WHO, ART guidelines, 2010 revision


Children with TB & HIVChildren with TB & HIV

• Start TB therapy & ART within 8 weeks– ART in HIV-TB coinfected adults mortality risk by

64-95%1

– Mortality rate 4-fold and TB rate 2-fold in patients on deferred vs early ART2

– Mortality associated with IRIS is low3

– Recent observational data in children support this guideline4

1 Harries AD, et al. Lancet 2010;375:1906-19192 Fitzgereald D. 5th IAS conference, Cape Town, July 2009; WESY201

3 Castelnuovo B, et al. Clin Infect Dis 2009;49:965-9724 Yotebieng M et al. AIDS 2010;24:1341-1349


Children with TB & HIV (2)Children with TB & HIV (2)

• 1st line ART < 3yrs: 2 NRTIs + NVP / 3 NRTIs– NVP containing regimens:

• Thai study (n=8); mean age (range): 9.7 (4.4 – 11.8) yrs; dosing with FDC (upper end NVP dose range: 150-220 mg/m2/dose) resulted in appropriate NVP exposure1

• Ugandan study (n=20; 7 on anti-TB Rx) mean age (range): 5.0 (1.2 – 11.3) yrs : Only 3/7 (43%) on FDC plus TB medication achieved adequate NVP trough level > 3 mg/L2

• Zambian study (n=21);median age (range): 1.55 (0.66 – 3.18) yrs;mean daily dose 353 mg/m2; median (range) pre-dose concentration (C0): 2.93 (1.06-11.4)mg/L; C0 <3.0 mg/L in 57%of children with TB and in 0% of children without TB3

1 Prasitsuebsai W, et al. 16th CROI, poster 908, Montreal, February 2009 2 Barlow-Mosha L, et al. 16th CROI, poster 909, Montreal, February 20093 Oudijk JM, et al. 5th IAS Conference, Cape Town, 2009, LBPEB10


Children with TB & HIV (3)Children with TB & HIV (3)• 1st line ART > 3 yrs: 2 NRTIs + EFV

– South Africa: Cmin < 1 mg/ml in 50% on Std. EFV doses1,2

– EFV Cmin was similar during and after TB medication2

– Burkina Faso: 9/48 (19%) had Cmin < 1 mg/ml; 8/9 < 15 kg representing 44% of all children < 15 kg3

– Thailand: 8/63 (13%) had [EFV] < 1 mg/ml (measured 12-16 hrs after last dose); no correlation between [EFV] and virological response4

– Revised doses proposed, based on West African results3

– WHO revised doses in latest guidelines5

1 Ren Y, et al. JAIDS 2007;45(2):133-1362 Ren Y, et al. JAIDS 2009;50(5):439-4433 Hirt D, et al. Antimicrob Agents Chemother 2009;53:4407-4413

4 Puthanakit T, et al. Antivir Ther 2009;14:315-3205 WHO, ART guidelines, 2010 revision


Children with TB & HIV (4)Children with TB & HIV (4)• 1st line ART < 2 yrs + NVP exposed: 3 NRTIs

– SA: virological failure in 7/15 children after 24 wks of ART1

– USA: 3 NRTIs associated with delayed virologic control (< 1 log10 VL drop after 12wks in 86%) and poor longer term virologic control (> 400 copies/ml in 44% after 24 wks and in 69% after 48 wks)

– Italian study: Children suppressed on PI-containing regimen and switched to 3 NRTIs: 19/20 maintained VL <50 c/ml for 96 wks3

– No studies evaluating 3 NTRIs in TB-co-infected children

1 Bobat R, et al. 4th IAS Conference, 2007, TUPEB0532 Neely M, et al. 17th CROI, February 2010; Poster #8793 Palma P, et al. AIDS 2007;21:2465-2472


Children who develop TB on ARTChildren who develop TB on ART• LPV/r-based regimens during TB treatment

– Adults studies: Boosted LPV/r or double dose LPV/r may overcome the effects of rifampicin on LPV metabolism1

– LPV/r boosted with additional RTV maintained LPV Cmin > 1 mg/ml in 13/15 children aged 7 mo -3.9 yrs2

– No data on boosted LPV/r in children aged < 6 months– Double-dose LPV/r results in sub-optimal [LPV]: pre-dose [LPV]

reduced in 80% of children with TB and 12/20 (60%) had Cmin < 1 mg/ml3

– Boosted LPV/r associated with good 6 & 12 months VL outcomes4

– WHO recommendation: RTV 50 mg heat stable sprinkle / tablet

• Role of rifabutin remains unclear– Concerns: (1) limited efficacy data in HIV-infected adults, (2)

expense, (3) dosing modifications with RTV-co-treatment, (4) paediatric formulations & dosing and efficacy studies5,6

1 La Porte CJL, et al. Antimicrob Agents Chemother 2004;48:1553-15602 Ren Y, et al. J Acquir Immune Defic Syndr 2008;47:566-5693 McIlleron H, et al. 2010 (submitted)

4 Moodley M, et al. 17th CROI 2010, paper #1605 Cochrane Database Syst Rev 2007;4:CD0051596 Maartens G, et al. Antivir Ther 2009;14:1039-1043


Optimal dosages of TB drugsOptimal dosages of TB drugs• Isoniazid1

– Study: n=56, 22 (39%) HIV+, median age: 3.22 (IQR: 1.58-5.38) years– At a dose of 4-6 mg/kg/day: Cmax was < 3mg/L in 70% of children– At a dose of 8-12 mg/kg/day: All children achieved a Cmax > 3mg/L– Multivariate analysis: NAT2 genotype but not age, sex or HIV status

was associated with Cmax

• Rifampicin2

– Prospective study: 21 HIV+ children – mean age: 3.73 yrs and 33 HIV-children – mean age 4.05 yrs

– Mean dose of 9.61 mg/kg: 2-hour rifampicin concentrations were 3.9 and 4.8 l/ml in HIV+ and HIV- children respectively

– After 4 months of treatment: 3(6%) had 2-hour RMP concentration >8 l/ml and 25 (43%) were < 4 l/ml

1 McIlleron H, et al. Clin Infect Dis 2009;48:1547-15532 Schaaf S, et al. BMC Med 2009;7:19


WHO daily recommended dosagesWHO daily recommended dosagesDrug 2006

Daily dosage in mg/kgRange (maximum)

2010Daily dosage in mg/kg

Range (maximum)Isoniazid 4 - 6 (300 mg) 10 – 15 (300 mg)

Rifampicin 8 -12 (600 mg) 10 – 20 (600 mg)

Pyrazinamide 20 - 30 30 – 40 (2000 mg)

Ethambutol Children: 15 – 25Adults: 15 – 20

15 – 25 (1200 mg)

Streptomycin 12 - 18 12 – 18 (1000 mg)

WHO, WHO/HTM/TB/2006.361, 2006WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)


Duration of TB treatmentDuration of TB treatment20061 •6-month regimen recommended

•Some national guidelines: 9 months for PTB & 12 months for EPTB•Most HIV-infected children respond to 6-month regimen

20102 •6-month regimen, then evaluate whether complete resolution has occurred •If there is inadequate response continuation of therapy may be required

Variable3 Treatment failure, aRR (95% CI)

p Relapse, aRR(95% CI)

p Death during TB treat-ment, aRR (95%

CI)

p

Duration of rifampicin therapy

2 Months 1.3 (0.4-0.41) .67 3.6 (1.1-11.7) .14 1.8 (1.0-3.1) .03

6 Months 1.0 (0.4-2.8) 2.4 (0.8-7.4) 1.0 (0.6-1.6)

≥ 8 Months 1.0 (reference) 1.0 (reference) 1.0 (reference)

Intermittent therapy

Initial phase daily 1.0 (reference) .02 1.0 (reference) .002 1.0 (reference) .42

Initial phase thrice weekly 4.0 (1.5-10.4) 4.8 (1.8-12.8) 1.3 (0.7-2.3)

Receipt of ART

Some or all patients 1.0 (reference) .10 1.0 (reference) .21 1.0 (reference) .39

None or not started 3.8 (0.9-16.4) 3.5 (0.5-26) 0.8 (0.5-1.5)

Dispersion parameter for model 0.3 (-0.1 to 0.7) 0.22 (-0.04 to 0.53) 0.13 (-0.02 to 0.31)1 WHO, WHO/HTM/TB/2006.361, 20062 WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)3 Khan FA, et al. Clin Infect Dis 2010;50:1288-1299


DrugDrug--resistant TBresistant TB• Poor countries do not have routine access to DST• Prevalence of childhood MDR-TB is increasing1

• Treatment based on approaches in adults2

• MDR-TB: Optimal regimen & duration3

– Individualised regimens had higher treatment success [64%, CI: 59-68%] than standardised regimens [54%, CI: 43-68%]

• Outcome XDR-TB: 19% culture conversion rate, 70% within 6 months4

• New drugs– TMC207 phase II RCT results5

– PA-824 [nitroimidazo-oxazine] and OPC-67683 [nitroimidazo-oxazole] are currently in clinical trials6

• Chemoprophylaxis efficacy trials7

1 Schaaf HS, et al. Am J Public Health 2009;99:1486-14902 Chiang C-Y, et al. Int J Tuberc Lung Dis 2010;14:672-6823 Orenstein EW, et al. Lancet Infect Dis 2009;9:153-1614 Dheda K, et al. Lancet 2010;375:1798-1807

5 Diacon AH, et al N Engl J Med 2009;360:2397-24056 Ma Z, et al. Lancet 2010;375:2100-21097 Sneag DB, et al. Pediatr Infect Dis J 2007;26:1142-1146


ConclusionConclusion

• New guidelines for treating children co-infected with HIV and TB are an improvement on previous recommendations and helps to refocus the research agenda

• Further study is required to resolve outstanding controversies. Priority questions include:– Optimal ART strategies in children co-treated with

rifampicin– Optimal duration of TB treatment– Optimal doses of TB drugs

tb - diagnosis, treatment & controversies in paediatric...

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