HIV-TB co-infection: overview and recent update Brian Eley Paediatric Infectious Diseases Unit Red Cross War Memorial Children’s Hospital School of Child and Adolescent Health University of Cape Town
HIV-TB co-infection: overview
and recent update
Brian Eley
Paediatric Infectious Diseases Unit
Red Cross War Memorial Children’s Hospital
School of Child and Adolescent Health
University of Cape Town
HIV prevalence in patients with TB
http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf
Madhi SA, et al. Int J Tuberc Lung Dis 2000;4(5):448-454
Kiwanuka J, et al. Ann Trop Paediatr 2001;21:5-14
Jeena P, et al. Int Tub ercJ Lung Dis 2002;6(8):672-678
Schaaf 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%]
TB risk in HIV-infected children
Hesseling A, et al. Clin Infect Dis 2009;48:108-114
Effect of cART on 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 py
Model-estimated TB Hazard ratio for cART: 0.51 [0.27-0.94]
• Reconstitution of specific antimycobacterial immunityKampmann B, et al. AIDS 2006; 20:1011-1018
Tena-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
• 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
Diagnostic certainty
Definite TB Isolation of Mycobacterium tuberculosis on culture of sputum,
gastric washings, CSF or tissue from a site that is normally
sterile e.g. bone marrow, lymph node or other tissue
Probable TB Symptoms or signs consistent with TB plus two or more of the
following: known TB contact, TST 10mm, acid fast bacilli on
microscopy, chest radiograph findings consistent with PTB or
CSF findings CT scan findings consistent with TBM, and a
good response to treatment
Possible TB Symptoms or signs consistent with TB plus one of the
following: known TB contact, TST 10mm, chest radiograph
findings consistent with PTB or CSF findings CT scan
findings consistent with TBM, and a good response to
treatment
Impact of HIV on TB diagnosis
History including contact history NB because of poor sensitivity of TST
Symptoms consistent with TB Lower specificity due to overlap between
symptoms of TB & HIV
High 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 clinicians
Lacks 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)
Culture-confirmed TB
Interferon- release assays (IGRAs)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
• ‘Rule-in’ vs ‘rule-out’
•ELISPOT & Quantiferon assays produce discordant results
•In the absence of clinical & radiological signs IGRAs do not distinguish
between 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 children
Liebeschuetz S, et al. Lancet 2004;364:2196
Davies M, et al. AIDS 2009;23:961-969
Mandalakas AM, et al. Int J Tuberc Lung Dis 2008;12;417-423
Gallant CJ, et al. Chest 2010;137:1071-1077
Connell TG, et al. BMC Infect Dis 2010;10:138
Newer (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-S27
Pai M, et al. Sem Respir Crit Care med 2008;29:560-568
Swaminthan S et al. Clin Infect Dis 2010;50(S3):S184-S194
Wallis RS, et al. Lancet 2010;375:1920-1937
Lawn , et al. AIDS 2009;23:1875-1880
HIV testing rates in TB patients
http://www.who.int/tb/publications/global_report/2009/pdf/full_report.pdf
Recommended TB regimens
TB disease Regimen
Intensive phase Continuation phase
New smear-negative PTB 2HRZ 4HR
Less severe forms EPTB [LN
disease, pl effusion]
2HRZ 4HR
New smear positive PTB with
extensive parenchymal involvement
2HRZE 4HR
Severe concomitant HIV infection 2HRZE 4HR
TB meningitis 6 HRZEo [Double the standard doses]
H=Isoniazid, R=rifampicin, Z=pyrazinamide, E=ethambutol, Eo=ethionamide
WHO, WHO/HTM/TB/2006.361, 2006
National ART Guidelines 2010
Preventive therapy • Routine TB prophylaxis for HIV-infected children is not
recommended
• All HIV-infected children, regardless of age should receive
INH x 6 months if exposed to close adult contact with PTB
• In the source case is resistant to INH, rifampicin 10-15
mg/kg/day should be administered for 4 months
ART & concomitant
TB
• If a child in on EFV, do not change the ARVs and add
standard TB therapy
• If the child is on LPV/r add additional RTV at a dose of 0.75
x the volume of the LPV/r dose
• In older children taking LPV/r the dose may be doubled
to roughly 600 mg/m2 of LPV (this is similar to the adult
guidelines)
• If the child in on NVP, ALT must be monitored. If
hepatitis develops refer to an expert
• If the child is unable to tolerate the large number of tablets,
ART should be interrupted until TB therapy has been
completed
National Department of Health. Guidelines for the Management of HIV in Children, 2nd Edition, 2010
Double dose LPV/r and rifampicin co-
treatment in children
Variable TB/HIV controls p value
Male : Female 4:11 16:8 0.015
Age (years) 1.25 (1.03,2.08) 1.59 (1.15,2.23) 0.603
Weight (kg) 8.8 (7.0,10.3) 10.6 (8.4,12.6) 0.015
BSA (m2) 0.43 (0.36,0.48) 0.48 (0.40,0.54) 0.022
Cpre (mg/L) 0.63(0.11,1.62) 4.25(3.42,8.10) 0.0001
Cmax (mg/L) 4.45(2.51, 8.22) 7.94(6.86,13.4) 0.006
AUC0-8h (mg.h/L) 22.29(13.78,65.50) 48.33(40.78,86.56) 0.013
McIlleron H, et al. CROI, February 2009
NVP and rifampicin co-treatment
• 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
New Global Treatment
Guidelines and Research Gaps
WHO Recommendations, 2010Infants and children diagnosed with TB & HIV Strength of
recommendation
Quality 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
Conditional Very low
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
Conditional Very low
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
Conditional Very low
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
Conditional Very low
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 ;http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf
Children with HIV & TB
• 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 HIV & TB (2)
• 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 http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf
Children with HIV & TB (3)
• 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 / tablet5
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 http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf
Optimal 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 dosages
Drug 2006
Daily dosage in mg/kg
Range (maximum)
2010
Daily 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 – 25
Adults: 15 – 20
15 – 25 (1200 mg)
Streptomycin 12 - 18 12 – 18 (1000 mg)
WHO, WHO/HTM/TB/2006.361, 2006
WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)
Duration 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
Drug-resistant TB
• Prevalence of childhood MDR-TB is increasing1
• Treatment based on the approach 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
• Optimal dosing in drug-resistant TB?
• New drugs– TMC207 phase II RCT results5
– PA-824 [nitroimidazo-oxazine] and OPC-67683 [nitroimidazo-oxazole] are currently in clinical trials6
• Chemoprophylaxis efficacy trials?7
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
Conclusions
• New global guidelines for treating children co-infected with HIV & TB are an improvement on previous recommendations and help to refocus the research agenda
• The applicability of these revised guidelines in South Africa should be established
• Priority research questions include:– Optimal duration of TB treatment
– Optimal doses of second-line drugs