HIV-TB co-infection: overview and recent update

Transcription

1 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

2 HIV prevalence in patients with TB Madhi SA, et al. Int J Tuberc Lung Dis 2000;4(5): Kiwanuka J, et al. Ann Trop Paediatr 2001;21:5-14 Jeena P, et al. Int Tub ercj Lung Dis 2002;6(8): Schaaf HS, et al. BMC Infect Dis 2007;7:140 Paediatric studies: HIV prevalence in TB Madhi 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%]

3 TB risk in HIV-infected children Hesseling A, et al. Clin Infect Dis 2009;48:

4 Effect of cart on TB risk Reconstitution of specific antimycobacterial immunity Kampmann B, et al. AIDS 2006; 20: Tena-Coki N, et al. Am J Respir Crit Care Med 2010 Mar 11. [Epub ahead of print] Ref Design TB incidence rate / TB risk 1 Cohort (n=1132) SA 2 Cohort (n=6535) DRC 3 Cohort (n=364) Kenya Pre-cART: 21.1 / 100 py vs on cart: 6.4 / 100 py a crude reduction of 70% On cart: 7.2 / 100 py vs not on-cart: 22.2 / 1 py; IRR for cart = 0.32 [ ] Adjusted for other factors, cart was associated with marked reduction in TB risk; AHR: 0.15 [ ] On-cART: 10.2 / 100 py vs not on-cart: 20.4 / 100 py Model-estimated TB Hazard ratio for cart: 0.51 [ ] 1 Martinson NA, et al. Int J Tuberc Lung Dis 2009;13(7): ; 2 Braitstein P et al. P Infect dis J 2009;28: Edmonds A, et al. Int J Epidemiol 2009;38:

5 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

6 Diagnostic certainty Definite TB Probable TB Possible 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 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 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

7 Impact of HIV on TB diagnosis History including contact history Symptoms consistent with TB Examination including growth NB because of poor sensitivity of TST Lower specificity due to overlap between symptoms of TB & HIV High proportion of patients with short duration of symptoms Lower specificity because malnutrition common in TB & HIV Tuberculin skin testing Lower sensitivity; TST positivity with immunosuppression Bacteriological confirmation Investigations relevant for suspected PTB and EPTB Chest radiograph findings Important but beyond capabilities of many clinicians Lacks sensitivity Wide range of diagnostic possibilities because of other HIV-related disease Lower specificity: overlap with HIVrelated disease Adapted from: WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)

8 Culture-confirmed TB

9 Interferon- release assays (IGRAs) Reference Results Liebeschuetz (2004) Davies (2009) 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 + 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: Mandalakas AM, et al. Int J Tuberc Lung Dis 2008;12; Gallant CJ, et al. Chest 2010;137: Connell TG, et al. BMC Infect Dis 2010;10:138

10 Newer (potential) diagnostic tests Microscopic 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: Swaminthan S et al. Clin Infect Dis 2010;50(S3):S184-S194 Wallis RS, et al. Lancet 2010;375: Lawn, et al. AIDS 2009;23:

11 HIV testing rates in TB patients

12 Recommended TB regimens TB disease Intensive phase Regimen Continuation phase New smear-negative PTB 2HRZ 4HR Less severe forms EPTB [LN disease, pl effusion] New smear positive PTB with extensive parenchymal involvement 2HRZ 2HRZE 4HR 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

13 National ART Guidelines 2010 Preventive therapy ART & concomitant TB 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 mg/kg/day should be administered for 4 months 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/m 2 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, 2 nd Edition, 2010

14 Double dose LPV/r and rifampicin cotreatment in children Variable TB/HIV controls p value Male : Female 4:11 16: Age (years) 1.25 (1.03,2.08) 1.59 (1.15,2.23) Weight (kg) 8.8 (7.0,10.3) 10.6 (8.4,12.6) BSA (m 2 ) 0.43 (0.36,0.48) 0.48 (0.40,0.54) C pre (mg/l) 0.63(0.11,1.62) 4.25(3.42,8.10) C max (mg/l) 4.45(2.51, 8.22) 7.94(6.86,13.4) AUC 0-8h (mg.h/l) 22.29(13.78,65.50) 48.33(40.78,86.56) McIlleron H, et al. CROI, February 2009

15 NVP and rifampicin co-treatment Thai study (n=8); mean age (range): 9.7 ( ) yrs; dosing with FDC (upper end NVP dose range: mg/m 2 /dose) resulted in appropriate NVP exposure 1 Ugandan study (n=20; 7 on anti-tb Rx) mean age (range): 5.0 ( ) yrs : Only 3/7 (43%) on FDC plus TB medication achieved adequate NVP trough level > 3 mg/l 2 Zambian study (n=21);median age (range): 1.55 ( ) yrs; mean daily dose 353 mg/m2; median (range) pre-dose concentration (C 0 ): 2.93 ( )mg/L; C 0 <3.0 mg/l in 57%of children with TB and in 0% of children without TB 3 1 Prasitsuebsai W, et al. 16 th CROI, poster 908, Montreal, February Barlow-Mosha L, et al. 16 th CROI, poster 909, Montreal, February Oudijk JM, et al. 5 th IAS Conference, Cape Town, 2009, LBPEB10

16 New Global Treatment Guidelines and Research Gaps

17 WHO Recommendations, 2010 Infants and children diagnosed with TB & HIV 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 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 Strength of recommendation Strong Conditional Conditional Conditional Conditional Quality of evidence Very low Very low Very low Very low Very low WHO, ART guidelines, 2010 revision ;

18 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 ART 2 Mortality associated with IRIS is low 3 Recent observational data in children support this guideline 4 1 Harries AD, et al. Lancet 2010;375: Fitzgereald D. 5 th IAS conference, Cape Town, July 2009; WESY201 3 Castelnuovo B, et al. Clin Infect Dis 2009;49: Yotebieng M et al. AIDS 2010;24:

19 Children with HIV & TB (2) 1 st line ART > 3 yrs: 2 NRTIs + EFV South Africa: C min < 1 mg/ml in 50% on Std. EFV doses 1,2 EFV C min was similar during and after TB medication 2 Burkina Faso: 9/48 (19%) had C min < 1 mg/ml; 8/9 < 15 kg representing 44% of all children < 15 kg 3 Thailand: 8/63 (13%) had [EFV] < 1 mg/ml (measured hrs after last dose); no correlation between [EFV] and virological response 4 Revised doses proposed, based on West African results 3 WHO revised doses in latest guidelines 5 1 Ren Y, et al. JAIDS 2007;45(2): Ren Y, et al. JAIDS 2009;50(5): Hirt D, et al. Antimicrob Agents Chemother 2009;53: Puthanakit T, et al. Antivir Ther 2009;14:

20 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 metabolism 1 LPV/r boosted with additional RTV maintained LPV C min > 1 mg/ml in 13/15 children aged 7 mo -3.9 yrs 2 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 C min < 1 mg/ml 3 Boosted LPV/r associated with good 6 & 12 months VL outcomes 4 WHO recommendation: RTV 50 mg heat stable sprinkle / tablet 5 1 La Porte CJL, et al. Antimicrob Agents Chemother 2004;48: Ren Y, et al. J Acquir Immune Defic Syndr 2008;47: McIlleron H, et al (submitted) 4 Moodley M, et al. 17 th CROI 2010, paper #

21 Optimal dosages of TB drugs Isoniazid 1 Study: n=56, 22 (39%) HIV+, median age: 3.22 (IQR: ) years At a dose of 4-6 mg/kg/day: C max was < 3mg/L in 70% of children At a dose of 8-12 mg/kg/day: All children achieved a C max > 3mg/L Multivariate analysis: NAT2 genotype but not age, sex or HIV status was associated with C max Rifampicin 2 Prospective study: 21 HIV+ children mean age: 3.73 yrs and 33 HIVchildren 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: Schaaf S, et al. BMC Med 2009;7:19

22 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) (300 mg) Rifampicin 8-12 (600 mg) (600 mg) Pyrazinamide (2000 mg) Ethambutol Children: Adults: (1200 mg) Streptomycin (1000 mg) WHO, WHO/HTM/TB/ , 2006 WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft)

23 Duration of TB treatment month regimen recommended Some national guidelines: 9 months for PTB & 12 months for EPTB Most HIV-infected children respond to 6-month regimen month regimen, then evaluate whether complete resolution has occurred If there is inadequate response continuation of therapy may be required Variable 3 Treatment failure, arr (95% CI) p Relapse, arr (95% CI) p Death during TB treatment, arr (95% CI) p Duration of rifampicin therapy 2 Months 1.3 ( ) ( ) ( ).03 6 Months 1.0 ( ) 2.4 ( ) 1.0 ( ) 8 Months 1.0 (reference) 1.0 (reference) 1.0 (reference) Intermittent therapy Initial phase daily 1.0 (reference) (reference) (reference).42 Initial phase thrice weekly 4.0 ( ) 4.8 ( ) 1.3 ( ) Receipt of ART Some or all patients 1.0 (reference) (reference) (reference).39 None or not started 3.8 ( ) 3.5 (0.5-26) 0.8 ( ) 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/ , WHO & IUATBLD, Guidance for national tuberculosis & HIV programmes, 2010 (near-final draft) 3 Khan FA, et al. Clin Infect Dis 2010;50:

24 Drug-resistant TB Prevalence of childhood MDR-TB is increasing 1 Treatment based on the approach in adults 2 MDR-TB: Optimal regimen & duration 3 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 months 4 Optimal dosing in drug-resistant TB? New drugs TMC207 phase II RCT results 5 PA-824 [nitroimidazo-oxazine] and OPC [nitroimidazo-oxazole] are currently in clinical trials 6 Chemoprophylaxis efficacy trials? 7 1 Schaaf HS, et al. Am J Public Health 2009;99: Chiang C-Y, et al. Int J Tuberc Lung Dis 2010;14: Orenstein EW, et al. Lancet Infect Dis 2009;9: Dheda K, et al. Lancet 2010;375: Diacon AH, et al N Engl J Med 2009;360: Ma Z, et al. Lancet 2010;375: Sneag DB, et al. Pediatr Infect Dis J 2007;26:

25 Conclusions New global guidelines for treating children coinfected 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