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Dr Sam Walters

3 rd Annual Conference of the Children’s HIV Association ‘ Young People and HIV: Back to the Future’. Dr Sam Walters. Imperial College School of Medicine London. Friday 15 May, The Bridgewater Hall, Manchester. HIV/TB CO-INFECTION SAM WALTERS St MARY’S HOSPITAL IMPERIAL LONDON.

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Dr Sam Walters

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  1. 3rd Annual Conference of the Children’s HIV Association ‘Young People and HIV: Back to the Future’ Dr Sam Walters Imperial College School of Medicine London Friday 15 May, The Bridgewater Hall, Manchester

  2. HIV/TB CO-INFECTION SAM WALTERS St MARY’S HOSPITAL IMPERIAL LONDON

  3. 2007: ESTIMATED 13.7 x 106 TB CASES 9.27 x 106 new cases: 95% in developing world 1.37 x 106 HIV +ve (79% in SSA) 1.5 x 106 children DEATHS: 1.8 x 106: 1 every 15 seconds 98% in developing world 450,000 in children 460,000 HIV +ve (25%); ? in children NEW CASES 2007

  4. CASE 1: 10 yr boy -3/12 cough, fevers, Wt loss -lives in London with aunt -born in Zimbabwe, no early problems -4 yrs; chest infection; hospital 1 week -then frequent coughs; 7 yrs shingles -9 yrs came to UK after mother died of pneumonia -wasted, BCG scar -non-productive cough, T 38.30C, hepatosplenomegally -chest x-ray; L lower + R middle consolidation -HIV Ab +ve; CD4 120, VL 17,000 -Mantoux 6mm, IGRA (Quantiferon) +ve ISSUES; -needs ARVs -has he active or latent TB? (full treatment or chemoprophylaxis) -what drugs and when?

  5. CASE 2: 13 month girl in Zimbabwe -lives with grandmother, mother died with pneumonia 6/52 ago -FTT, ‘always ill’, diarrhoea, cough, thrush, hepatomegally -newly Ded HIV antibody +ve, CD4 awaited ISSUES; -what investigations/treatments are possible -has she got tuberculosis? -? needs ARVs -what drugs and when

  6. HIV-TB COINFECTION RARE RESOURCE-RICH USUALLY GOOD ACCESS TO HEALTH SERVICES USUALLY POOR SUBSAHARAN AFRICA SUBSAHARAN AFRICA Highest; Highest; HIV-TB COINFECTION COMMON - TB incidence rates - TB incidence rates - HIV incidence rates - HIV prevalence rates - children in SSA have greatest burden of - children in SSA have greatest burden of RESOURCE-POOR HIV-TB co-infection HIV-TB co-infection

  7. CHALLENGES IN DIAGNOSIS OF TB Symptoms of TB, overlap with HIV Chest X-ray, appearances overlap

  8. CHALLENGES IN DIAGNOSIS Symptoms, overlap with HIV Chest X-ray, appearances overlap Microbiological identification ‘Gold Standard’ -low sensitivity in children -pauci-bacillary -sputum collection difficult

  9. THE GREATEST BREAKTHROUGH SINCE LUNCHTIME

  10. INDUCED SPUTUM Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. H J Zar et al. Lancet, 2005; 365:130-134 ? better than gastric lavage

  11. INDUCED SPUTUM Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. H J Zar et al. Lancet, 2005; 365:130-134

  12. CHALLENGES IN DIAGNOSIS Symptoms, overlap with HIV Chest X-ray, appearances overlap Microbiological ‘Gold Standard’ -low sensitivity in children -pauci-bacillary -sputum collection difficult Algorithms

  13. -algorithms/score systems do not work with HIV

  14. -but:

  15. CHALLENGES IN DIAGNOSIS Symptoms, overlap with HIV Chest X-ray, appearances overlap Microbiological ‘Gold Standard’ -low sensitivity in children -pauci-bacillary -sputum collection difficult Algorithms Tuberculin skin test: TST

  16. DIAGNOSIS OF TB -TST (Tuberculin Skin Test) limited use in young children -worse if HIV infected -interpretation not improved with CD4 or other skin tests

  17. Diagnostic tests Microbiology Organism smear culture DNA Immunology Host response Tuberculin antigen-specific skin test (TST) production of IFN Histology

  18. Principal of T cell / IFN- based assays Whole blood or PBMC Assay with ELISPOT ESAT 6, CFP 10, TB 7.7 from MTB complex NOT BCG Each spot is an individual T cell that has released interferon gamma. Assay with ELISA Therefore more specific than tuberculin skin test

  19. What we need from IFN release assays: Better than TST -  sensitivity -HIV (immunocompromised)-young children -early infection -active and latent infection -  specificity -esp. with BCG vaccinated - good negative predictive value -active and latent infection -very young

  20. -sensitivity ELISPOT 73% >> TST 36%

  21. -in house IGRA assay -Red Cross Children’s Hospital, Capetown

  22. Two commercial IFN release assays T SPOT-TB QUANTIFERON GOLD-in-TUBE (TB 7.7) -distinguish between MTB infection and BCG exposure -expensive, laboratory infrastructure, trained personnel -do not distinguish between active disease and latent infection -not adequately validated in HIV-infected children

  23. TREATMENT CHALLENGES When to start Which drugs How long to treat TB

  24. WHEN TO START -tuberculosis; cannot delay -?HIV; Drug burden Additive toxicities IRIS(Immune Reconstitution Inflammatory Syndrome) or IRD (Immune Reconstitution Disease) -adverse consequence of restoration of pathogen- specific immune responses during early HAART -most frequently with mycobacterial infection -sub-clinical infection is ‘un-masked’ -partially treated infections deteriorate with HAART

  25. MACROPHAGE CD4 T-CELL MTB GRANULOMA FORMATION LIMITS MTB REPLICATION & SPREAD CD4 TH1 IL-2 IFN-g IL-12 Macrophage TNF-a ACTIVE DISEASE WHEN MTB REPLICATION PERSISTS INFLAMMATION  SYMPTOMS (IMMUNOPATHOLOGY)

  26. HIV INHIBITION of GRANULOMA FORMATION CD4 TH1 IL-2 IFN-g IL-12 Macrophage TNF-a  BACTERIAL LOAD & SPREAD BUT  INFLAMMATION  TISSUE DAMAGE  CLINICAL SYMPTOMS • CD4 lymphopaenia  IL2 mediated activation & proliferation

  27. HAART ENHANCED GRANULOMA FORMATION RESTORATION OF IMMUNE FUNCTION •  HIV viral load • CD4 cells • (initially memory CD45Ro in adults) * -FEVERS -RESPIRATORY DETERIORATION - LYMPHADENOPATHY -NEW LYMPHADENOPATHY - ABSCESS -EFFUSIONS SYMPTOMATIC DISEASE: IRIS (RESURGENCE OF IMMUNOPATHOLOGY)

  28. IRIS (sparse paediatric data) More likely if - ART started within 2/12 of TB treatment - advanced HIV (high viral load / low CD4) - good early response to ART (rapid ↓ in VL, ↑ CD4) So delay treatment for 2/12 ?

  29. 0 CD4<50 ART Awaiting ART 30 60 90 120 150 180 1.00 CD4<100 0.90 Immune Reconstitution Disease Mortality with active TB 0.80 Survival probability 0.70 0.60 0.50 Days from TB diagnosis 100 80 60 Risk TB IRD (%) 40 20 0 0-30 31-60 61-90 91-120 >120 Interval from TB treatment to ART Initiation (days) Stephen D. Lawn, Landon Myer, Linda-Gail Bekker, Robin Wood: CROI 07

  30. Early Mortality if ART Delayed IRIS with Early ART

  31. IRIS IN KIDS JO BURG -prospective 2005 – 2006, 162 ARV naïve < 2 yrs, initiated HAART -34/162 (21%) Ded with IRIS -onset median 16 days (range 7 - 115) -BCG IRIS 24/34 (71%); immunisation site/axillary lymphadenitis -TB IRIS 12/34 (41%); (-6 also with BCG ? BCGosis) -6 TB only median onset 34 days

  32. BCG IRIS

  33. IRIS MANAGEMENT (in UK, ? resourse-poor) (lack of controlled data) -delay ART for 2/12 (if possible 6/12) (but significant mortality in first 2/12) -symptomatic treatments, steroids

  34. WHICH DRUGS • -interactions • -unpredicted • -predicted • CYTOCHROME P450 HAEMOPROTEINS Metabolise thousands of endogenous and exogenous compounds, including drugs RIFAMPICIN Induces CY P450 3A4

  35. TREATMENT CHALLENGES RIFAMPICIN ARVs low levels → HIV resistance (long-term) ARVs high levels → toxicities (short-term) NRTIs mostly compatible - but triple NRTI regimens ↓ efficacy NNRTIs - AUC: Nevirapine ↓ 37%, ? ↑ by 30%, ? hepatotoxicity Efavirenz ↓ 26%, possibly OK Etravirine ↓ ? Induces hepatic CY P450 3A4

  36. RIFAMPICIN PROTEASE INHIBITORS PIs - mostly incompatible - can use Ritonavir (taste) - ? ↑ Ritonavir boost for Kaletra

  37. RIFAMPICIN • Resource-poor countries • - fixed dose ARV combination tabs may need • augmenting with individual component drugs • - use Efavirenz or Ritonavir + NRTIs • Resource-rich countries • - ↑ doses → TDM → adjust dosing • - rifabutin (instead of rifampicin) • (↓ rifabutin dose with PIs, check with NNRTIs) • Maintaining simultaneous treatment • -adherence • -overlapping side-effects • -pill burden • -continued drug supply • -intact health systems • -health of parent

  38. ? RIFAMPICIN DOSING TOO LOW

  39. TREATMENT CHALLENGESHow long; ? 6 months treatment (no controlled trials) -recurrence is common; ≈ 10% -1/3 due to relapse

  40. PREVENTION CHALLENGES(Resource-poor countries) • -INH prophylaxis -significant ↓ TB and mortality, ? INH resistance -supported by Cochrane review 2009 Jan 21;(1):CD006418

  41. PREVENTION CHALLENGES(Resource-poor countries) • -BCG -does not work Disseminated BCG >> in HIV infected children WHO Jan 07;BCG vaccine should not be used in children known to be HIV-infected

  42. WE NEED MORE GREATEST BREAKTHROUGHS SINCE LUNCHTIME We desperately need an effective TB vaccine

  43. XDR-TB: EXTENSIVE DRUG RESISTANT TB -resistance to INAH and Rifampicin, any fluoroquinolone and 1 of the injectable drugs (amikacin, capreomycin, kanamycin) -USA 2006; 4% of MDR TB isolates met XDR criteria -Latvia 2006; 19% of MDR TB isolates met XDR criteria 51 KWAZULU NATAL

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