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25 August, 2009 Report on TB sub-meeting from IAS Andreas Jahn

25 August, 2009 Report on TB sub-meeting from IAS Andreas Jahn. Catalysing HIV/TB Research: Innovation, Funding and Networking. WHO TB/HIV Working Group of the Stop TB Partnership and Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) Cape Town, 18-19 July 2009

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25 August, 2009 Report on TB sub-meeting from IAS Andreas Jahn

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  1. 25 August, 2009 Report on TB sub-meeting from IAS Andreas Jahn

  2. Catalysing HIV/TB Research:Innovation, Funding and Networking WHO TB/HIV Working Group of the Stop TB PartnershipandConsortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) Cape Town, 18-19 July 2009 Lessons Learnt from an IAS Satellite Meeting

  3. Session Overview • Funding landscape • Highlights from presentations • TB diagnostics • TB vaccines • Prevention: IPT • Community TB case finding • Combining ART and TB Rx • TB in mothers and children • MDR and XDR TB • Immune Reconstitution Syndrome (IRIS) • Research questions • Your proposals and ideas? • What was proposed at the meeting

  4. The Scale of TB and HIV • 1.37 million new TB cases in the HIV+ in 2007 • 79% of TB-HIV disease is in sub-Saharan Africa • 29% of all cases in South Africa alone • 15% of global TB burden is in HIV+ • TB is the main OI: 23% of AIDS mortality • Main threat to ART success • Zambia: • Active TB at ART initiation: NOT risk factor for mortality • Developing TB after ART start: MUCH HIGHER risk of mortality • Lawn, Churchyard. Curr Opin HIV AIDS 2009; 4(4): 325-33

  5. Funding: Investment into HIV • USD 39 Billion cumulative funding for HIV (NIH) • 200,560 HIV-related publications in PubMed as of July 2009 • Almost normal life expectancy with HIV in rich nations: >69 years if infected at age 20 (Lancet) • 4 million people in developing world received ART

  6. Funding: Investment into TB • USD 665,000 for TB Research (1985 NIAID) • Consequences of inattention to TB research: • TB research has been left behind by technology advances • 9 million active TB cases per year but no effective vaccine against PTB • No new drugs licensed in decades • Cumbersome regimens with high risk of DR • Antiquated diagnostics, non standardised, imprecise

  7. Slide from: AS Fauci: Research on TB and HIV/AIDS: Progress and Challenges

  8. Slide from: AS Fauci: Research on TB and HIV/AIDS: Progress and Challenges

  9. TB Diagnostics

  10. TB Diagnostics

  11. TB Vaccines BCG Pros • 77% efficacy against military TB (Big meta-analysis) • 75% efficacy against disseminated and CNS TB in children Cons • BCG ineffective against adult PTB in Africa • BCG IRIS rate of 10-15% in ART roll-out programs • Disseminated BCG disease in HIV infected infants • 1% risk 1) with high case fatality • Needs high index suspicion: GA, Bct, BM, PCR 1) Hesseling et al: Bull WHO DOI: 10.2471/BLT.08.055657 2009

  12. TB Vaccines BCG WHO revised guidelines not practical and feasible “Children with HIV infection regardless of symptoms should not be BCG vaccinated” • Asymptomatic HIV infected child at later risk of disseminated BCG • How to rule out HIV infection? • Maternal antibody masks antibody tests • Detection of virus required (PCR, p24 Ag?) • Very difficult to implement in many places

  13. TB Vaccines Innovations • Desperately need new vaccine for infants, latently infected adults • Making BCG safer • rBCG30 is more immunogenic • Not replicating • AD 35 viral vector • Introduced TB Ag • Not replicating in humans • Can result in very high CD8 response • Vaccine response can be much better if introduced in the lung

  14. TB Vaccines Innovations • 4 TB vaccines currently being tested in Africa • 2 recombinant proteins • 2 non-replicating viral vectored vaccines • Initial trials in PLWH: 2 of 4 are safe and immunogenic • Another about to enter large-scale safety and proof of principle efficacy trials in adults with HIV, most are latently infected with TB • Efficacy trial of another recently begun in infants in South Africa • Expect clinical use of adjuvanted proteins and new viral vectors in next 2 years

  15. Prevention: IPT • SA trial: Reduction in TB AND all-cause mortality in young children • Concurrent CPT may explain non-specific mortality effect co-trimoxazole • Non-specific effect because of undiagnosed TB? • IPT improves survival on ART (Golub, AIDS 2009, 23:661) • IPT after exposure is more effective than primary prophylaxis • Maybe cost-effective to target children in households with HIV or TB • National programs include IPT for children <5 years but implementation lacking

  16. Prevention: IPT • Not teratogenic • Hepatotoxicity • Abnormal liver enzymes :1-25% • Symptomatic liver disease 5.2 per 1000 patients in a study where 20,838 given INH for 12 mo. • Risk factors age, alcohol, underlying liver disease including chronic Hep B • Hepatoxicity when combined with HAART in pregnancy unknown • Breastmilk: safe Concentration 1% up to 20% • Generally safe in children • Most first line drugs safe in pregnancy except aminoglycosides and quinolones

  17. Community TB Case Finding • Conducted by mass X-ray 1930-50s • Moved to ‘passive case finding’: Most TB cases were symptomatic and can be picked up at the health facility if DOTS works well • Move back to active case finding in poorly functioning health services and high HIV? • Increasing case detection from 50% to 67% and decreasing detection from 6 to 4 months will have dramatic effect on TB incidence (math model)

  18. Community TB Case Finding ZAMSTAR Community randomized trial • Sputum collection within 30mins from home and smear result in 48 hrs • ‘Open access sputum collection’ – like VCT • 21% of TB cases were detected through the intervention • TB community case finding is feasible, cheap intervention but cost effectiveness has not yet been analysed as impact not yet known • Treatment completion rates were similar in both clusters

  19. Community TB Case Finding DetecTB CRT in Zimbabwe • 70 % of TB cases in Zimbabwe (DetecTB) had not presented to health services although they lived within 2km of health facilities. • Reasons: ‘hunger, being worn out by hard work, long queues, too busy to queue, insulted by health workers, being too weak to go.’

  20. Community TB Case Finding Research Questions • Feasible / sustainable / costs? • Which method? • Linkage with case finding of HIV • Replacement of clinic activity? • Impact? • Does it reduce the prevalence or transmission of TB at community level?

  21. TB Risk Throughout HIV Infection and ART Source: Havlir DH: Catalyzing HIV and TB Research (Presentation)

  22. ART as TB Intervention • TB incidence inversely related to CD4 count: both on and off ART • Starting ART at CD4 200-350 reduces TB incidence and mortality (CIPRA HT 001, Haiti) • 18 new TB cases in patients who started at CD4 200-350 • 36 new TB cases in patients starting at CD4 <200 • ART effect on individual and population TB incidence depends on level of initial and sustained CD4 count • ART has potential to reverse 10 years of rising TB incidence

  23. ART as TB Intervention • Start ART at CD4 count 500 to impact population TB incidence? • But: • Overlapping drug side effects • PK interactions • High pill burden • Risk of IRIS

  24. Combining TB Rx and ART • Rifampicin • Reduces NVP below effective levels in 50% of patients • Very strong interaction with PI: need to double LPV, but even that in children insufficient • EFV not significantly reduced • 1.7 fold risk of viral failure if ART is started on TB Rx • No sub-therapeutic NVP levels when starting TB Rx on ART • No major risk of increased toxicity • NVP is better than EFV in Africa

  25. Combining TB Rx and ART • Rifabutin now on WHO essential drugs list • Challenge to implement added TB regimen in peripheral clinics • Urgently need studies on toxicity and PK for PI and rifampicin as in future many patients will be on 2nd line.

  26. Combining TB Rx and ART: Research Questions • Timing of ART and TB Rx • Coordination between programs: who and where for ART + TB Rx • Hepatotoxicity & PK of “super-boosted” PIs needs to be defined in adults with HIV-TB coinfection • Effectiveness studies in adults & children • Rifabutin not currently an option – need for more evidence of efficacy vs rifampicin in HIV-TB coinfection • Alternative regimens (triple NRTI, double dose raltegravir)

  27. TB in Children Risk of disease progression • Age • 43% of infants (children < 1year) • 25% of children aged one to five years • 15% of adolescents • Recent infection (1-2 years) • Malnutrition • HIV Marais, 2004, Nelson, 2005

  28. TB in HIV Infected Children • High risk of TB infection and disease • Diagnostic challenges • Co-morbidities • Bacteriological confirmation: Immune suppression, paucibacillary • Infection vs. disease

  29. TB / HIV in Mothers and Infants: Epidemiology • 15% of maternal deaths due to HIV/TB • Postpartum TB higher in women with low CD4, high VL, pos. TST • Active maternal TB increases HIV transmission • 25-fold increased TB progression risk in HIV+ infants • 52% of HIV+ children in Kayelitsha TB infected (ELISPOT) by age 4 • 1% of HIV+ children develop disseminated BCG disease (but not in those on ART) • EPTB is in fact lower in HIV+ than in HIV- children

  30. TB / HIV in Mothers and Infants: Diagnosis • HIV in household is good proxy for TB exposure in Western Cape • Symptoms often unspecific • Paucibacillary disease • MGIT: faster and more sensitive than conventional culture • CXR: difficult, can be misleading • TST • Novel diagnostics: IGRAs

  31. TB / HIV in Mothers and Infants: Management • WHO has released paediatric TB guidelines • IPT for all children who are TB household contacts: 40% will otherwise get infected • 30% increase of NVP dose needed for children on rifampicin • But: CD4 and VL studies using FDC (showing inadequate PK) were not different • Poor VL outcomes with PIs on TB Rx, even doubling the dose of LPV/r did not lead to adequate doses • INH use 10mg/kg • Rifa use 15mg/kg • In WHO Stage 3 and 4: start TB Rx and start ART within 2-8 weeks

  32. TB / HIV in Mothers and Infants • Focus on PMTCT of TB as TB diagnosis in infants is so difficult • TB screening should be included in PMTCT • Symptom screening found 2% of HIV+ mums had TB (South Africa) • CXR not useful in pregnancy in addition to clinical screening • TST poor sensitivity in pregnancy • TB culture from placenta? • INH should be offered routinely to HIV+ pregnant women • not teratogenic • poss. increased risk of heamorrhagic infant disease • unclear risk of hepatotoxicity

  33. TB / HIV in Mothers and Infants Research Questions • Best TB screening methods in PMTCT settings? • Role of TST, IGRAs, sputum, CXR,… • New TB drugs for pregnant & lactating women • Safety, tolerability • PK and drug interactions • Safety and efficacy of IPT in mother • Antenatal or postnatal • Timing of IPT initiation in young children • Difficult to rule out TB in infants

  34. TB / HIV in Mothers and Infants Research Questions • Rifabutin for children • Unknown efficacy • What dosage / formulations? • What inclusion criteria for TB drug trials for children • Only bacteriologically confirmed vs. clinically diagnosed? • Timing of BCG vaccination needs to be re-evaluated

  35. MDR and XDR TB • MDR (Multi drug resistanant) TB • Resistance to at least INH and Rifampicin • XDR (Extensively drug resistant) TB • MDR, and • Resistance to fluoroquinolones, and • One second-line injectable drug (amikacin, kanamycin, capreomycin)

  36. MDR and XDR TB

  37. MDR and XDR TB

  38. MDR and XDR TB • 511,000 MDR TB cases globally (2007) • Mainly China, India, Russia, South Africa • 50,000 XDR TB cases • Africa: No clear association between HIV and MDR TB • Excluding outbreaks • Russia: risk factors were previous TB Rx and HIV+ • Only 3% of MDR cases are expected to be treated in 2009 (WHO) • Most African countries don’t diagnose because they can’t treat!

  39. MDR and XDR TB • Most die before diagnosis (culture) is made • 16 days median survival of XDR TB in South Africa • Most XDR TB is from recent transmission! (Genotyping) • Clear evidence: insufficient Rx of MDR has led to XDR • Long delay in diagnosis and Rx start • Inadequate treatment options • Poor infection control • Evidence for TB transmission in health care settings • Half of XDR TB cases in recent outbreak in South Africa • Health care workers at 5 fold increased TB risk

  40. MDR and XDR TB New WHO guideline for TB infection control (July 2009) • Culture + DST • Lymphocyte Proliferation Assays • PICT • Empirical treatment for MDR in HIV+: • At least 4 drugs • Include injectables • Do not use cipro • BUT: ART may be the only effective treatment in our settings

  41. MDR and XDR TB Research Questions • Epidemiology • What is the true incidence? • Tip of the iceberg: high early mortality and difficult diagnosis • 10-20% of MDR diagnosis can be lab cross-contamination • How and where is drug resistance being created/transmitted? • Drug quality? • Health system/patient management failures? • Transmission in health care facilities, eg ART clinics, community?

  42. MDR and XDR TB Research Questions • Diagnosis • What are the best diagnostic algorithms for MDR-TB patients with HIV? • Impact of new diagnostic technologies: LPA, GenXpert • Best model of ICF for TB in HTC, ART clinics and the community? • Can cell phones be used to accelerate communication of diagnosis?

  43. MDR and XDR TB Research Questions • Treatment • Where and how can MDR-TB be best managed? Hospital vs community • How can TB patients better access ART? • Drug interactions between 2nd line anti-TB drugs and ARVs

  44. MDR and XDR TB Research Questions • Infection control • How to separate infectious cases from susceptible contacts in a health facility / at home • Do surgical masks on patients work? • Do respirators on staff and visitors work? • How can behaviour change in HCWs be encouraged and maintained? • What indicators should be used?

  45. TB IRIS • 20% of TB ART patients develop IRIS • Mortality <15%, duration 2-3 months, hospitalization 21-48% • Risk factors • Low CD4 • Disseminated TB • Early ART after TB Rx start • Diagnosis • Difficult without TB culture • Clinical deterioration in 3 months of ART • By exclusion: no alternative diagnosis • DD: MDR TB! • 10% of TB IRIS suspects in South Africa had RH resistance

  46. TB IRIS: Management • Prednisolone (1.5mg/kg) significantly reduces morbidity • No mortality difference • Many relapse after 4 weeks • Steroids are harmful if wrong diagnosis (MDR TB) • Only give in tertiary settings

  47. TB IRIS Research Questions • What immuno-mechanism? • No established lab tests

  48. www.stoptb.org/wg/tb_hiv/meetingsevents.asp

  49. Next session: 10 September, 2009 Listserv: itechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

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