25 august 2009 report on tb sub meeting from ias andreas jahn
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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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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 PartnershipandConsortium to Respond Effectively to the AIDS/TB Epidemic (CREATE)

Cape Town, 18-19 July 2009

Lessons Learnt from an IAS Satellite Meeting

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

  • 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

    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

    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

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

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

    TB Diagnostics

    TB Diagnostics

    TB VaccinesBCG


    • 77% efficacy against military TB (Big meta-analysis)

    • 75% efficacy against disseminated and CNS TB in children


    • 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

    TB VaccinesBCG

    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

    TB VaccinesInnovations

    • 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

    TB VaccinesInnovations

    • 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

    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

    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

    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)

    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

    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.’

    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?

    TB Risk Throughout HIV Infection and ART

    Source: Havlir DH: Catalyzing HIV and TB Research (Presentation)

    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

    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

    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

    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.

    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)

    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

    TB in HIV Infected Children

    • High risk of TB infection and disease

    • Diagnostic challenges

      • Co-morbidities

      • Bacteriological confirmation: Immune suppression, paucibacillary

      • Infection vs. disease

    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

    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

    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

    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

    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

    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

    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)

    MDR and XDR TB

    MDR and XDR TB

    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!

    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

    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

    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?

    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?

    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

    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?


    • 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

    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


    Research Questions

    • What immuno-mechanism?

    • No established lab tests


    Next session: 10 September, 2009

    Listserv: itechdistlearning@u.washington.edu

    Email: DLinfo@u.washington.edu

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