Welcome to a Special I-TECH Distance Learning Session

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

andConsortium 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 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, PCR1) Hesseling et al: Bull WHO DOI: 10.2471/BLT.08.055657 2009

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

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

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

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 FindingZAMSTAR 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

• HIVMarais, 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?

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

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

TB IRIS

Research Questions• What immuno-mechanism?

• No established lab tests

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

Thank you!Next session: 10 September, 2009

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