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No One Left Behind: HIV and Tuberculosis co-infection
Thank you to my co-authors
Mark Harrington Soumya Swaminathan Haileyesus Getahun
Diane Havlir, University of California, San Francisco
In 2014… We have
Evidence based prevention for HIV/TB New TB diagnostics Ability to cure most TB in 6 months and to
reduce mortality with ART
Over 1 million new TB cases in HIV+ persons and 320,000 HIV/TB deaths EVERY YEAR
1.We are not maximally implementing evidence based interventions
2.Most at risk populations (MARPS) for HIV/TB have not received adequate attention
3.Our care delivery is often disease (ie HIV or TB ) and NOT patient centric
Why do we still have so much death and suffering from TB in the
HIV epidemic?
2004: HIV/TB rampant overwhelming communities and health systems
Rapid, unabated increase in TB caseload due to HIV/TB interaction
Karim, Lancet, 2009
TB risk increase 12-20 fold in HIV+
Source: Global tuberculosis report 2013. Geneva, World Health Organization, 2013 .
2014: Policy, advocacy and implementation have produced results
Over 40% decline in HIV/TB deaths and over 1.3 million lives saved
• Diagnose and treat TB
• Diagnose and treat HIV
Moving forward in 2014: Combination Prevention for HIV/TB
ART: 65% reduction in TB(1) ART + isoniazid preventive
therapy (IPT) additional 35% reduction in TB in high TB transmission areas(2) • NO TB SKIN TEST NEEDED
Transmission reduction strategies• Enhanced case finding (3) • Infection control
ART
IPT
Transmission reduction strategies
1. Suthar, PLOS Medicine , 2012; 2. Rangaka, Lancet, 2014 3. Lorent PLOS One, 2014
Combination Prevention
2014: New and better diagnostics
XPERT MTBRIF: 2 hour molecular test for M.TB diagnosis and rifampin resistance(1) • More sensitive than AFB smear• Works in children and
extrapulmonary TB • Screen for MDR and XDRTB
LAM: POC urine test(2) • 85% TB cases detected in
HIV+ persons with < 100 CD4+ cells entering hospital with new TB diagnosis
1. Lawn, Lancet ID, 2013 ;2. Lawn, CROI, 2014
CAMELIA (Cambodia) SAPIT (South
Africa)
STRIDE (multicontinent)
2014: Treatment strategy of immediate TB therapy +early ART (2 vs 8 weeks) that saves lives and
reduces HIV complications
WHO 2010 ART Guidelines
• Start ART at CD4 <500• Provide IPT for HIV-positive
patients without active TB • For those with TB, ART initiated
as soon as possible after the start of TB treatment
• At 2 weeks when CD4<50; no later than 8 weeks
WHO Policy– Harmonized to optimize outcomes in HIV and TB
Prevent and Treat HIV and Prevent TB
Reduce HIV/TB deathsAnd HIV morbidity
Stepping up the pace requires we: Understand who is dying and why they are dying Adapt care delivery systems so we can apply the
evidence Pay more attention to HIV/TB MARPs Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
Who is dying from HIV/TB?
1. South Africa 88,000
2. Mozambique 45,000
3. India 42,000
4. Nigeria 19,000
5. Zimbabwe 18,000
6. Uganda 9,200
7. Kenya 7,700
8. Tanzania 7,000
9. DRC 6,300
10. Ethiopia 5,600
TOP 10 COUNTRIES WITH HIV/TB DEATHS
Global TB report, 2012 data
1. Cambodia 560
2. China 1,200
3. Russia 1,800
4. Indonesia 2100
5. Viet Nam 2100
6. Thailand 2200
7. Brazil 2500
8. Myamar 4600
TOP 8 COUNTRIES WHERE ELIMINATION OF HIV/TB DEATHS IS WITHIN REACH
Global TB report, 2012 data, high burden countries
Reasons for HIV/TB Deaths
HIV not diagnosed TB not diagnosed TB not treated HIV not promptly
treated MDRTB
Some reasons for HIV/TB Deaths
TB not recognized (until autopsy)
CROI, 2013
HIV is not diagnosed in TB; ART cannot be started
Global TB report, 2012
Globally, Only 40% TB cases HIV status known
ART start lags behind guidelines
Malawi Program Data – before and after new 2011 country guidelines (1)
685 HIV/TB cases ART at any time increased from 70% to 78% ART within 2 weeks increased from 30% to 46%
1.Best case scenarios: Less than half patients receiving ART in timely way to reduce mortality
2.Time to ART start not routinely collected in country programs
1. Tweya, BMC Public Health, 2014, 2014
Stepping up the pace requires we: Understand who is dying and why they are dying Adapt care delivery systems so we can apply the
evidence Pay more attention to HIV/TB MARPs Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
Active TB DiagnoseTB
Start ART2 weeks
CompleteTB
treatment
Transition to HIV care
Treat TB
Undiagnosed TB late ART start bad care
The HIV/TB Care Cascade needs to be monitored and fixed
What is the best model for HIV/TB care?
The one that is convenient for the patient and delivers quality care• There is no one size fits all• Will vary according to HIV and TB prevalence
Possible HIV/TB clinic models • Referral models- 2 separate clinics • Integrated and co-located models
Considerations • Integrated models are optimal but require more effort on
staff training and considerations such as infection control• Co-location not sufficient for optimal delivery of care• Most systems are still burdensome to the patient
Legidor Quigley, Trop Med Int Health, 2013; Schwartz, IJTLD, 2013; Uyei, Health Policy and Planning, 2014
Adapting Care: Xpert MTB/Rif for Faster TB detection
• Nurses coordinated Xpert use
• Time to TB diagnosis less with Xpert and smear vs TB culture
• More TB cases detected from Xpert vs smear
• Time to TB treatment reduced with Xpert
Theron, Lancet, 2013
We now need to overcome logistical challenges of Xpert scale up
Adapting Care: Increase in HIV testing in TB patients in India
Challenge: HIV testing in low prevalence setting
Adapting Care: Isoniazid preventive therapy (IPT) in Brazil
THRIO Goal: increase IPT uptake for among HIV+ persons
12,816 persons in 29 HIV clinics in Rio de Janeiro Intervention
• Operational training on TB skin test and IPT• Active TB screening within ART program • Supply chain fortification
27% reduction in TB; 31% reduction in TB or death during the intervention period
Globally, Only 1/3 patients in HIV care prescribed IPT (1)
1. Global TB report, 2012; 2. Durovni, Lancet ID 2013
Stepping up the pace requires we: Understand who is dying and why they are
dying Adapt care delivery systems so we can apply
the evidence Develop strategies for HIV/TB MARPs
• Children• Miners and their families and contacts • Persons who inject drugs (PWID)• Incarcerated populations
Invest in research to improve prevention, diagnosis and treatment of TB and HIV/TB
Children– Left Behind
Children have more rapid progression of TB from infection to disease vs adults
TB diagnosis is more difficult in children than adults
TB/ART dosing and dose adjustments are more complex
Cascade of care even more challenging for children
530,000 TB cases; 78,000 deaths in children*
*WHO estimate; Recent estimates by Dodd,( Lancet 2014 ) 650,000;Jenkins, (Lancet, 2014) 1 million
Children– Some sobering data
32% HIV + children enrolled in Malawi cohort 2004-2010 diagnosed with TB
20% with TB died 8.8 fold increase in death
in those not starting ART vs those starting ART within 2 months
1713 children presented with cough >2 weeks duration in rural Uganda clinics
Only 17.5% referred for microscopy
Among those found to be AFB smear positive, only approximately half started TB therapy
High TB Burden and Mortality
Broken care cascade
Buck, IJTLD, 2013 Marquez, submitted
Children– What Next?
Prevent all HIV transmission (MTCT B+) Start ART in all children IPT for all children exposed to TB cases
Childhood TB infection relevant to all of HIV/TB and TB control because much of global TB reservoir is established in childhood
Roadmap for Childhood tuberculosis – Towards Zero Deaths, WHO 2013
Miners – “a public health catastrophe” Extraordinary rates of TB 4000-7000/100,000 in
miners vs general population in SSA Second largest driver of TB in South Africa (after
HIV) is mining HIV and mining lethal combination
• Silica exposure– increase risk 3 fold• HIV + increase risk greater than 10 fold• HIV + silica- exposure - increased risk 15 fold • Poor living conditions– increased risk many fold
All forms of TB are a problem• Latent TB- 89% in miners!• New TB infections and TB re-infections• MDRTB 3.6% (miners) vs 1.9% non miners
Dharmadadhikari, Int J Health Services, 2013
Miners– What next?
Improved housing and mining conditions HIV/TB prevention and screening as part of
employee health contract• HIV testing • Offer ART start for all HIV+ persons (best TB prevention!)• Routine TB screening symptoms and radiograph• IPT (not just 6 months!) while in high risk setting• Continuity in care when miners come and go from employment• Xpert accessible for rapid diagnosis and identification of high
risk for MDRTB
Declaration on tuberculosis in the Mining Industry Zero deaths from TB, Maputo, 2012
Persons who inject drugs: intersection of HIV/TB/HCV
One third PWID are HIV-infected; two thirds are HCV infected
High rates of TB infection Human rights violations drive PWID away from
care
Getahun, Curr Opin HIV/AIDs, 2012; Grenfell Drug and Alcohol Dependence, 2013; Schluger, Drug and Alcohol Dependence, 2013
Incarcerated Populations- Left Behind High rates of incarceration exacerbate TB
spread• 1/11 of TB transmission in prison on high income countries • 1/16 of TB transmissions in low and middle income
countries Crowded conditions Limited health access
Declaration on tuberculosis for PWID or incarcerated populations
DOES NOT EXIST
PWID and Prisoners -Next Steps
Improved housing On-site HIV/TB prevention and screening
• Routine HIV/TB screening• ART offered for all HIV+ • IPT (not just 6 months!) while in high risk setting• Opioid substitution therapy and compatible TB therapy/ART• Xpert accesible for rapid diagnosis and identification of high
risk for MDRTB• Rapid ART start for new cases of TB in HIV+ patients
Getahun, Curr Opin HIV/AIDs, 2012; Grenfell Drug and Alcohol Dependence, 2013; Schluger, Drug and Alcohol Dependence, 2013
Stepping up the pace requires we: Understand who is dying and why they are
dying Adapt care delivery systems so we can apply
the evidence Pay more attention to HIV/TB MARPs Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
TAG TB Research and Development Report, 2013
TB reservoir– it matters
What is TB reservoir?• Persistent infection with
TB that can reactivate• HIV and aging both risk
factors for this reservoir to develop into active disease
Why does it matter?• Estimated that 1/3 worlds
population is infected with TB
• Achilles heal of elimination of TB
Lung granulomas are dynamic and independent in metabolic activity and size
Lin, AAC, 2013
Shorter TB prevention for ALL populations
Standard– Isoniazid 6-9 months New 3 month regimen works!
• INH/Rifapentine once per week – total 12 doses• Works in HIV+ population• Rifapentine can be administered with efavirenz
Even shorter- 1 month regimen under study Daily high dose INH + rifapentine (ACTG 5279)
Sterling, NEJM 2011: Sterling, CROI, 2014
We need to answer the question if even these more potent short course regimens work and are sufficient
in high transmission settings.
Shorter TB treatment
We cannot shorten TB treatment to 4 months with current drugs at standard doses • OFLOTUB study (gatifloxacin)• RIFAQUIN study (moxifloxacin/rifapentine )
We cannot rely on the week 8 culture results to tell us if we need to extend treatment
Some of the TB agents in development interact with HIV medications and some are stalled in development
What do we want? Once daily, few pills, few side effects, compatible with ART, TB cures at 2 weeks, treatment for children
THE BAD NEWS
The good news… (with more not so good news)
We may be able to combine available drugs using higher doses to shorten TB therapy• Rifapentine• Rifampin
We may be able to design regimens with new drugs that treat both drug sensitive and drug resistant TB
TB Research and Development Investment• Reduced by 4.6% from 2011-2012• Fell short of projected need in 2012 by over 1.2 billion USD
Summary
HIV/TB rates are declining- but there are still over 1 million HIV/TB cases and 300,000 HIV/TB deaths
We need to deploy targeted strategic approaches ,
• Combination prevention for HIV/TB• New diagnostics • Rapid ART start
Stepping up the pace requires structural changes • Fix HIV/TB care cascade with a patient centric system• New HIV/TB MARPS programs- children, miners, PWID,
prisoners Research investment and renewed advocacy
Conclusion
“Every HIV/TB case is a public health failure”
Helen Ayles, 2014
Every HIV/TB case prevented and every death averted is a public health success and puts us one step closer to ending the dual epidemic of HIV and TB
Melbourne IAC, 2014
WHO Post 2015 Strategy and Targets for TB; TB Elimination by 2035Endorsed by World Health Assembly, May 2014