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 42,0004. Nigeria 19,000

5. Zimbabwe 18,0006. Uganda 9,200

7. Kenya 7,7008. Tanzania 7,000

9. DRC 6,30010. Ethiopia 5,600

TOP 10 COUNTRIES WITH HIV/TB DEATHS

Global TB report, 2012 data

1. Cambodia 5602. China 1,200 3. Russia 1,8004. Indonesia 21005. Viet Nam 2100 6. Thailand 22007. 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