1. 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

2. 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

3. 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?

4. 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+

5. 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

6. 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

7. 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

8. 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

9. 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 deaths And HIV morbidity

10. 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

11. Who is dying from HIV/TB? 1. South Africa 88,000 2. Mozambique45,000 3. India 42,000 4. Nigeria19,000 5. Zimbabwe18,000 6. Uganda 9,200 7. Kenya7,700 8. Tanzania7,000 9. DRC6,300 10. Ethiopia5,600 TOP 10 COUNTRIES WITH HIV/TB DEATHS Global TB report, 2012 data

12. 1. Cambodia 560 2. China1,200 3. Russia1,800 4. Indonesia 2100 5. Viet Nam 2100 6. Thailand 2200 7. Brazil 2500 8. Myamar4600 TOP 8 COUNTRIES WHERE ELIMINATION OF HIV/TB DEATHS IS WITHIN REACH Global TB report, 2012 data, high burden countries

13. 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

14. HIV is not diagnosed in TB; ART cannot be started Global TB report, 2012 Globally, Only 40% TB cases HIV status known

15. 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

16. 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

17. Active TB Diagnose TB Start ART 2 weeks Complete TB 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

18. 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

19. 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

20. Adapting Care: Increase in HIV testing in TB patients in India Challenge: HIV testing in low prevalence setting

21. 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

22. 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

23. 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

24. 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, 2013Marquez, submitted

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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.

34. 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

35. 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

36. 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

37. 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 2035 Endorsed by World Health Assembly, May 2014