TB-HIV Presentation International Press Corp

1. TB-HIVPresentation International Press Corp E. Jane Carter, MD Associate Professor of Medicine Alpert School of Medicine at Brown University TB HIV Technical Consultant- AMPATH Partnership Eldoret, kenya

2. Outline of talk • Basic terminology and pathophysiology • Epidemiology of TB and HIV • Why entertwined? • Challenges of two diseases? • Question and (Maybe) Answers

3. TB Transmission • Tuberculosis is spread through the air • Index case must have the pulmonary form of the disease • Tb can cause disease anywhere in the body but only the pulmonary ( lung ) form is contagious to others • Index case breathes or coughs the germ into the air • MTB remains aerosolized for up to 6 hours • Others walking through the same airspace can become infected by breathing the contaminated air

4. Stages of Tuberculosis • Exposure • Infection • Disease • Contagion • Not every exposure results in infection • Asymptomatic state of being a germ carrier • 1/10 carriers will develop disease • Only pulmonary cases are contagious to others

5. Tuberculosis Treatment • TB infection can be cured by treatment with a single drug • IPT = isoniazid preventive therapy • Length of therapy is long ( 9-36 months) • TB disease must be treated with a combination of medications • Generally 4 drug for 2 months followed by 2 drugs for at least 4 months • For the simplest of cases

6. Global Burden

7. TB World Incidence

8. HIV World Incidence

10. TB case notification DLTLD Kenya: 1990-2010

11. HIV and TB trends in Kenya: 1990 – 2005

13. Burden of TB • 9.4 million new cases of TB disease per year • 1.1 million cases of co-infection • 2 million deaths • 380,000 in PLWHA • 1 infection per second • Leading cause of death in PLWHA • Leading cause of death in women of child bearing years globally

14. TB HIV Interactions Clinical Implications

15. TB Stages How does HIV affect these stages? • Exposure • Infection • Disease • Contagion • More likely to result in infection • 1/10 chance per year of developing disease • Severity increased in parallel to the HIV immunosuppression • Unclear if more or less contagious

16. TB HIV interactions • People who are infected with both HIV and latent TB have a much higher risk of developing active TB • Annual risk of developing active TB of 5-10% • Lifetime risk of 50%

17. Clinical Concern • TB progresses faster in HIV-infected patients • More rapidly moves from infection to disease • More rapidly develops severe forms of disease • The rate of progression is determined by the immunosuppression of the HIV patient • TB is the earliest OI to occur in HIV, appearing at an increased rate even when the CD 4 count is still relatively preserved • TB in HIV-infected patients is more likely to be fatal if undiagnosed or left untreated

18. Natural History – pre HAART • 1992 Outbreak in an HIV Hospice • 12 cases December 1990-April1991 • In the preceding 6 months 2 patients being treated for TB had been admitted • RFLP demonstrated all 12 matched but was a different strain than the previous 2 • First of the 12 patients was the source case • Accelerated progression from exposure to death from TB in as short as 12 weeks • NEJM 1992;326:231-235

19. Clinical Concerns • TB is harder to diagnose in HIV-infected patients • Patients become ill with lower organism burdens • PLWA have increased extrapulmnary disease • Diagnostic challenges • Contagious pulmonary cases are diagnosed by smear microscopy • Early disease may not be diagnosed by microscopy and require culture • Disease outside of the chest usually requires culture diagnosis

20. TB World Incidence

21. END result Autopsies show undiagnosed TB caused death in 14-54% of PLHIV

22. TB fuels HIV • TB increases HIV load and hetergeneity, locally and systemically • Increases cytokines linked to HIV activation • Decreases cytokines that suppress HIV growth • Studies have varied on the clinical outcomes of TB on HIV • Adverse survival has been shown for TB/HIV patients versus HIV alone • HIV progression was not any faster when compared to other AIDS defining conditions (KS,PCP, esoph, candidiasis) • TB occurs at all levels of CD4 depression

24. Treatment concerns • TB treatment involves for drugs • HIV treatment involves 3 drugs • Usually patients are on CPT as well to prevent other OIs • Translates into a minimum of 8 drugs • Adherence • Drug Interactions and Side Effects

25. Treatment of TB Disease • In order to effect a cure, TB must be treated with at least two drugs to which the organism is susceptible. • Two drugs – the uncoupling of drugs leads to drug resistance

26. Treatment concerns • Because the treatment combinations are complex- • Questions were always should one treatment precede the other? • TB treatment could never be delayed due to risk of death but when?

27. Challenges of Concomitant TB/HIV Treatment

28. Is it necessary to Treat Concomitantly? • Retrospective Studies • Madrid* Meta-analysis of 6934 patients • 63% increase in survival amongst patients initiating ART during TB therapy • Thailand** study of 1003 • 20 X greater mortality risk in patients receiving only TB compared to those receiving ART/TB *Velasco et. al. JAIDS 2009;50:148-52. **Manosuthi et. al. JAIDS 2006;43:42-6.

29. Is it necessary to Treat Concomitantly? • Prospective, open label, randomized Control trial, South Africa • Three arms • start ARV (EFV, dDI, 3TC) within 4 weeks of starting TB therapy • start ARV within 4 weeks of continuation phase of TB therapy • start ARV within 4 weeks of completing TB therapy • Arm 3 halted after enrollment complete N Engl J Med 2010;362:697-706.

30. Reduction in mortality in combined treatment versus sequential therapy • 5.4 deaths/100 person years group 1 and 2 • 12.1 deaths/100 person years group 3 • hazard ratio in the combined integrated-therapy groups, 0.44 • 95% confidence interval, 0.25 to 0.79; P = 0.003 • Mortality lower in all cd4 stratifications • Adverse events in groups were not different

31. Timing of therapy • IN HIV ARV timing of ARV initiation was timed to level of immunosuppression • 2009 WHO recommended ART for all TB patients – but when is best time to start? • NEJM Series of articles last week • For those with CD4 count < 50 immediate ART is beneficial in preventing death and further OIs

32. TB World Incidence

33. Interactions are bidirectional • HIV increases the risk of both primary and reactivation TB in both high and low burden settings • Risk of active TB increases with advancing HIV • TB as the initial AIDS defining illness in associated with an adverse outcome when compared to HIV+

34. We know what to do….. But how to do it? • It appears to be beneficial to start early ART in TB patients… • Adherence? • Side effects? • Monitoring?

35. TB Drug resistance • Occurs by means of a genetic mutation • The genetic mutations occurs spontaneously and randomly in the environment • These mutations occur at know rates for each of the drugs • The mutations are independent of each other

36. Acquisition of Drug Resistance • Primary Drug Resistance • TB Drug resistance that is present BEFORE the patient has started any TB drugs • The patient was infected with a resistant organism • Secondary Drug Resistance • TB Drug resistance that was not present when the patient started TB drugs but occurs while on therapy • Caused by uncoupling of the medications • Non adherence, poor drug formulation, malabsorption, etc.

37. Therapeutic implications

38. But we have talked about ………… • Rapid progression of Tb in HIV patients. • Challenges of Diagnosis • Challenges of Treatment So what does drug resistance imply for our HIV patients…..

39. XDR TB as a cause of death Gandhi et al. • Enhanced surveillance for drug resistance in KwaZulu Natal • Rural clinic • DOTS since 1993 • Site of a demonstration project to treat HIV since 2004

40. Enhanced Surveillance Group 1 = per South Africa guidelines Group 2 =consecutive patients on TB ward Group 3 = consecutive TB suspects (9 months)

41. Characteristics of XDR patients

42. Survival After Sputum Collection 52 of 53 patients died Median survival 16 days ( range 2-210)

43. Global Response: Collaborative TB/HIV activities B. To decrease the burden of TB in PLHIV- Three Is B.1. Intensified TB case finding B.2. Isoniazid preventive therapy B.3. TB infection control in health care and other settings A. Establish the mechanism for collaboration A.1. TB/HIV coordinating bodies A.2. HIV surveillance among TB patient A.3. TB/HIV planning A.4. TB/HIV monitoring and evaluation C. To decrease the burden of HIV in TB patients C.1. HIV testing and counselling C.2. HIV preventive methods C.3. Cotrimoxazole preventive therapy C.4. HIV/AIDS care and support C.5. Antiretroviral therapy to TB patients.

44. True challenges of TB HIV care is the translation of scientific advancement into day to day practice