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TB-HIV Presentation 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. Outline of talk. Basic terminology and pathophysiology Epidemiology of TB and HIV

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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


Outline of talk

  • Basic terminology and pathophysiology

  • Epidemiology of TB and HIV

  • Why entertwined?

  • Challenges of two diseases?

  • Question and (Maybe) Answers


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


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


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


Global Burden


TB World Incidence


HIV World Incidence


TB case notification DLTLD Kenya: 1990-2010


HIV and TB trends in Kenya: 1990 – 2005


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


TB HIV Interactions Clinical Implications


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


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%


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


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


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


TB World Incidence


END result

Autopsies show undiagnosed TB caused death in 14-54% of PLHIV


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


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


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


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?


Challenges of Concomitant TB/HIV Treatment


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.


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.


  • 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


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


TB World Incidence


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+


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?


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


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.


Therapeutic implications


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…..


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


Enhanced Surveillance

Group 1 = per South Africa guidelines

Group 2 =consecutive patients on TB ward

Group 3 = consecutive TB suspects (9 months)


Characteristics of XDR patients


Survival After Sputum Collection

52 of 53 patients died

Median survival 16 days ( range 2-210)


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.


True challenges of TB HIV care

is the translation of scientific advancement into day to day practice


What I have tried to do for you….

  • Provide a foundation of terminology to build upon

  • Highlight the problems inherent in TB HIV care globally – across a gradient of disease and resources

  • Provide merely an introduction to the problem through which you can access the conference findings


Questions?

Maybe there will be answers,

maybe not yet…..


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