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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 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





1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

2004 2005 2006 2007

HIV Prevalence in Kenya 1990 - 2007

TB case notification DLTLD Kenya: 19902010

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 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
Length of treatment Pansusceptible 6 months # of drugs Cure rate

H/R/Z x 2, H/R x 4 2 (R/E)


INH resistance

12 months


Rifampin resistance INH and Rifampin resistance INH, Rifampin plus

18 months

2 (H/E)


18-24 months

24 months after sputum culture conversion

4 to include amikacin and a quniolone At least 5 to include an injectible


Consider surgery Consider surgery


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

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
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

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

Maybe there will be answers, maybe not yet..