TB and HIV (Dr. E. Jane Carter)

TB-HIVPresentation International Press Corp

E. Jane Carter, MDAssociate Professor of Medicine

Alpert School of Medicine at Brown UniversityTB 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

Length of treatment

# of drugs Cure rate

Pansusceptible 6 months H/R/Z x 2, H/R x 4

99%

INH resistance 12 months 2 (R/E) 95%

Rifampin resistance

18 months 2 (H/E) 95%

INH and Rifampin resistance

18-24 months 4 to include amikacin and a quniolone

70% Consider surgery

INH, Rifampin plus

24 months after sputum culture conversion

At least 5 to include an injectible

70% 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

Median survival 16 days ( range 2-210)

52 of 53 patients died

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 collaborationA.1. TB/HIV coordinating bodiesA.2. HIV surveillance among TB patientA.3. TB/HIV planningA.4. TB/HIV monitoring and evaluation

C. To decrease the burden of HIV in TB patientsC.1. HIV testing and counsellingC.2. HIV preventive methodsC.3. Cotrimoxazole preventive therapyC.4. HIV/AIDS care and supportC.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…..