Welcome to I-TECH HIV/AIDS Clinical Seminar Series

November 19, 2009Tuberculosis in Persons with HIV/AIDS: Opportunities for Prevention

Charles Nolan, M.D.

Case for discussion• A 22 yr old woman, recently diagnosed with HIV

infection at the time of delivery of her second child, was referred for clinical and laboratory staging

• The evaluation revealed clinical stage 2 HIV infection (weight loss of perhaps a few kg over the past two months), and her CD4 cell count was 240 cells/mm3

• The patient said that she has experienced a dry cough for around 3 weeks. She denied having fever.

Case for discussion (continued)

How would you proceed to evaluate and manage this patient?

Considerations for this patient

• Further clinical evaluation because of symptoms – yes/no

• Antiretroviral therapy – yes/no• Cotrimoxazole preventive therapy – yes/no• Screening for TB - yes/no• Isoniazid preventive therapy – yes/no

Strategies for prevention of TB in persons with HIV infection

• The “three I’s” (from WHO)

1. Intensified TB case finding2. Isoniazid preventive therapy3. Infection control in health care facilities

• Anti-retroviral therapy

Tuberculosis pathogenesis

6

1. 2.

3. 4.

Natural history of TB

Exposure to an infectious case

Focus in infection in lung

Silent dissemination of infection and containment by host defenses (98%)

Latent TB infectionPt asymptomatic, TST positive

Activation of latent infection (5-10%)

Patient symptomatic, based on site of activation (70% pulmonary)

Lifetime dormancy (90-95%)

Preventive Interventions against TB

Exposure to an infectious case

Focus in infection in lung

Dissemination of infection and/or containment by host defenses

Latent TB infection

Activation of infection

Patient symptomatic, based on site of activation (70% pulmonary)

immunization

Treatment of Latent TB Infection

Treatment of active TB

Natural history of TB in persons with HIV infection

Exposure to an infectious case

Focus in infection in lung

Silent dissemination of infection and containment by host defenses (98%)

Latent TB infectionPt asymptomatic, TST pos/neg

Activation of latent infection (Lifetime odds of disease 5-10%)

Patient symptomatic, based on site of activation (70% pulmonary)

Lifetime dormancy (??)

Clinical disseminationAnd disease(1-2%)

25%

Annual risk of disease 10%

75%

Preventive Interventions against TB in Persons with HIV infection

Exposure to an infectious case

Focus in infection in lung

Dissemination of infection and/or containment by host defenses

Latent TB infection

Activation of infection

Patient symptomatic, based on site of activation

Immunization

Treatment of Latent TB Infection

Treatment of active TB

ART

Infection control

ART

Summary of the effect of antiretroviral therapy on rates of active TB

• In multiple studies done in a variety of settings, use of antiretroviral therapy decreases the rate of active TB in the population being treated

• The effect of antiretroviral therapy is greatest in areas with high rates of TB and among patients with lower CD4 cell counts

• Decreasing the risk of active TB is an important benefit of antiretroviral therapy

Traditional DOTS approach to TB case detection

• A patient seeks medical care, generally in a primary health center, because of feeling unwell

• The patient is identified as a TB suspect on the basis of typical symptoms: cough >2 weeks in duration, fever, loss of weight

• The diagnosis of TB is made most often by microscopic examination of sputum for acid-fast bacilli

TB treatment

The advantages of early detection of TB cases in persons with HIV infection

• Early case detection leads to early institution of treatment, and to A better chance for cure for the sick patient,

and Early termination of infectiousness and

transmission

• Early case detection allows early assessment of contacts, including children, for TB and HIV infection

The importance of early detection of TB in persons with HIV infection

A study from South Africa* found that patients with HIV infection who were found to have active TB on routine screening were six times less likely to die during TB treatment that those who sought care for TB associated symptoms

*Churchyard et al. Int J Tuberc Lung Dis 4:705-712, 2000

Proposed flow chart for IPT in patients with HIV infection

Ait-Khaled et al. Int J Tuberc Lung Dis 13:927, 2009

TST?

TB Rates by ART and INH Treatment Status, 2003-2005

Exposure category

Person-Years

TB Cases

Incidence Rate(per 100 PYs)

IncidenceRate Ratio

No Rx 3,865 155 4.01 (3.40-4.69) 1.0

ART only 11,627 221 1.90 (1.66-2.17) 0.48 (0.39-0.59)

IPT only 395 5 1.27 (0.41-2.95) 0.32 (0.10-0.76)

Both 1,253 10 0.80 (0.38-1.47) 0.20 (0.09-0.91)

Total 17,140 391 2.28 (2.06-2.52)

Golub et al., AIDS 2007;21:1441-8

Efficacy of IPT in reducing the risk of TB in HIV+ Adults

• 11 randomised trials with 8,130 HIV+ participants overall reduction in TB = 36%, reduction PPD+ = 62%

0.95

0.64

TB incidence

Death

Relative Risk (Fixed)95% CI

Reference1.0

Woldehanna and Volmink, Cochrane Review 2006

Despite good evidence of IPT efficacy, recommendations from WHO guidelines, and the adoption of national guidelines, in 2007 only 0.1% (29,000) of the estimated 33.2 million people living with HIV infection were put on IPT.

Why is this?

Unresolved issues with IPT

• Who should supervise IPT?• Should tuberculin skin testing be used to

identify IPT candidates?• How and in whom should active TB be ruled

out?• Does IPT lead to an increased risk of INH

resistance?• How durable is a 6-9 month course of IPT?• How safe is IPT in patients receiving ART?

Side effects of INH

• GI intolerance PIs, ZDV, ddI• Skin rash ABC, NNRTIs, • Peripheral neuropathy ddI, d4T, ddC

(Rare if pyridoxine is given concomitantly)

• Hepatotoxicity PIs, NNRTIs

Effect also seen with ARVs

Types of adverse events from INH for latent TB in persons with HIV infection - Zambia

Adverse event leading to drug discontinuation

Hepatitis

Rash

GI symptoms

Others

Placebo(n = 360)

0

0

1 (0.3%)

2 (0.6%)

INH(n = 360)

3 (0.8%)

1 (0.3%)

5 (1.4%)

3 (0.8%)

AIDS 1998;12:2447-57

effect of IPT on drug susceptibility of subsequent TB cases – South African

gold miners

TB Cases following IPT (n = 57)

TB cases in comparison group (n = 97)

INH resistant cases

7 (13.2%)

8(8.2%)

Churchyard G, et al. Unpublished observations

Topic for discussion

How does your institution protect its staff members, including those with HIV infection, from acquiring TB?

The importance of TB infection control in HIV care

• Because undiagnosed TB is so common in PLWHA, TB is being transmitted in health care facilities from patient to patient and to health care workers

• Health care workers are 5-fold more likely to acquire TB compared to the general population

• Outpatient and inpatient sites are potential sites of TB spread: Emergency rooms, hospital wards, primary health care clinics, ART clinics, PMTCT clinics, VCT sites, and other sites inclujding jails, drug rehab centers….

• Approximately half of cases in the XDR-TB outbreak in Kwa-Zulu Natal, South Africa were associated with health care sites

To reduce the spread of TB, all HIV care facilities should implement…

• Good work practices and administrative control measures

• Environmental control measures

WHO 2009

The hallmark of good work practices to control TB is a TB infection

control plan• Through screening,

identify TB suspects and and separate them from other patients in a well ventilated space

• Institute cough hygiene for TB suspects, including tissues and face masks

• Minimize time TB suspects spend in clinic, but deliver services they came for

• Evaluate TB suspects promptly or have a plan to refer them for evaluation

• Identify an Infection Control Officer to administer the plan

Environmental control measures for prevention of TB spread

• Environmental control is secondary to good work practices

• Mechanical ventilation systems are expensive and suitable for referral hospitals

• Natural ventilation can be utilized in many health care settings

• Open windows, open doors, and fans can efficiently bring outside air into a room, diluting droplet nuclei containing M.tb.

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Email: DLinfo@u.washington.edu

Next session: December 3 – HIV and Women

Thank you!Next session: December 3, 2009

Dr Scott McClellandHIV and Women, Part 2