TUBERCULOSIS IN THE AGE OF HIV

Dr. Terry Baker Physician National Chest Hospital

THE PROBLEM

Global epidemic of HIV infection. HIV- infected persons highly susceptible to M. tuberculosis disease. Impact of HIV epidemic and TB greatest in the developing world. 33% HIV infected population co-infected with TB. TB - the most common opportunistic lung infection.

Tuberculosis & HIV

Region Adults & Children Adult living with HIV/AIDS Prevalence Rate Sub-Saharan 8.0 % Latin America 0.57 % Caribbean 1.96% Western Europe 0.25% North America 0.56% 23.3 million 1.3 million 360,000 520,000 920,000

World HIV/AIDS Statistics by Region, December 1999

New AIDS Cases Per Year

Per 100,000 Population
35 30 25 20 15 10 5 0 90 91 92 93 94 95 96

Caribbean

North America Latin America

2000

Reported AIDS Cases in Barbados 1984 - 1998

180

Tuberculosis & HIV

130 119 113 95

168

160

140

120

Number of Cases

100 78 61 60 40 21 20 2 1984 (20) 1985 1986 1987 1988 1989 1990 1991 1992 9 24 15 78

90

80

40

1993

1994

1995

1996

1997

1998

Years

Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

Reported AIDS Cases in Trinidad & Tobago 1983 - 1999

800 700 600

Tuberculosis & HIV

677

500 Number of Cases 400 300 198 166 115 100 8 13 83 52 164 298 249 302 264 399

468 408

459

200

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 (100) Years

Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

Reported AIDS Cases in Jamaica 1982 - 1999

1000 900 800 700 Number of Cases 609 600 505 500 400 300 200 100 0 1 0 1 3 6 63 62 359 236 133 33 30 527 645

Tuberculosis & HIV

892

99

1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Years

Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

CO-INFECTION RATES
Jamaica
YEAR 1994 1995 1996 1997 1998 1999 2000 No. Tb Cases 109 109 121 118 121 108 124 No Tb/HIV 5 7 14 14 10 8 18 Percent co infected 4.6% 6.4% 11.6% 11.9% 8.3% 7.4% 14.5%

CO-INFECTION RATES
T / H C -ine t dC s s Ja a a1 9 -2 0 b IV o f c e a e , mic 9 1 0 0
1. 0 60 % 1. 0 40 % 1. 0 20 % 1. 0 00 % 80 % .0 60 % .0 40 % .0 20 % .0 00 % .0
19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00

T /HV b I

TUBERCULOSIS AND HIV

Implications: two-fold One epidemic (i.e. HIV) can potentially drive a second epidemic (i.e. Tuberculosis). Intersection of both epidemics could potentially spawn a third: i.e. Multiple Drug Resistant Tuberculosis ( MDRTb ).

Tuberculosis & HIV

MDRTb : Tb resistant to conventional therapy: Isoniazid ( INH ) and Rifampicin Treatment regimen is six-seven drugs Mortality remains in excess of 80 % Has the potential to infect both HIV and nonHIV populations

Tuberculosis & HIV

Conversion ( to active Tb disease after infection ) : Non-HIV : following infection, conversion is 5-10% over a lifetime HIV: conversion is 5-10% per year

PATHOGENESIS OF CO-INFECTION

HIV-infected persons are at risk for primary or reactivated TB, and for second episodes of TB. Reduced T1 response. CD 4+ lymphocytes unable to produce alpha- interferon. Alpha-interferon central to anti- mycobacterial immune defenses.

PATHOGENESIS OF CO-INFECTION

Presence of TB up-regulates retroviral replication. TB infection produces proinflammatory cytokines. Risk of death 2x greater in HIVinfected patients with TB. Death due to progression of HIV and not TB.

CLINICAL PRESENTATION

Dependent on degree of immunosuppression. Presentation varied. Extra-pulmonary TB, particularly lymph node involvement more common.

Diagnosis

History- Malaise, weight loss, fever, cough, haemoptysis Physical Examination Laboratory Examinations AFB smear, lymph node biopsy, BAL, pleural biopsy, cultures Chest X-ray findings variable ? Mantoux Test ? Rapid diagnostic tests- identifies TB RNA or DNA

Central bronchiectasis and LULobe cavity

RULobe abscess

LULobe pneumonia with air bronchograms

HIV AND THE TREATMENT OF TUBERCULOSIS

Six months vs. Nine months Clinical or bacteriological delayed response- Longer therapy. Lack of adherence to therapy most important impediment to cure. Higher risk of MDRTb Greater risk of prolonged disease. Strong public health services (DOT) improve outcome.

TREATMENT OF TUBERCULOSIS

First line drugs- Rifampin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin. Rifampin- most important and most potent. Second line drugs- Quinolones, Amikacin, Capreomycin.

ANTI-RETROVIRAL THERAPY

HAART dramatic improvement in prognosis for HIV- infected patients. Drug interactions complicate the management of tuberculosis. Interaction is mainly with the Rifamycins.

PHARMACOKINETICS OF ARVS AND ANTI-TB DRUGS

Rifamycins induce CYp450, decreasing serum levels of the protease inhibitors. Protease inhibitors inhibit CYp450 system, increasing serum rifamycins levels to possibly toxic levels. Net effect is that protease inhibitors may lose their efficacy and rifamycin toxicity may be increased.

PHARMACOKINETICS OF ARVS AND ANTI-TB DRUGS

q q

Rifampicin is the most potent inducer CYp450 Rifabutin is the least potent inducer and may be substituted for rifampicin. Clinical trials have demonstrated comparable safety and efficacy. The dose of rifabutin should be reduced from 300 to 150 mg daily in pts. on Protease Inhibitors.
CDC. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998; 48 ( No. RR-5): 1 -63

PHARMACOKINETICS OF ARVS AND ANTI-TB DRUGS

Protease inhibitors that can be concurrently administered with Rifabutin are Indinavir and Nelfinavir. More recently: Lopinavir, Amprenavir can be given, but with adjusted doses of Rifabutin: 150mg daily.

PHARMACOKINETICS OF ARVS AND ANTI-TB DRUGS

NNRTIs - may inhibit or induce p450. Efavirenz - rifabutin dosage should be increased. Nevirapine can be used without dosage adjustment. NRTIs- Rifamycins can be used without dose adjustment.

PHARMACOKINETICS OF ARVS AND ANTI-TB DRUGS

Regimens with rifamycins are shorter, have faster conversion and lower relapse rates than those without. HIV-infected TB patients treated without rifamycins may have a higher risk of dying.

CONTROVERSIES

? Continuation of anti-retroviral therapy during Anti-TB therapy. ? Anti-TB regimens not including a rifamycin. ? When to initiate anti-retroviral therapy in HIV-infected TB patient. ? Risk of paradoxical reactions and glucocorticoid therapy. ? Malabsorption of anti-TB meds.

PARADOXICAL REACTIONS
q

Up to 1/3 of co-infected patients on anti-Tb meds will experience paradoxical worsening when antiretroviral therapy is introduced. The clinical manifestation is usually fever, intrathoracic and cervical lymphadenopathy, pleural effusions and/or skin lesions. Usually occurs within 15 days of initiation of therapy.
Paradoxical worsening of Tb following antiretroviral therapy in pts with AIDS Am. J Respir Crit Care Med 1998; Nariita M et al Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J. Infect Dis 1987; 15: 1-3

PARADOXICAL REACTIONS
q

This appears to be associated with a marked drop in HIV viral load even though the peripheral CD4+ remains abnormally reduced Paradoxical reactions have been attributed to strengthening of the hosts delayed hypersensitivity response, a decrease in suppressor mechanisms and / or an increased exposure to mycobacterial antigens following bactericidal TB chemotherapy

CHEMOPROPHYLAXIS FOR TB

Need to exclude active disease. Recommended for recent close contact with potentially infectious persons with TB. ? Positive Mantoux test and need for prophylaxis. Isoniazid for nine months OR Rifampin/ Rifabutin & Pyrazinamide for two months.

THE FUTURE

Decline in the number of TB cases in persons with HIV due to better availability of ARV. Development of new anti-Tb and ARV with fewer drug interactions essential to reduce morbidity and mortality. Strengthened Public Health Services

Thank you