Tuberculosis in the Age of Hiv

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    TUBERCULOSIS IN THE AGEOF HIV

    Dr. Terry Baker

    Physician

    National Chest Hospital

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    THE PROBLEM

    Global epidemic of HIV infection.

    HIV- infected persons highly susceptibleto M. tuberculosis disease.

    Impact of HIV epidemic and TB greatestin the developing world.

    33% HIV infected population co-infectedwith TB.

    TB - the most common opportunistic lunginfection.

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    Tuberculosis & HIV

    Region Adults & ChildrenAdult living with HIV/AIDS

    Prevalence Rate

    Sub-Saharan 23.3 million8.0 %

    Latin America 1.3 million0.57 %

    Caribbean 360,000

    1.96%Western Europe 520,000

    0.25%

    North America 920,0000.56%

    World HIV/AIDS Statistics by Region, December 1999

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    New AIDS Cases Per YearPer 100,000 Population

    0

    5

    10

    15

    20

    25

    30

    35

    90 91 92 93 94 95 96 2000

    Latin America

    North America

    Caribbean

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    Tuberculosis & HIV

    Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

    Reported AIDS Cases in Barbados 1984 - 1998

    29

    2124

    15

    40

    61

    78 78

    90

    119

    95

    130

    113

    168

    (20)

    -

    20

    40

    60

    80

    100

    120

    140

    160

    180

    1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

    Years

    NumberofC

    ases

    n

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    Tuberculosis & HIV

    Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

    Reported AIDS Cases in Trinidad & Tobago 1983 - 1999

    8 1352

    83115

    166 164

    198

    249

    298 302

    264

    399

    468

    408

    459

    677

    (100)

    -

    100

    200

    300

    400

    500

    600

    700

    800

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

    Years

    NumberofCa

    ses

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    Tuberculosis & HIV

    Caribbean Epidemiology Centre (CAREC/PAHO/WHO)

    Reported AIDS Cases in Jamaica 1982 - 1999

    1 0 1 633 30

    63 62

    133

    99

    236

    359

    505

    527

    609645

    892

    30

    100

    200

    300

    400

    500

    600

    700

    800

    900

    1000

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

    Years

    Numberof

    Cases

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    CO-INFECTION RATES

    Jamaica

    YEAR No. Tb Cases No Tb/HIV Percent co -

    infected

    1994 109 5 4.6%

    1995 109 7 6.4%

    1996 121 14 11.6%

    1997 118 14 11.9%

    1998 121 10 8.3%

    1999 108 8 7.4%

    2000 124 18 14.5%

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    CO-INFECTION RATES

    Tb/ HIV Co-infected Cases, Jamaica 1991-2000

    0.00%

    2.00%

    4.00%

    6.00%

    8.00%

    10.00%

    12.00%

    14.00%

    16.00%

    1991

    1992

    1993

    1994

    1995

    1996

    1997

    1998

    1999

    2000

    Tb/ HIV

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    TUBERCULOSIS AND HIV

    Implications: two-fold

    One epidemic (i.e. HIV) can potentiallydrive a second epidemic (i.e.Tuberculosis).

    Intersection of both epidemics couldpotentially spawn a third:

    i.e. Multiple Drug Resistant Tuberculosis( MDRTb ).

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    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 non-HIV populations

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    Tuberculosis & HIV

    Conversion ( to active Tb disease afterinfection ) :

    Non-HIV : following infection, conversionis 5-10% over a lifetime

    HIV: conversion is 5-10%per year

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    PATHOGENESIS OF CO-INFECTION

    HIV-infected persons are at risk forprimary or reactivated TB, and forsecond episodes of TB.

    Reduced T1 response. CD 4+ lymphocytes unable to

    produce alpha- interferon.

    Alpha-interferon central toanti- mycobacterial immunedefenses.

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    PATHOGENESIS OF CO-INFECTION

    Presence of TB up-regulatesretroviral replication.

    TB infection producesproinflammatory cytokines.

    Risk of death 2x greater in HIV-infected patients with TB.

    Death due to progression of HIVand not TB.

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    CLINICAL PRESENTATION

    Dependent on degree ofimmunosuppression.

    Presentation varied. Extra-pulmonary TB, particularly

    lymph node involvement morecommon.

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    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

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    Central bronchiectasis and LULobe cavity

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    RULobe abscess

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    LULobe pneumonia with air bronchograms

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    HIV AND THE TREATMENT OF

    TUBERCULOSIS

    Six months vs. Nine months Clinical or bacteriological delayed

    response- Longer therapy.

    Lack of adherence to therapy mostimportant impediment to cure.

    Higher risk of MDRTb Greater risk of prolonged disease.

    Strong public health services (DOT)improve outcome.

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    TREATMENT OF TUBERCULOSIS

    First line drugs- Rifampin, Isoniazid,Pyrazinamide, Ethambutol,Streptomycin.

    Rifampin- most important and mostpotent.

    Second line drugs- Quinolones,

    Amikacin, Capreomycin.

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    ANTI-RETROVIRAL THERAPY

    HAART dramatic improvement inprognosis for HIV- infected patients.

    Drug interactions complicate themanagement of tuberculosis.

    Interaction is mainly with theRifamycins.

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    PHARMACOKINETICS OF ARVS AND

    ANTI-TB DRUGS

    Rifamycins induce CYp450, decreasingserum levels of the protease inhibitors.

    Protease inhibitors inhibit CYp450system, increasing serum rifamycinslevels to possibly toxic levels.

    Net effect is that protease inhibitors maylose their efficacy and rifamycintoxicity may be increased.

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    PHARMACOKINETICS OF ARVS AND

    ANTI-TB DRUGS

    q Rifampicin is the most potent inducer CYp450

    q Rifabutin is the least potent inducer and maybe substituted for rifampicin.

    q Clinical trials have demonstrated comparablesafety and efficacy.

    q The dose of rifabutin should be reduced from300 to 150 mg daily in pts. on Protease

    Inhibitors.

    q CDC. Report of the NIH panel to define principles of therapy of HIV infection and guidelines forthe use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998; 48 ( No.RR-5): 1 -63

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    PHARMACOKINETICS OF ARVS AND

    ANTI-TB DRUGS

    Protease inhibitors that can beconcurrently administered withRifabutin are Indinavir and Nelfinavir.

    More recently: Lopinavir, Amprenavir

    can be given, but with adjusted dosesof Rifabutin: 150mg daily.

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    PHARMACOKINETICS OF ARVS AND

    ANTI-TB DRUGS

    NNRTIs - may inhibit or induce p450.

    Efavirenz - rifabutin dosage should beincreased.

    Nevirapine can be used without dosageadjustment.

    NRTIs- Rifamycins can be used withoutdose adjustment.

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    PHARMACOKINETICS OF ARVS AND

    ANTI-TB DRUGS

    Regimens with rifamycins are shorter,have faster conversion and lowerrelapse rates than those without.

    HIV-infected TB patients treated withoutrifamycins may have a higher risk ofdying.

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    CONTROVERSIES

    ? Continuation of anti-retroviraltherapy 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 andglucocorticoid therapy. ? Malabsorption of anti-TB meds.

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    PARADOXICAL REACTIONS

    q Up to 1/3 of co-infected patients on anti-Tbmeds will experience paradoxical worseningwhen antiretroviral therapy is introduced.

    q The clinical manifestation is usually fever,intrathorac