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worsening of infiltrate on chest x-ray. new areas of infiltrate developing on therapy ... enlarging lymph nodes often with rupture and drainage if close to skin ... – PowerPoint PPT presentation

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  • A. Edward Khan, M.D.

  • Worldwide, TB is the leading cause of HIV-related
  • One third of AIDS deaths are due to TB
  • Recent estimates are that 5-6 million people are
    coinfected with HIV and TB
  • Although western nations co-epidemic is leveling
    off, developing nations rates are still rapidly
    climbing Africa, S and SE Asia

Global TB-HIV Rates
  • Of the 8 million annual TB cases worldwide 14
    are HIV-related
  • Vast majority in Africa, South and SE Asia
  • Marked variation nationally and regionally
  • Uganda, Zambia 60 TB cases are HIV positive
  • Kenya (Nairobi) 30
  • Nigeria 5
  • Thailand 25
  • India 9
  • U.S.A. 3 (median) - 46 (NYC)

HIV-TB United States
  • In U.S., there was a steady annual decline in TB
    cases until 1986, when steady increase began
    which peaked in 1992
  • New epidemic of TB included people at higher risk
    for HIV
  • men
  • racial and ethnic minorities
  • age 25-44
  • living in group settings such as prisons, shelters

TB in HIV Risks
  • Profound increase in development of active TB in
  • due to both reactivation and primary infection
  • In normal hosts, there is a 10 lifetime risk of
    active TB once exposed
  • In HIV patients, risk is 10 per year
  • This is due to the progressive decline in
    cell-mediated immunity in HIV which is necessary
    to keep quiescent tubercle bacilli in latent state

TB in HIV Reactivation vs New Infection
  • Initially assumed that in low TB prevalence
    country such as U.S., most new cases were due to
    reactivation of latent infection
  • However recent studies using strain
    finger-printing have shown that two thirds of new
    TB cases in HIV were due to recent infection (NYC
    and San Francisco)
  • Increased susceptibility in HIV to TB dramatic
  • exogenous reinfection with new (MDR) strain
    demonstrated even while patient on therapy

TB/HIV Clinical Aspects
  • MTB,because of its virulence, is an early
    opportunist in HIV
  • active disease while CD4 counts still high
  • progressive susceptibility as CD4 lt 500 cells/cc
  • Clinical presentation variable reflecting degree
    of immune impairment

TB/HIV Clinical Aspects (cont)
  • With high CD4 counts, TB presents similar to
    non-HIV hosts (upper lobe disease, cavitation,
    positive PPD)
  • In advanced HIV/AIDS, atypical pulmonary
    presentations common, as well as extra-pulmonary
  • General symptoms such as cough, fever, night
    sweats, weight loss are similar to non-HIV TB
    patients (may be shorter duration)

TB/HIV Clinical Aspects (cont)
  • Atypical pulmonary features include
  • lack of apical infiltrates
  • isolated lower or middle lobe disease
  • extensive, diffuse infiltrates
  • lack of cavitation
  • hilar and/or mediastinal lymphadenopathy
  • miliary disease
  • Normal chest x-ray (10 of HIV-TB cases)

TB/HIV Clinical Aspects (cont)
  • Extrapulmonary manifestations especially high
    when CD4 lt 100 sites include
  • CNS (meningitis, tuberculomas, abcesses)
  • lymph nodes
  • bone marrow
  • blood (cultures positive in one third of
  • liver, spleen, kidney
  • pericardium and peritoneal
  • miliary

TB/HIV Infection of Contacts
  • Questionable whether HIV-TB patients are more
    infectious to contacts than non-HIV
  • Lack of cavitation in HIV-TB results in less
    active discharge of bacilli into airways
  • Advanced debilitation and weakness render HIV
    patients less able to generate good cough
  • However, lack of immunity allows greater
    multiplication of organisms in host
  • Overall, smear positivity rates and skin test
    conversion of contacts appears similar

Effect of TB on HIV Infection
  • Active tuberculosis accelerates progression of
    HIV virologically, immunologically and clinically
  • virologically increased HIV viral load
  • immunologically lowered CD4 counts
  • clinically more opportunistic infections and
    increased mortality rates
  • HIV viral load and CD4 count improve following
    treatment of TB

Effect of TB on HIV (cont)
  • MTB in macrophages induces production of
    proinflammatory cytokines (IL-1,2,6, TNF) which
    upregulate transcription of HIV
  • IL-1 and TNF-alpha enhance replication of HIV via
    enhancer, NF-KB, which binds at the 5 LTR of HIV
    (also act directly)
  • TB cell wall antigen, lipoarabinomannan (LAM) can
    directly stimulate HIV through this mechanism

TB/HIV Diagnosis Caveats
  • Similar evaluation as for HIV negative patients
    with suspected TB
  • Must maintain high index of suspicion for TB in
    any HIV patient with new symptoms
  • Recall that 10 HIV-TB have normal CXR
  • Low threshold for respiratory isolation until TB
    ruled out
  • Almost any CXR abnormality compatible with TB in
    HIV, especially when HIV advanced

TB/HIV Diagnosis (cont)
  • Mycobacteremia often present in both local-ized
    and disseminated disease thus should obtain
    mycobacterial blood cultures
  • Maintain high index of suspicion for
    extra-pulmonary involvement
  • A negative PPD (lt 5mm) should not dissuade
    further evaluation for TB
  • Anergy more common as CD4 drops (e.g. 40 if lt
    200, almost all anergic if lt 100)

Diagnosis TB vs dMAC
  • Major differential diagnosis is disseminated
    Mycobacterium avium complex (dMAC)
  • occurs in advanced HIV/AIDS typically when CD4 lt
  • presents with fever, sweats, lymphadenopathy,
    hepatosplenomegaly, pancytopenia
  • AFB positive organisms present in tissue

Diagnosis TB vs dMAC (cont)
  • both may have granulomas (note that TB granulomas
    in HIV may not be caseating)
  • await culture/specific nucleic acid probe to
    confirm species identification
  • helpful clue is frequent/relative lack of
    pulmonary involvement in dMAC
  • often need to empirically cover both while
    waiting for culture data

TB/HIV Treatment
  • Focus on how treatment of TB may differ in HIV
    infected individuals and some unique confounding
  • In HIV negative patients, therapy 1 is IRZ for 2
    months, followed by IR for 4 months
  • If primary INH resistance prevalence gt 4, add E
    or S to initial regimen until DST known
  • If PZA not part of initial regimen, total
    duration should be 9-12 months

TB/HIV Treatment (cont)
  • Current debate whether HIV-TB patients require
    longer duration of therapy
  • Treatment response rates similar but probable
    higher relapse rates with 6 month regimen
  • Zairian study showed 12 months therapy reduced
    relapse rates from 9 to 2
  • U.S. (CDC) Guidelines currently favor 9 months of
    total therapy in HIV-TB

TB/HIV Treatment (cont)
  • In HIV, due to high incidence of peripheral
    neuropathy, all patients should have 50mg
    pyridoxine (B6) added daily to regimen
  • Adherence to regimen critical for favorable
    treatment outcome and to avoid resistance
  • DOT (Directly Observed Therapy) and combin-ation
    tablets (Rifamate, Rifater, Rifinah) help in this

TB/HIV Treatment (cont)
  • May need to empirically treat for both TB and MAC
    until culture results known
  • Suggested regimen INH/RFB/PZA/EMB/Clarithro /-
  • add parenteral agent if patient very ill

TB/HIV Drug Interactions
  • Drug interactions may be problematic when patient
    taking medications for both HIV and TB
  • Protease inhibitors (PI) and non-nucleoside
    reverse transcriptase inhibitors (NNRTI) both
    significantly interact with rifamycins via
    hepatic cytochrome P450 enzyme system

TB/HIV Drug Interactions
  • Rifamycins are potent inducers of P450 enzymes,
    which metabolize both PI and NNRTI
  • The accelerated degradation of these HIV
    medications results in subtherapeutic levels with
    usual dosing and the subsequent development of
    drug-resistant HIV

TB/HIV CDC Old Recommendations
  • Prior to March 2000, CDC recommended three
    options to treat TB and HIV
  • withholding PI or NNRTI-based therapy for
    duration of rifampin containing regimen
  • withholding PI/NNRTI for initial 2 months while
    using RIF, then resume PI/NNRTI and finish TB
    therapy with 16 months INH/EMB
  • Using rifabutin at half dose with a PI-based
    regimen with indinivir or saquinivir

TB/HIV CDC New Recommendations
  • In March 2000, CDC made additional options
  • Rifampin can be used with PI-based regimen using
    ritonivir with or without saquinivir
  • Rifampin can be used with efavirenz
  • Rifabutin (lower dose) can be used with RTV /-
    SQV, or with efavirenz (higher dose RFB)

TB/HIV Drug Interactions
  • Note that other drugs commonly used in HIV also
    interact with rifamycins (azole antifungals,
    macrolide antibiotics) and may require dose
  • Clinicians and pharmacists must be highly
    vigilant to monitor for toxicities and side
    effects of these drugs (e.g. RFB-induced uveitis
    or leukopenia) as well inefficacy of either TB or
    HIV therapy

TB/HIV Response to Treatment
  • HIV patients with TB generally respond well to
    standard regimens
  • Similar rates to HIV negative comparing
  • time to sputum conversion
  • clinical / radiographic improvement
  • overall rates of cure
  • Question as to whether relapse rate higher in
    HIV-TB (would support longer treatment duration)

TB/HIV Response to Treatment
  • Despite similar responses, higher mortality rates
    in HIV associated TB
  • 5 to 14 increased mortality during therapy
  • also increased mortality following completion of
    six month regimens, however deaths largely due to
    progression of HIV and not TB relapse

TB/HIV Adverse Drug Reactions
  • Adverse reactions to TB drugs initially reported
    as higher in HIV patients (18), but subsequent
    studies have not confirmed this
  • Thiacetazone, commonly used worldwide but not in
    U.S., strongly associated with severe cutaneous
    reactions in HIV-TB with high fatality rate
    (Stevens-Johnson, TEN)

HIV/TB Response to Therapy
  • Low serum drug levels frequently reported in
    HIV-TB patients (RIF, EMB), however routine
    monitoring not indicated unless patient not
    responding to therapy
  • Evaluate patient monthly for clinical status,
    sputum evaluation, assessment of adherence to
    therapy and adverse events

HIV/TB Slow Responders
  • If sputum still positive after 2-3 months on
    therapy, need to consider evaluation of
  • adherence
  • drug resistance (may need to repeat DST)
  • repeat chest x-ray
  • serum drug levels
  • possible impaired blood flow to diseased lung
    (perfusion scan)

Paradoxical Responses
  • Prior to HIV, well known phenomenon of
    paradoxical response while on appropriate
    therapy for TB
  • Typically manifested as
  • worsening of infiltrate on chest x-ray
  • new areas of infiltrate developing on therapy
  • enlargement of pleural effusion
  • enlarging lymph nodes often with rupture and
    drainage if close to skin

Paradoxical Response (cont)
  • These phenomena are not due to bacteriologic
    progression of disease, but to restoration of
    anti-TB immune responses and subsequent increased
  • Main consideration is distinguishing between true
    worsening of disease or treatment failure

Immune Reconstitution Syndrome
  • Similar to paradoxical response, a perhaps even
    more exaggerated phenomenon has been observed
    during HIV therapy as immunity is restored
    against clinically silent opportunistic pathogens
  • enlargement/drainage of MAC lymphadenitis
  • worsening of CMV retinitis
  • worsening of chronic active hepatitis B
  • development of active sarcoidosis

Immune Reconstitution HIV/TB
  • In patients receiving treatment for both HIV and
    TB, a marked and rapid enhancement of immune
    response may occur, resulting in
  • worsening infiltrates and development of acute
    respiratory failure
  • enlarging hilar/mediastinal lymphadenopathy
  • cerebral tuberculomas
  • numerous focal syndromes due to enhanced
    inflammation at extrapulmonary TB sites

Immune Reconstitution HIV/TB Treatment
  • When reaction is severe, steroids are often used
    in conjunction with TB and HIV therapy
  • Typically at prednisone dose of 60mg daily
    followed by a slow taper over two months
  • Alternative is to defer HIV therapy until TB
    infection is controlled

Latent TB Infection in HIV
  • Previously referred to as preventative therapy
    or prophylaxis
  • LTBI defined by a positive PPD skin test but no
    evidence of active TB disease
  • Because of high incidence of active TB developing
    in HIV patients exposed to TB, it is important to
    recognize and treat
  • Recall that in HIV patient exposed to TB, risk of
    active disease is 10 per year

LTBI in HIV (cont)
  • Screening for TB is with PPD skin test
  • 0.1ml of 5 tuberculin units
  • For HIV, gt 5mm induration is positive
  • HIV patients should get PPD annually
  • Anergy is common in HIV, especially as the CD4
    count falls

LTBI in HIV (cont)
  • Treatment of LTBI in HIV has been shown to reduce
    active TB rates by 3-5 fold
  • Treatment of LTBI recommended for any HIV patient
  • a positive PPD
  • high risk exposure to an active case regardless
    of skin test status (due to high risk of anergy)
  • Empiric therapy of LTBI in anergic HIV no benefit
    despite high local prevalence (10)

LTBI in HIV Treatment
  • Several regimens available for treatment of LTBI
    in HIV
  • INH x 9 months (can also be given as 900mg
    biweekly directly observed (DOPT) but efficacy
    not proven)
  • Rifampin (or rifabutin) x 6 months
  • RIF PZA daily for 2 months
  • EMB (either PZA or oflox) for 12 months
  • Tailor therapy if drug resistant case contact
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