Download Treating Opportunistic Infections Among HIV

Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected Adults
and Adolescents
Mycobacterium Tuberculosis
Gabriel Rebick, MD, MPH – STAR Clinic
Downstate Medical Center
Slides Prepared by the AETC National Resource Center based on
recommendations from the CDC,
National Institutes of Health, and HIV Medicine Association/Infectious Diseases
Society of America
MTB: Epidemiology
 Worldwide, 10 million people coinfected
with HIV and MTB
 90% in developing countries
 Most common cause of death in AIDS
patients
 In the United States, decline in HIVrelated TB since 1992, likely related to
ART
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MTB: Epidemiology (2)
 Infection via inhalation of droplet nuclei with
MTB organisms
 Latent TB infection (LTBI): immune system
usually limits multiplication of TB bacilli, but
bacilli may persist
 Persons with LTBI are asymptomatic and are not
infectious
 Active TB disease: can develop immediately
after infection (primary TB) or with reactivation
of LTBI
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TB re-activation
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MTB: Epidemiology (3)
 Reactivation of latent TB:
 More likely in HIV-infected patients; risk increases
soon after HIV infection
 In non-HIV infected individuals:
 10% lifetime risk of re-activation (5% in first 2 years, 5% in
rest of life)
 Increased risk associated with: ESRD, silicosis, smoking,
diabetes, H+N cancer, immunosuppression/txp’t
 3-16% annual risk in HIV-infected patients
 TB disease can occur at any CD4 count, but
risk increases with progression of
immunodeficiency
 TB coinfection increases HIV viral loads and
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TB Disease: Clinical Manifestations
 Common symptoms included cough, fever,
sweats, weight loss, fatigue
 May be subclinical or have few symptoms, even
if culture positive
 Immune reconstitution following ART initiation
can unmask subclinical TB, with inflammatory
reactions at site of infection
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TB Disease: Clinical Manifestations (2)
 Degree of immunosuppression influences clinical,
radiographic, and histopathologic presentation of
active TB
 CD4 count >350 cells/µL: as in HIV uninfected
 TB usually limited to lungs
 Chest X ray: upper lobe infiltrates, +/− cavitation
 Extrapulmonary disease (pleuritis, pericarditis,
meningitis, lymphadenitis), more common in HIV
infection, regardless of CD4 count
 More common in advanced immunosuppression
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TB Disease: Clinical Manifestations (3)
 Advanced HIV
 TB may be systemic disease: high fevers, rapid
progression, sepsis syndrome
 Extrapulmonary TB, with or without pulmonary disease,
in most TB patients with CD4 count <200 cells/µL
 TB may be subclinical or with few symptoms
 Chest X ray: lower lobe, middle lobe, interstitial, and
miliary infiltrates are common; cavitation less common
 Intrathoracic lymphadenopathy is common
 Granulomas may be poorly formed or absent
 Sputum smear and culture may be positive even with
normal chest X ray
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TB Disease: Clinical Manifestations (4)
Chest X ray: TB manifesting as a
focal opacity in the right lung
Credit: L. Huang, MD; HIV InSite
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Chest X ray: TB with bilateral hilar
lymphadenopathy and diffuse interstitial
and airspace opacities
Credit: L. Goozé, MD; C. Daley, MD;
HIV InSite
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Pulmonary TB
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TB Disease: Clinical Manifestations (5)
Chest X ray: miliary pattern of TB in an HIV-infected patient
with advanced immunosuppression
Credit: HIV Web Study (www.hivwebstudy.org) © 2006, University of Washington
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Miliary TB
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TB lymphadenitis (Scofula)
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TB Disease: Diagnosis
Screening
 Test all for LTBI at time of HIV diagnosis
(regardless of TB risks)
 If CD4 count <200 cells/µL and no indications for
empiric LTBI treatment, retest for LTBI when count
rises to ≥200 cells/µL on ART
 Annual testing only for those at high risk or
repeated or ongoing exposure to active TB
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TB Disease: Diagnosis (2)
Testing methods
 Tuberculin skin test (TST):
 0.1 mL purified protein derivative (PPD)
 In HIV infection, positive is induration ≥5 mm at 48-72
hours
 Specificity 56-95%
 Requires 2 office visits; lower specificity in recipients of
BCG vaccination
 Interferon-gamma release assay (IGRA):
 IFN-γ release in response to MTB-specific peptides
 Higher specificity (92-97%); less cross-reactivity
resulting from BCG vaccination or other non-TB
mycobacterial exposure
 Advanced immunosuppression may cause
false-negative results to both tests, perhaps
less with IGRAs
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TB Disease: Diagnosis (3)
 In the U.S., only 47-65% complete TST
screening; use of IGRA may result in
better rates of screening
 Use of both TST and IGRA is not
recommended in the U.S.
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TB Disease: Diagnosis (4)
TST or IGRA test results
 If negative and CD4 count <200 cells/µL:
retest after ART initiation and increase in
CD4 count to >200 cells/µL
 If positive test: chest X ray and clinical
evaluation to screen for active TB
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Interpreting PPD tests
 An induration of 5 or more millimeters is
considered positive in
 -HIV-infected persons
 A recent contact of a person with TB disease
 Persons with fibrotic changes on chest radiograph
consistent with prior TB
 Patients with organ transplants
 Persons who are immunosuppressed for other
reasons (e.g., taking the equivalent of >15 mg/day of
prednisone for 1 month or longer, taking TNFa antagonists)
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Interpreting PPD tests
 An induration of 10 or more millimeters is
considered positive
 Recent immigrants (< 5 years) from high-prevalence
countries
 Injection drug users
 Residents and employees of high-risk congregate
settings
 Mycobacteriology laboratory personnel
 Persons with clinical conditions that place them at
high risk
 Children < 4 years of age
 Infants, children, and adolescents exposed to adults in
high-risk categories
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Interpreting PPD tests
 An induration of 15 or more millimeters
 is considered positive in any person, including
persons with no known risk factors for TB. However,
targeted skin testing programs should only be
conducted among high-risk groups.
 >5mm – High risk for re-activation
 >10mm – High risk for true positive test
 >15mm – All others
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Testing pitfalls - PPD
 False Positive tests
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Infection with nontuberculosis mycobacteria
Previous BCG vaccination
Incorrect method of TST administration
Incorrect interpretation of reaction
Incorrect bottle of antigen used
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Testing pitfalls - PPD
 False Negative tests
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Cutaneous anergy
Recent TB infection (within 8-10 weeks of exposure)
Very old TB infection (many years)
Very young age (less than 6 months old)
Recent live-virus vaccination (e.g., measles and
smallpox)
Overwhelming TB disease
Some viral illnesses (e.g., measles and chicken pox)
Incorrect method of TST administration
Incorrect interpretation of reaction
 Useful website:
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http://www.tstin3d.com/en/calc.html
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Why do a “two-step” test (PPD)
 What is a Boosted Reaction?
 “waning” T-cell immunity makes initial PPD test falsely
negative.
 Second serial PPD elicits a true-positive response
(boosted by initial test.
 Why is Two-Step Testing Conducted?
 Two-step testing is useful for the initial skin testing of
adults who are going to be retested periodically.
 This two-step approach can reduce the likelihood that
a boosted reaction to a subsequent TST will be
misinterpreted as a recent infection.
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TB Disease: Diagnosis
 Direct initial testing at site of symptoms or signs
 Chest X ray
 Perform in all with HIV+ with suspected TB, even if no
pulmonary symptoms – pulmonary involvement is
common
 Normal chest X ray does not rule out active pulmonary
TB
 Sputum samples for AFB smear and culture
 3 samples recommended
 Sputum smear negativity is common in HIV, especially
in severe immunodeficiency and noncavitary disease
 AFB culture sensitivity not affected by HIV or
immunodeficiency
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TB Disease: Diagnosis (2)
 Extrapulmonary TB: sample suspected
tissue or fluid
 Lymph nodes: histopathology, smear, and
culture
 Pleural or pericardial fluid, ascites, CSF
 Urine and blood cultures: sensitivity relatively
high in advanced immunodeficiency
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TB Disease: Diagnosis (3)
 Nucleic acid amplification (NAA)
 May rapidly identify M tuberculosis
 NAA recommended on at least 1 specimen from
all patients with suspected pulmonary TB
 In AFB smear-positive specimens, highly
predictive of TB
 Can be used to direct therapy and make clinical
decisions
 More sensitive than AFB smear
 Positive in 50%-80% of smear-negative, culturepositive specimens
 Licensed only for sputum samples
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TB Disease: Diagnosis (4)
 TST or IGRA may be useful in unusual
circumstances (eg, if definitive culture
evidence for active TB cannot be obtained)
 Evidence of previous infection increases
likelihood of TB
 Negative test result does not rule out TB
disease
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TB Disease: Diagnosis (5)
 Drug susceptibility testing on initial isolates
from all patients with suspected TB
 Test first-line TB drugs
 Repeat if sputum cultures remain positive
for MTB at/after 4 months of treatment, or
become positive again after ≥1 month of
negative cultures
 Second-line drug susceptibility testing:
 Only in reference laboratories, only on
specimens with resistance to first-line TB
medications
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TB Disease: Diagnosis (6)
 Conventional susceptibility testing is well
validated by requires culture of M
tuberculosis; may take 6 weeks
 Genotypic testing allows rapid detection of
resistance (24 hrs)
 Commercial tests available for RIF and INH
resistance
 Commercial tests for other TB drugs are in
development
 CDC can provide rapid molecular testing for
patients who do not have local access to
this testing
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TB Disease: Diagnosis (7)
 Consider drug resistance testing:
 Known exposure to drug-resistant TB
 Country or area with high rates of drugresistant TB
 Persistently positive smear or culture results
at/after 4 months of treatment
 Previous TB treatment, particularly if no DOT
of if interrupted
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Drug resistance in TB
 Drug resistant TB
 Resistant to one of the first line TB drugs:
 Isoniazid, Rifampin, Ethambutol, Pyrazinamide,
Streptomycin
 Multi-drug resistant TB (MDR-TB)
 Resistant to isoniazid AND rifampin (and possibly
other drugs)
 Extensively drug resistant TB (XDR-TB)
 Resistant to Isoniazid, rifampin, quinolones and at
least one injectable agent (amikacin, capreomycin)
 Totally drug resistant TB (TDR-TB)
 Resistant to all locally tested drugs
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Worldwide TB incidence
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MDR TB – Worldwide map
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XDR-TB Worldwide case reports
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TB Disease: Treatment
 For patients with clinical and radiographic
presentation suggestive of TB, start empiric
treatment for TB, after collection of specimens
for culture and molecular diagnostic tests
 Early diagnosis and treatment are critical – TB
can progress rapidly in advanced
immunodeficiency
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TB Disease: Treatment
 Rule out active TB: chest X ray and clinical
evaluation
 All HIV-infected persons should be treated, if no
evidence of active TB and:
 Positive screening test for LTBI and no history of
treatment for active or latent TB
 Close contact with someone with infectious TB,
regardless of LTBI test results
 For HIV-infected persons who are anergic and
no recent contact with infectious TB: LTBI
treatment not recommended (no evidence of
clinical benefit)
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Latent TB:Treatment (3)
 Regimens duration less than 9 months may
enhance adherence
 Ideally – 9 months of daily isoniazid – 300 mg daily
(Decreases risk of reactivation by ~90%)
 3-month regimen of once weekly INH + rifapentine as
effective as 9-month INH regimen; not recommended
for HIV-infected persons on ART because of potential
interactions between some ARVs and rifapentine
 2-month regimen of rifampin + pyrazinamide not
recommended: risk of severe hepatotoxicity
 4-month regimen with rifampin alone good alternative
 ART decreases risk of TB disease; use of both
ART and LTBI treatment is recommended
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TB Disease: Treatment (2)
General principles
 2 phases: intensive (2 months) and continuation
(4+ months)
 If TB is suspected, empiric treatment should be
started and continued until diagnostic workup is
complete
 DOT is recommended for all
 Addition of case management, other social support,
and linkage to HIV care further increases likelihood of
successful treatment (enhanced DOT)
 Treatment duration based on total number of
doses ingested, rather than on duration of
treatment administration
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TB Disease: Treatment (3)
For drug-susceptible pulmonary TB
 Intensive phase: 2 months
 Isoniazid (INH), rifampin (RIF) or rifabutin
(RFB), pyrazinamide (PZA), ethambutol
(EMB)
 If concern about resistance to RIF, use
expanded regimen (consult with expert)
 If organism is susceptible to INH and RIF,
may discontinue EMB
 Continuation phase: ≥4 months
 INH + RIF (or RFB)
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TB Disease: Treatment (4)
Frequency of dosing for HIV-infected patients:
 Intensive phase
 Daily therapy by DOT recommended (7 days/week for
56 doses or 5 days/week for 40 doses)
 2-3 times weekly dosing: increased risk of treatment
failure or relapse, with rifamycin resistance
 Continuation phase
 Daily (5-7 days/week) or TIW dosing recommended
 Less-frequent dosing: increased risk of treatment
failure, relapse, and rifamycin resistance
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TB Disease: Treatment (5)
 Duration of treatment for HIV-infected patients
(drug-susceptible TB):
 Optimal duration unknown; some data in
high-burden settings show higher rates of
recurrence if treated 6 months vs 9 or 12
months
 In the U.S., 6 months recommended for
most with drug-susceptible TB
 9 months if sputum culture positive at 2 months
 9-12 months if CNS involvement
 6-9 months if bone and joint TB
 6-9 months if extrapulmonary TB at other sites
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TB Disease: Treatment (Drug Sensitive) (6)
 Intensive phase (8 weeks), QD dosing (5-7
days/week):
 INH 5 mg/kg (usual dose 300 mg) PO QD +
 RIF* 10 mg/kg (usual dose 600 mg) PO QD (or
RFB** 5 mg/kg (usual dose 300 mg) PO QD) +
 PZA 40-55 kg, 1,000 mg PO QD; 56-75 kg, 1,500
mg PO QD; >75 kg, 2,000 mg PO QD +
 EMB 40-55 kg, 800 mg PO QD; 56-75 kg, 1,200 mg
PO QD; >75 kg, 1,600 mg PO QD
 For TIW regimens, see Guidelines
* Rifampin interacts with many ARVs and other drugs; consult
information on contraindicated combinations
** Adjust dosage for interacting ARVs
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TB Disease: Treatment (Drug Sensitive) (7)
 Continuation phase (≥16 weeks)
 QD regimen (5-7 days/week):
 INH 5 mg/kg (usual dose 300 mg) PO QD + RIF*
10 mg/kg (usual dose 600 mg) PO QD (or RFB** 5
mg/kg [usual dose 300 mg] PO QD)
OR
 TIW regimens:
 INH 15 mg/kg (usual dose 900 mg) PO TIW + RIF*
10 mg/kg (usual dose 600 mg) PO TIW (or RFB** 5
mg/kg [usual dose 300 mg] PO TIW)
* Rifampin
interacts with many ARVs and other drugs; consult
information on contraindicated combinations
** Adjust dosage for interacting ARVs
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TB Disease: Treatment (8)
Other therapies
 Pyridoxine (25-50 mg QD) for all on INH (to
decrease risk of neuropathy)
 Corticosteroids improve survival for CNS or
pericardial disease (in constrictive
pericarditis)
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TB Disease: Monitoring
 Monitor monthly for adherence and drug toxicity
 Directly observed therapy (DOT) should be used
with intermittent dosing regimens
 INH: liver toxicity possible, check baseline AST
or ALT, bilirubin; repeat if abnormal; monitor
closely if viral hepatitis
 Asymptomatic patients: discontinue INH if AST
increases >5 times upper limit of normal (ULN)
 Symptomatic patients: discontinue INH if AST
increases >3 times ULN
 Baseline elevated transaminases: discontinue INH if
AST increases >2 times ULN
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TB Disease: Starting ART
 For optimal management of HIV-related
TB, treat both infections
 Sequential treatment of TB followed by HIV
treatment is not recommended
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TB Disease: Starting ART (2)
 Cotreatment :
 Improves survival, particularly if CD4 count
<50 cells/µL
 Decreases risk of other OIs
 Can achieve high rates of HIV suppression
 May improve TB treatment outcomes
 Risks of early ART:
 Multidrug therapy for 2 infections, drug-drug
interactions, overlapping side effects, IRIS
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TB Disease: Starting ART (3)
 ART-naive patients:
 CD4 <50 cells/µL: start ART within 2 weeks
 CD4 ≥50 cells/µL: start ART by 8-12 weeks
 TB meningitis and low CD4: optimal timing of
ART is not clear; risk of severe adverse events
with early ART; consult with experts
 Patients on ART:
 Start TB treatment immediately
 Optimize ART if needed to suppress HIV
 Modify ART to reduce risk of drug interactions
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Rates of Death, AIDS-Defining Illness or Death, and IRIS, According to Baseline CD4+ T-Cell Count.
Abdool Karim SS et al. N Engl J Med 2011;365:1492-1501.
SAPIT STUDY: Kaplan–Meier Curves for Survival without an AIDS-Defining Illness.
Abdool Karim SS et al. N Engl J Med 2011;365:14921501.
TB Disease: Starting ART (4)
Drug-drug interactions
 Rifamycins (especially RIF)
 Induce CYP3A metabolism of many drugs, including
most protease inhibitors (PIs) and nonnucleoside reverse
transcriptase inhibitors (NNRTIs)
 Have other complex interactions with some ARVs
 Dosage adjustments may be required, and some
combinations cannot be used
 Considerable interpatient variations: consider therapeutic
drug monitoring for RFB and/or PIs or NNRTIs
 Despite these issues, rifamycins should be used for
treatment of TB, if possible
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TB Treatment + ART – practical issues
 Recommended regimen:
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Efavirenz based (ie. EFV/TDF/FTC)
Dose of efavirenz may require adjustment
Boosted-PI not recommended w/ rifampin
Integrase inhibitors are not recommended
 If rifabutin is used – more flexibility
 Can use boosted-Pis
 Can use integrase inhibitors
 Dose adjustment of rifabutin may be required
 Suggest involving pharmacy in all pts!
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TB Disease: Monitoring
 Close follow-up is essential to ensure treatment
success
 Pulmonary TB: monthly sputum smear and
culture until 2 consecutive negative cultures
 Sputum cultures usually convert to negative with 2
months of TB therapy; may be longer if high burden of
disease (eg, cavitary TB)
 Positive cultures after 4 months: evaluate for possible
treatment failure and acquired drug resistance
 Extrapulmonary TB: follow-up evaluation
depends on sites involved
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TB Disease: Monitoring (2)
 Clinical and laboratory assessments at least
monthly (liver and renal function tests, CBC,
platelets, CD4)
 At each visit, screen for lapses in adherence,
possible adverse effects
 Patient on EMB: ask about blurred vision or scotomata;
test for visual acuity and color discrimination (Ishihara
testing)
 Routine drug level monitoring is not
recommended (consider if slow response to
treatment)
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TB Disease: Adverse Events
 First-line TB medications should not be
stopped permanently without strong
evidence that a TB drug was the cause of
a reaction
 Consult with experts
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TB Disease: Adverse Events (2)
 GI reactions: common with most TB drugs;
usually can be managed symptomatically; check
AST and bilirubin
 Rash: common with all TB drugs; if minor, use
antihistamines for symptomatic relief; if severe,
stop all TB drugs until rash is substantially better;
restart TB drugs one by one at intervals of 2-3
days; if recurrence: stop the last drug added
 If generalized rash + fever or mucous membrane
involvement, stop all drugs, switch to alternative TB
medications; consult with expert
 Fever after several weeks of TB treatment:
exclude worsening TB, superinfection, IRIS; if
drug fever suspected, stop all TB drugs; after
resolution of fever, restart as above
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TB Disease: Adverse Events (3)
 AST elevation: common, may be caused by INH,
RIF/RFB, or PZA; risk higher in patients taking
other hepatotoxic drugs and in those with liver
disease
 If no symptoms and AST <3 times ULN, continue TB
therapy but increase frequency of monitoring
 If AST ≥5 times ULN, or ≥3 times ULN with symptoms,
or if significant increase in bilirubin or alkaline
phosphatase, stop hepatotoxic drugs and evaluate
patient (eg, for symptoms, viral hepatitis, hepatotoxins)
 Substitute nonhepatotoxic drugs, until alternative longer-term
regimen is designed
 After AST decreases to <2 times ULN, may restart suspected
TB meds one at a time; if hepatotoxicity recurs, stop the last
drug added
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TB Disease: Adverse Events (4)
 EMB may cause visual disturbances
 Monthly review of symptoms
 Monthly visual acuity and color discrimination
testing for all patients on dosages that are
higher than recommended and all patients on
EMB >2 months
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Ishihara testing (Ethambutol)
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TB Disease: IRIS
 Paradoxical TB IRIS: temporary exacerbation of
symptoms, signs, or radiographic manifestations
of TB after initial improvement on TB treatment;
may include:
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High fever
Worsening respiratory status
New or worsening lymphadenopathy
Worsening CNS lesions or symptoms
Worsening pulmonary infiltrates
Increasing pleural effusions
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TB Disease: IRIS (2)
 Symptoms usually begin in the first 1-4 weeks
after starting ART, usually last 2-3 months
 Risk factors: low CD4 count at start of ART
(especially <100 cells/µL), disseminated or
extrapulmonary TB, ART started shortly after start
of TB therapy (particularly within first 2 months of
TB therapy)
 No definitive tests; may be difficult to distinguish
IRS from worsening of TB, treatment failure, new
infection, adverse drug reaction, etc.
 Evaluate thoroughly for other causes
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TB Disease: IRIS (3)
Management
 Usually self-limited; can be prolonged and severe
 Mild IRIS
 Symptomatic treatment, NSAIDs
 Aspiration of fluid collections, if indicated for symptomatic relief
 Moderate-to-severe IRIS
 Consider corticosteroids:
 Some data show more rapid improvement, though no mortality benefit in nonCNS TB IRIS
 CNS TB IRIS: corticosteroids decreased mortality
 Taper corticosteroids over 4 weeks or longer, based on clinical assessment
 Avoid in patients with Kaposi sarcoma
 Continue TB therapy
 Continue ART if possible (unless IRIS is life threatening)
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TB Disease: IRIS (4)
 Unmasking TB IRIS: patients with unrecognized
TB when they start ART; may develop accelerated
and inflammatory presentation of TB in the first
weeks of ART
 May have rapid onset of symptoms, features similar to
bacterial pneumonia, and/or abscesses and
lymphadenitis
 Treatment: standard TB treatment; corticosteroids if lifethreatening manifestations
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TB Disease: Treatment Failure
 Causes include
 Undetected primary drug resistance, inadequate
adherence to therapy, incorrect or inadequate
regimen, subtherapeutic drug levels (malabsorption,
drug interactions), superinfection with resistant MTB,
acquired drug resistance
 Evaluate with history, physical exam, chest X ray
 Review initial test results, therapy regimen,
adherence
 Repeat culture and susceptibility testing; sample
all available sites
 Perform rapid resistance testing on direct specimens
or positive cultures
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TB Disease: Treatment Failure (2)
 Pending repeat culture and resistance test
results, broaden treatment using second-line TB
drugs (consult with expert)
 Drug-resistant TB: optimal management not
established
 Resistance to INH:
 Evidence of increased risk of treatment failure with
baseline INH resistance
 Substitute fluoroquinolone for INH, at least for first 2
months of therapy and perhaps for continuation
phase, with RIF and EMB; total duration 9 months
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TB Disease: Treatment Failure (3)
 Resistance to RIF:
 Treatment is more complex, less effective,
and of longer duration
 Second- and third-line TB medications should
be used, based on drug susceptibility results
 New drugs are in development
 Consult with expert
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