Transcript Mycobacterial Infections

Guidelines for Prevention and Treatment of Opportunistic
Infections in HIV-Infected Adults and Adolescents
Mycobacterial Infections Slide Set
Prepared by the AETC National Coordinating Resource Center based on
recommendations from the CDC, National Institutes of Health, and HIV
Medicine Association/Infectious Diseases Society of America
About This Presentation
These slides were developed using recommendations
published in May 2013. The intended audience is
clinicians involved in the care of patients with HIV.
Users are cautioned that, because of the rapidly
changing field of HIV care, this information could
become out of date quickly. Finally, it is intended that
these slides be used as prepared, without changes in
either content or attribution. Users are asked to honor
this intent.
- AETC National Coordinating Resource Center
http://www.aidsetc.org
www.aidsetc.org
May 2013
2
Mycobacterial Infections


Mycobacterium tuberculosis (MTB) disease
Disseminated Mycobacterium avium complex
(MAC) disease
www.aidsetc.org
May 2013
3
Mycobacterium tuberculosis (MTB) Disease






Epidemiology
Prevention
Diagnosis
Treatment
Clinical Manifestations
Considerations in Pregnancy
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 HIV-related TB
since 1992, likely related to ART
www.aidsetc.org
May 2013
5
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
www.aidsetc.org
May 2013
6
MTB: Epidemiology (3)
 Reactivation of latent TB:
 More likely in HIV-infected patients; risk increases soon
after HIV infection
 3-16% annual risk in HIV-infected patients; in HIV
uninfected, ~5% lifetime risk
 TB disease can occur at any CD4 count, but risk
increases with progression of immunodeficiency
 TB coinfection increases HIV viral loads and
progression of HIV
www.aidsetc.org
May 2013
7
MTB: Preventing Exposure
 HIV-infected patients who travel or work in highprevalence settings should be counseled about
TB infection risk and tested for LTBI
 Exposure risks in some health care and
correctional settings in the United States – usual
precautions
www.aidsetc.org
May 2013
8
MTB: Preventing Disease
 Diagnosis and treatment of LTBI is key aspect of
preventing active TB
 Treatment of LTBI lowers risk of TB disease (by
62%) and death (by 26%)
www.aidsetc.org
May 2013
9
Latent 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
www.aidsetc.org
May 2013
10
Latent 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
www.aidsetc.org
May 2013
11
Latent 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.
www.aidsetc.org
May 2013
12
Latent 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
www.aidsetc.org
May 2013
13
Latent 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)
www.aidsetc.org
May 2013
14
Latent TB Disease: Treatment (2)
 Preferred (duration: 9 months):
 INH 300 mg PO QD (+ pyridoxine 25 mg PO QD, to reduce
risk of peripheral neuropathy)
 INH or 900 mg PO BIW (+ pyridoxine 25 mg PO QD)
 Alternative (duration: 4 months):
 Rifampin: 600 mg PO QD
 Rifabutin: dose adjusted according to concomitant ARVs
 Note: potential drug interactions between rifamycins and
PIs, NNRTIs, integrase inhibitors; dosage adjustments may
be required; some combinations are contraindicated
 For persons exposed to drug-resistant TB: consult
with experts
www.aidsetc.org
May 2013
15
Latent TB Disease: Treatment (3)
 Regimens duration less than 9 months may
enhance adherence
 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
 ART decreases risk of TB disease; use of both
ART and LTBI treatment is recommended
www.aidsetc.org
May 2013
16
Latent 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
www.aidsetc.org
May 2013
17
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
www.aidsetc.org
May 2013
18
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
www.aidsetc.org
May 2013
19
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
www.aidsetc.org
May 2013
20
TB Disease: Clinical Manifestations (4)
Chest X ray: TB manifesting as a
focal opacity in the right lung
Credit: L. Huang, MD; HIV InSite
www.aidsetc.org
Chest X ray: TB with bilateral hilar
lymphadenopathy and diffuse interstitial and
airspace opacities
Credit: L. Goozé, MD; C. Daley, MD; HIV InSite
May 2013
21
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
www.aidsetc.org
May 2013
22
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
www.aidsetc.org
May 2013
23
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
www.aidsetc.org
May 2013
24
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, culture-positive
specimens
 Licensed only for sputum samples
www.aidsetc.org
May 2013
25
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
www.aidsetc.org
May 2013
26
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
www.aidsetc.org
May 2013
27
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
www.aidsetc.org
May 2013
28
TB Disease: Diagnosis (7)
 Consider drug resistance testing:
 Known exposure to drug-resistant TB
 Country or area with high rates of drug-resistant TB
 Persistently positive smear or culture results at/after 4
months of treatment
 Previous TB treatment, particularly if no DOT of if
interrupted
www.aidsetc.org
May 2013
29
TB Disease: Diagnosis (8)
 Multidrug resistant (MDR): resistance to at least
INH and RIF
 Extensively drug resistant (XDR): resistance to
MDR TB plus resistance to a fluoroquinolone and
either kanamycin, amikacin, or capreomycin
 High risk of treatment failure and relapse; consult
with specialist
www.aidsetc.org
May 2013
30
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
www.aidsetc.org
May 2013
31
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
www.aidsetc.org
May 2013
32
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)
www.aidsetc.org
May 2013
33
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
www.aidsetc.org
May 2013
34
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
www.aidsetc.org
May 2013
35
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
www.aidsetc.org
May 2013
36
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
www.aidsetc.org
May 2013
37
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
www.aidsetc.org
May 2013
38
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
www.aidsetc.org
May 2013
39
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
www.aidsetc.org
May 2013
40
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
www.aidsetc.org
May 2013
41
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
www.aidsetc.org
May 2013
42
TB Disease: Starting ART (5)
 NRTIs: no significant interactions with rifamycins
 NNRTIs:
 Efavirenz 600 mg QD + 2 NRTIs is preferred ART regimen
for patients taking RIF
 Dosage adjustments for weight >60 kg appears not supported by
good data
 Nevirapine- more significant interactions with RIF.
 Can be used for patients unable to take efavirenz
 Nevirapine + didanosine + lamivudine inferior to efavirenz with
the same NRTIs
 Monitor HIV RNA closely
 If on RIF for ≥2 weeks, omit lead-in dose of nevirapine
 RFB: increased dosage of RFB needed if used with
efavirenz
www.aidsetc.org
May 2013
43
TB Disease: Starting ART (6)
 PIs:
 RIF lowers serum levels of most PIs, including ritonavirboosted PIs: contraindicated
 RFB has little effect on levels of ritonavir-boosted PIs but all
PIs markedly increase RFB concentrations
 Dosage reduction of RFB is needed, though optimal dosing is not
clear
 150 mg QD recommended for those on boosted PI, at least during first
2 months of TB treatment
 Some reports of acquired rifamycin resistance with 150 mg TIW dosing
of RFB + a boosted PI
 Consider therapeutic drug monitoring for RFB
 Closely monitor ART adherence (need to increase
RFB dosage if PI is stopped)
www.aidsetc.org
May 2013
44
TB Disease: Starting ART (7)
 Integrase inhibitors:
 Raltegravir: RIF decreases raltegravir levels
 Raltegravir 800 mg BID recommended but not studied in clinical
trials
 Elvitegravir + cobicistat: no data; drug interactions expected
to be similar to those with boosted PIs
 Use only when required for ARV potency; consult with an
expert
 CCR5 antagonist: RIF and possibly RFB decrease
maraviroc levels; few data; consult with expert
 Fusion inhibitor: enfuvirtide not affected by rifamycins
www.aidsetc.org
May 2013
45
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
www.aidsetc.org
May 2013
46
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
 Routine drug level monitoring is not
recommended (consider if slow response to
treatment)
www.aidsetc.org
May 2013
47
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
www.aidsetc.org
May 2013
48
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
www.aidsetc.org
May 2013
49
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
www.aidsetc.org
May 2013
50
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
www.aidsetc.org
May 2013
51
TB Disease: IRIS
 Paradoxical TB IRIS: temporary exacerbation of
symptoms, signs, or radiographic manifestations
of TB after initial improvement on TB treatment;
may include:
 High fever
 Worsening respiratory status
 New or worsening lymphadenopathy
 Worsening CNS lesions or symptoms
 Worsening pulmonary infiltrates
 Increasing pleural effusions
www.aidsetc.org
May 2013
52
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
www.aidsetc.org
May 2013
53
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 non-CNS 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)
www.aidsetc.org
May 2013
54
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
life-threatening manifestations
www.aidsetc.org
May 2013
55
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
www.aidsetc.org
May 2013
56
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
www.aidsetc.org
May 2013
57
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
www.aidsetc.org
May 2013
58
TB Disease: Management of Drug
Resistance
 Resistance to INH:
 (RIF or RFB) + EMB + PZA + (moxifloxacin or levofloxacin)
for 2 months, followed by RIF or RFB) + EMB +
(moxifloxacin or levofloxacin) for 7 months
 Empiric therapy for suspected resistance to rifamycin
+/− resistance to other drugs:
 INH + RIF or RFB + PZA + EMB + moxifloxacin or levofloxacin +
(an aminoglycoside or capreomycin)
 Suspected resistance to rifamycins +/− resistance to
other drugs:
 Individualize treatment and duration based on susceptibility,
clinical and microbiological responses
 Manage with specialist
www.aidsetc.org
May 2013
59
TB Disease: Preventing Recurrence
 Recurrence risk somewhat higher in HIV infection,
especially in TB-endemic settings, usually via
reinfection
 In U.S., reinfection is uncommon
 In high-burden settings (high risk of re-exposure),
treatment with INH for 6-9 months after completion of
standard TB therapy can decrease risk of reinfection
 Not recommended in low-burden settings
 ART probably decreases risk of reinfection with TB
www.aidsetc.org
May 2013
60
TB Disease: Considerations in
Pregnancy
 All pregnant women should be tested (TST),
unless documented negative TST result
 All at high risk of repeated or ongoing exposure should
be tested
 Limited data on IGRAs in pregnant women
 Diagnosis as in nonpregnant adults
(minimize fetal radiation exposure)
 TB (pulmonary or extrapulmonary) may increase
complications, including preterm birth, low
birthweight, intrauterine growth retardation
www.aidsetc.org
May 2013
61
TB Disease: Considerations in
Pregnancy (2)
 LTBI: consider treatment during pregnancy (after
ruling out active TB)
 Weigh risk of INH toxicity against consequences of
active TB
 High risk of maternal and infant mortality in HIV-infected
pregnant women with TB
 ART decreases risk of progression from LTBI to active
TB
www.aidsetc.org
May 2013
62
TB Disease: Considerations in
Pregnancy (3)
 TB disease:
 Treat as in nonpregnant adults
 Therapy should not be withheld because of pregnancy
www.aidsetc.org
May 2013
63
TB Disease: Considerations in
Pregnancy (4)
 Treatment considerations (1)
 INH: not teratogenic; hepatotoxicity may be more
frequent; monitor transaminases monthly through
postpartum period
 RIF: not teratogenic
 PZA: limited experience in human pregnancy (not
teratogenic in animals); WHO recommends routine
use, but limited data and not recommended in United
States; if PZA not used in initial treatment, minimum
duration of therapy is 9 months
www.aidsetc.org
May 2013
64
TB Disease: Considerations in
Pregnancy (5)
 Treatment considerations (2)
 EMB: teratogenic in animals at high doses; no
evidence of teratogenicity in humans; no evidence of
ocular toxicity in exposed infants
 Second-line drugs: limited experience; some should be
avoided; consult with experts
www.aidsetc.org
May 2013
65
Disseminated Mycobacterium avium
Complex (MAC) Disease






Epidemiology
Prevention
Diagnosis
Treatment
Clinical Manifestations
Considerations in Pregnancy
Disseminated MAC: Epidemiology
 Multiple related species of non-TB mycobacteria: M
avium, M intracellulare, others
 M avium is the causative agent in >95% of AIDS
patients with disseminated MAC disease
 MAC organisms are ubiquitous in the environment
 Transmission believed to be via inhalation, ingestion,
inoculation via respiratory or GI tract; person-toperson transmission unlikely
 Not associated with specific environmental
exposures or behaviors
www.aidsetc.org
May 2013
67
Disseminated MAC: Epidemiology (2)
 Usually occurs in people with CD4 count
<50 cells/µL
 Incidence: 20-40% in patients with advanced
AIDS who are not on effective ART or MAC
prophylaxis
 Other risk factors: plasma HIV RNA >100,000
copies/mL, previous opportunistic infections,
previous colonization with MAC
 10-fold decrease in incidence in areas with
effective ART
www.aidsetc.org
May 2013
68
Disseminated MAC: Clinical
Manifestations
 Usually a disseminated multiorgan infection
 Symptoms: fever, night sweats, weight loss, fatigue,
diarrhea, abdominal pain
 Localized manifestations most common in
persons on ART: lymphadenitis (cervical or
mesenteric), pneumonitis, pericarditis,
osteomyelitis, skin or soft tissue abscesses,
genital ulcers, CNS infection
 These also may be manifestations of IRIS
www.aidsetc.org
May 2013
69
Disseminated MAC: Clinical
Manifestations (2)
 Physical exam or imaging: hepatomegaly,
splenomegaly, or lymphadenopathy
(paratracheal, retroperitoneal, paraaortic, less
commonly peripheral)
 Laboratory abnormalities: anemia, elevated liver
alkaline phosphatase
www.aidsetc.org
May 2013
70
Disseminated MAC: Clinical
Manifestations (3)
 IRIS
 Focal lymphadenitis, fever; may have systemic
syndrome that is clinically indistinguishable from active
MAC infection
 No bacteremia
 Occurs in patients with low CD4 count and subclinical
or known MAC who begin ART and have rapid increase
in CD4 (≥100 cells/µL)
 May be benign and self-limited or may be severe and
require systemic antiinflammatory therapy
www.aidsetc.org
May 2013
71
Disseminated MAC: Diagnosis
 Confirmed diagnosis: compatible signs and
symptoms plus isolation of MAC from blood,
bone marrow, lymph node, or other normally
sterile tissue or fluid
 Species identification with specific DNA probes is
essential for differentiating MAC and TB
 Other studies may support diagnosis (eg, AFB
smear and culture of stool or tissue biopsy,
radiographic imaging)
www.aidsetc.org
May 2013
72
Disseminated MAC: Prevention
 Preventing exposure
 No recommendations; MAC organisms are common in the
environment
 Preventing disease
 Recommended for all with CD4 count <50 cells/µL
 Before prophylaxis, rule out disseminated MAC disease
(clinical assessment +/− blood culture)
 Stopping prophylaxis
 Discontinue in patient on ART with increase in CD4 count to
>100 cells/µL for ≥3 months
 Restart prophylaxis if CD4 count decreases to <50
cells/µL
www.aidsetc.org
May 2013
73
Disseminated MAC: Prevention (2)
 Primary prophylaxis
 Recommended
 Azithromycin 1,200 mg PO Q week
 Clarithromycin 500 mg PO BID
 Azithromycin 600 mg PO TIW
 Alternative
 RFB 300 mg PO QD (adjust dosage based on
interactions with ARVs)
 Rule out active TB before use
 Significant interactions with PIs and NNRTIs
www.aidsetc.org
May 2013
74
Disseminated MAC: Prevention (3)
 Clarithromycin + RFB not more effective than
clarithromycin alone; should not be used
 Azithromycin + RFB more effective than
azithromycin alone but higher cost, adverse
effects, risk of drug interactions, and no
demonstrated survival benefit: not recommended
www.aidsetc.org
May 2013
75
Disseminated MAC: Treatment
 Initial treatment (≥12 months)
 At least 2 drugs, to prevent resistance
 Preferred
 Clarithromycin 500 mg PO BID + ethambutol 15 mg/kg PO QD
 Azithromycin 500-600 mg PO QD + ethambutol 15 mg/kg PO
QD (when drug interactions or intolerance precludes use of
clarithromycin)
 Test MAC isolates for susceptibility to macrolides
www.aidsetc.org
May 2013
76
Disseminated MAC: Treatment (2)
 Consider adding 3rd or 4th drug, if CD4 count <50
cells/µL, high mycobacterial load, in absence of effective
ART, or if drug resistance likely
 Clarithromycin + ethambutol + rifabutin improved survival
and reduced emergence of resistance in earlier studies;
no data in context of effective ART
 Alternatives to rifabutin, or possible 4th agents: amikacin,
streptomycin, levofloxacin, moxifloxacin
 Rifabutin interacts with many ARVs: some combinations
are contraindicated; some require dosage adjustment
 Efavirenz may decrease clarithromycin levels (and
increase level of active metabolite); clinical significance is
unknown
www.aidsetc.org
May 2013
77
Disseminated MAC: Starting ART
 ART and immune reconstitution are important
aspects of MAC treatment
 ART generally should be started (or optimized)
as soon as possible after the first 2 weeks of
antimycobacterial therapy
 2-week delay may decrease risk of IRIS
www.aidsetc.org
May 2013
78
Disseminated MAC: Monitoring
 Clinical improvement and decrease in quantity of
MAC in blood or tissue are expected within 2-4
weeks after start of appropriate therapy; may be
delayed if extensive disease or advanced
immunosuppression
 If little or no clinical response to therapy: repeat
MAC blood culture 4-8 weeks after initiation of
therapy
www.aidsetc.org
May 2013
79
Disseminated MAC: Adverse Events
 Clarithromycin, azithromycin: nausea, vomiting,
abdominal pain, abnormal taste, transaminase
elevations, hypersensitivity
 Clarithromycin doses >1 g per day for MAC treatment
are associated with increased mortality, should not be
used
 Rifabutin doses ≥450 mg/day: higher risk of
adverse interactions with clarithromycin or other
inhibitors of cytochrome P450 3A4; possible
higher risk of uveitis, neutropenia, other adverse
effects
www.aidsetc.org
May 2013
80
Disseminated MAC: Adverse Events (2)
 IRIS: if moderate-severe symptoms of immune
reconstitution reaction, consider NSAIDs; if no
improvement, short-term corticosteroids (eg,
prednisone 20-40 mg QD for 4-8 weeks)
www.aidsetc.org
May 2013
81
Disseminated MAC: Treatment Failure
 Absence of clinical response and persistence of
mycobacteremia after 4-8 weeks of treatment
 Test MAC isolates for drug susceptibility
 Regimen of ≥2 new, active drugs, based on
susceptibility testing
 Optimize ART
www.aidsetc.org
May 2013
82
Disseminated MAC: Treatment
Failure (2)
 Second-line agents:
 If macrolide resistance, include ethambutol, rifabutin,
amikacin, streptomycin, or a fluoroquinolone
 Consider use of an injectable agent (eg, amikacin,
streptomycin)
 Unknown whether clarithromycin or azithromycin offer
benefit if resistance is present
 Clofazimine: should not be used; increased mortality
and limited efficacy
 Other agents: limited data
www.aidsetc.org
May 2013
83
Disseminated MAC: Preventing
Recurrence
 Secondary prophylaxis: chronic maintenance
therapy should be continued unless immune
reconstitution on ART
 Therapies same as treatment regimens
 Stopping secondary propnyhlaxis:
 Completed ≥12 months of MAC treatment,
asymptomatic, CD4 count >100 cells/µL for >6 months,
on ART
 Restart secondary prophylaxis if CD4 count
decreases to <100 cells/µL
www.aidsetc.org
May 2013
84
Disseminated MAC: Considerations in
Pregnancy
 Prophylaxis, diagnosis, and treatment as in
nonpregnant adults
 Clarithromycin not recommended as first-line
agent: increased risk of birth defects in animal
studies
 Azithromycin recommended for primary
prophylaxis; azithromycin + EMB recommended
for treatment and for chronic maintenance
therapy
 Limited data on azithromycin in 1st trimester
www.aidsetc.org
May 2013
85
MTB: Preventing Exposure (2)
 Increased risk of MTB infection with time in
congregate settings such as correctional facilities,
homeless shelters, nursing homes
 Patients with known or presumed infectious TB:
physically separate from other patients, especially
from HIV-infected patients
 Patients with infections TB should not return to
settings in which others might be exposed until on
treatment (or completed treatment), with 3
consecutive negative AFB smear results, plus clinical
improvement
 If MDR TB, some recommend that patients have negative
sputum culture
www.aidsetc.org
May 2013
86
MTB: Preventing Exposure (3)
 Treatment of LTBI is effective in reducing TB
transmission: test all HIV-infected persons with
risk factors for TB, and treat all with LTBI
 Treat presumptively for LTBI if significant history of TB
exposure, regardless of LTBI test results
 BCG vaccination contraindicated in HIV infection:
risk of disseminated disease
www.aidsetc.org
May 2013
87
Websites to Access the Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
www.aidsetc.org
May 2013
88
About This Slide Set
 This presentation was prepared by Susa Coffey,
MD, for the AETC National Coordinating
Resource Center in May 2013
 See the AETC NCRC website for the most
current version of this presentation:
http://www.aidsetc.org
www.aidsetc.org
May 2013
89