1. 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 Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Mycobacterial Infections Slide Set

2. May 2013www.aidsetc.org 2 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 About This Presentation

3. May 2013www.aidsetc.org 3  Mycobacterium tuberculosis (MTB) disease  Disseminated Mycobacterium avium complex (MAC) disease Mycobacterial Infections

4.  Epidemiology  Prevention  Diagnosis  Treatment  Clinical Manifestations  Considerations in Pregnancy Mycobacterium tuberculosis (MTB) Disease

5. May 2013www.aidsetc.org 5  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 MTB: Epidemiology

6. May 2013www.aidsetc.org 6  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 MTB: Epidemiology (2)

7. May 2013www.aidsetc.org 7  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 MTB: Epidemiology (3)

8. May 2013www.aidsetc.org 8  HIV-infected patients who travel or work in high- prevalence 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 MTB: Preventing Exposure

9. May 2013www.aidsetc.org 9  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%) MTB: Preventing Disease

10. May 2013www.aidsetc.org 10  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 Latent TB Disease: Diagnosis

11. May 2013www.aidsetc.org 11  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 Latent TB Disease: Diagnosis (2)

12. May 2013www.aidsetc.org 12  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. Latent TB Disease: Diagnosis (3)

13. May 2013www.aidsetc.org 13  TST or IGRA test results  If negative and CD4 count 200 cells/µL  If positive test: chest X ray and clinical evaluation to screen for active TB Latent TB Disease: Diagnosis (4)

14. May 2013www.aidsetc.org 14  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) Latent TB Disease: Treatment

15. May 2013www.aidsetc.org 15  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 Latent TB Disease: Treatment (2)

16. May 2013www.aidsetc.org 16  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 Latent TB Disease: Treatment (3)

17. May 2013www.aidsetc.org 17  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 Latent TB Disease: Monitoring

18. May 2013www.aidsetc.org 18  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 TB Disease: Clinical Manifestations

19. May 2013www.aidsetc.org 19  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 TB Disease: Clinical Manifestations (2)

20. May 2013www.aidsetc.org 20  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 TB Disease: Clinical Manifestations (3)

21. May 2013www.aidsetc.org 21 Chest X ray: TB manifesting as a focal opacity in the right lung Credit: L. Huang, MD; HIV InSite Chest X ray: TB with bilateral hilar lymphadenopathy and diffuse interstitial and airspace opacities Credit: L. Goozé, MD; C. Daley, MD; HIV InSite TB Disease: Clinical Manifestations (4)

22. May 2013www.aidsetc.org 22 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 TB Disease: Clinical Manifestations (5)

23. May 2013www.aidsetc.org 23  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 TB Disease: Diagnosis

24. May 2013www.aidsetc.org 24  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 TB Disease: Diagnosis (2)

25. May 2013www.aidsetc.org 25  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 TB Disease: Diagnosis (3)

26. May 2013www.aidsetc.org 26  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 TB Disease: Diagnosis (4)

27. May 2013www.aidsetc.org 27  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 TB Disease: Diagnosis (5)

28. May 2013www.aidsetc.org 28  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 TB Disease: Diagnosis (6)

29. May 2013www.aidsetc.org 29  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 TB Disease: Diagnosis (7)

30. May 2013www.aidsetc.org 30  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 TB Disease: Diagnosis (8)

31. May 2013www.aidsetc.org 31  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 TB Disease: Treatment

32. May 2013www.aidsetc.org 32  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 TB Disease: Treatment (2)

33. May 2013www.aidsetc.org 33  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) TB Disease: Treatment (3)

34. May 2013www.aidsetc.org 34  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 TB Disease: Treatment (4)

35. May 2013www.aidsetc.org 35  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 TB Disease: Treatment (5)

36. May 2013www.aidsetc.org 36  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 TB Disease: Treatment (Drug Sensitive) (6)

37. May 2013www.aidsetc.org 37  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 TB Disease: Treatment (Drug Sensitive) (7)

38. May 2013www.aidsetc.org 38  Other therapies  Pyridoxine (25-50 mg QD) for all on INH (to decrease risk of neuropathy)  Corticosteroids improve survival for CNS or pericardial disease TB Disease: Treatment (8)

39. May 2013www.aidsetc.org 39  For optimal management of HIV-related TB, treat both infections  Sequential treatment of TB followed by HIV treatment is not recommended TB Disease: Starting ART

40. May 2013www.aidsetc.org 40  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 TB Disease: Starting ART (2)

41. May 2013www.aidsetc.org 41  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 TB Disease: Starting ART (3)

42. May 2013www.aidsetc.org 42  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 TB Disease: Starting ART (4)

43. May 2013www.aidsetc.org 43  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 TB Disease: Starting ART (5)

44. May 2013www.aidsetc.org 44  PIs:  RIF lowers serum levels of most PIs, including ritonavir- boosted 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) TB Disease: Starting ART (6)

45. May 2013www.aidsetc.org 45  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 TB Disease: Starting ART (7)

46. May 2013www.aidsetc.org 46  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 TB Disease: Monitoring

47. May 2013www.aidsetc.org 47  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) TB Disease: Monitoring (2)

48. May 2013www.aidsetc.org 48  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 TB Disease: Adverse Events

49. May 2013www.aidsetc.org 49  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 TB Disease: Adverse Events (2)

50. May 2013www.aidsetc.org 50  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 TB Disease: Adverse Events (3)

51. May 2013www.aidsetc.org 51  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 TB Disease: Adverse Events (4)

52. May 2013www.aidsetc.org 52  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 TB Disease: IRIS

53. May 2013www.aidsetc.org 53  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 TB Disease: IRIS (2)

54. May 2013www.aidsetc.org 54  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) TB Disease: IRIS (3)

55. May 2013www.aidsetc.org 55  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 TB Disease: IRIS (4)

56. May 2013www.aidsetc.org 56  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 TB Disease: Treatment Failure

57. May 2013www.aidsetc.org 57  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 TB Disease: Treatment Failure (2)

58. May 2013www.aidsetc.org 58  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 TB Disease: Treatment Failure (3)

59. May 2013www.aidsetc.org 59  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 TB Disease: Management of Drug Resistance

60. May 2013www.aidsetc.org 60  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 TB Disease: Preventing Recurrence

61. May 2013www.aidsetc.org 61  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 TB Disease: Considerations in Pregnancy

62. May 2013www.aidsetc.org 62  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 TB Disease: Considerations in Pregnancy (2)

63. May 2013www.aidsetc.org 63  TB disease:  Treat as in nonpregnant adults  Therapy should not be withheld because of pregnancy TB Disease: Considerations in Pregnancy (3)

64. May 2013www.aidsetc.org 64  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 TB Disease: Considerations in Pregnancy (4)

65. May 2013www.aidsetc.org 65  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 TB Disease: Considerations in Pregnancy (5)

66.  Epidemiology  Prevention  Diagnosis  Treatment  Clinical Manifestations  Considerations in Pregnancy Disseminated Mycobacterium avium Complex (MAC) Disease

67. May 2013www.aidsetc.org 67  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-to- person transmission unlikely  Not associated with specific environmental exposures or behaviors Disseminated MAC: Epidemiology

68. May 2013www.aidsetc.org 68  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 Disseminated MAC: Epidemiology (2)

69. May 2013www.aidsetc.org 69  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 Disseminated MAC: Clinical Manifestations

70. May 2013www.aidsetc.org 70  Physical exam or imaging: hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, paraaortic, less commonly peripheral)  Laboratory abnormalities: anemia, elevated liver alkaline phosphatase Disseminated MAC: Clinical Manifestations (2)

71. May 2013www.aidsetc.org 71  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 Disseminated MAC: Clinical Manifestations (3)

72. May 2013www.aidsetc.org 72  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) Disseminated MAC: Diagnosis

73. May 2013www.aidsetc.org 73  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 Disseminated MAC: Prevention

74. May 2013www.aidsetc.org 74  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 Disseminated MAC: Prevention (2)

75. May 2013www.aidsetc.org 75  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 Disseminated MAC: Prevention (3)

76. May 2013www.aidsetc.org 76  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 Disseminated MAC: Treatment

77. May 2013www.aidsetc.org 77  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 Disseminated MAC: Treatment (2)

78. May 2013www.aidsetc.org 78  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 Disseminated MAC: Starting ART

79. May 2013www.aidsetc.org 79  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 Disseminated MAC: Monitoring

80. May 2013www.aidsetc.org 80  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 Disseminated MAC: Adverse Events

81. May 2013www.aidsetc.org 81  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) Disseminated MAC: Adverse Events (2)

82. May 2013www.aidsetc.org 82  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 Disseminated MAC: Treatment Failure

83. May 2013www.aidsetc.org 83  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 Disseminated MAC: Treatment Failure (2)

84. May 2013www.aidsetc.org 84  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 Disseminated MAC: Preventing Recurrence

85. May 2013www.aidsetc.org 85  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 Disseminated MAC: Considerations in Pregnancy

86. May 2013www.aidsetc.org 86  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 MTB: Preventing Exposure (2)

87. May 2013www.aidsetc.org 87  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 MTB: Preventing Exposure (3)

88. May 2013www.aidsetc.org 88  http://www.aidsetc.org  http://aidsinfo.nih.gov Websites to Access the Guidelines

89. 89  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 About This Slide Set May 2013www.aidsetc.org