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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 2 May 2013 www.aidsetc.org 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 3 May 2013 www.aidsetc.org TB re-activation 4 May 2013 www.aidsetc.org 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 5 May 2013 www.aidsetc.org 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 6 May 2013 www.aidsetc.org 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 7 May 2013 www.aidsetc.org 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 8 May 2013 www.aidsetc.org TB Disease: Clinical Manifestations (4) Chest X ray: TB manifesting as a focal opacity in the right lung Credit: L. Huang, MD; HIV InSite 9 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 www.aidsetc.org Pulmonary TB 10 May 2013 www.aidsetc.org 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 11 May 2013 www.aidsetc.org Miliary TB 12 May 2013 www.aidsetc.org TB lymphadenitis (Scofula) 13 May 2013 www.aidsetc.org 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 14 May 2013 www.aidsetc.org 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 15 May 2013 www.aidsetc.org 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. 16 May 2013 www.aidsetc.org 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 17 May 2013 www.aidsetc.org 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) 18 May 2013 www.aidsetc.org 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 19 May 2013 www.aidsetc.org 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 20 May 2013 www.aidsetc.org Testing pitfalls - PPD False Positive tests 21 Infection with nontuberculosis mycobacteria Previous BCG vaccination Incorrect method of TST administration Incorrect interpretation of reaction Incorrect bottle of antigen used May 2013 www.aidsetc.org Testing pitfalls - PPD False Negative tests 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: 22 http://www.tstin3d.com/en/calc.html May 2013 www.aidsetc.org 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. 23 May 2013 www.aidsetc.org 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 24 May 2013 www.aidsetc.org 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 25 May 2013 www.aidsetc.org 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 26 May 2013 www.aidsetc.org 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 27 May 2013 www.aidsetc.org 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 28 May 2013 www.aidsetc.org 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 29 May 2013 www.aidsetc.org 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 30 May 2013 www.aidsetc.org 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 31 May 2013 www.aidsetc.org Worldwide TB incidence 32 May 2013 www.aidsetc.org MDR TB – Worldwide map 33 May 2013 www.aidsetc.org XDR-TB Worldwide case reports 34 May 2013 www.aidsetc.org 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 35 May 2013 www.aidsetc.org 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) 36 May 2013 www.aidsetc.org 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 37 May 2013 www.aidsetc.org 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 38 May 2013 www.aidsetc.org 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) 39 May 2013 www.aidsetc.org 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 40 May 2013 www.aidsetc.org 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 41 May 2013 www.aidsetc.org 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 42 May 2013 www.aidsetc.org 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 43 May 2013 www.aidsetc.org 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) 44 May 2013 www.aidsetc.org 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 45 May 2013 www.aidsetc.org 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 46 May 2013 www.aidsetc.org 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 47 May 2013 www.aidsetc.org 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 48 May 2013 www.aidsetc.org 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 51 May 2013 www.aidsetc.org TB Treatment + ART – practical issues Recommended regimen: 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! 52 May 2013 www.aidsetc.org 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 53 May 2013 www.aidsetc.org 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) 54 May 2013 www.aidsetc.org 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 55 May 2013 www.aidsetc.org 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 56 May 2013 www.aidsetc.org 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 57 May 2013 www.aidsetc.org 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 58 May 2013 www.aidsetc.org Ishihara testing (Ethambutol) 59 May 2013 www.aidsetc.org TB Disease: IRIS Paradoxical TB IRIS: temporary exacerbation of symptoms, signs, or radiographic manifestations of TB after initial improvement on TB treatment; may include: 60 High fever Worsening respiratory status New or worsening lymphadenopathy Worsening CNS lesions or symptoms Worsening pulmonary infiltrates Increasing pleural effusions May 2013 www.aidsetc.org 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 61 May 2013 www.aidsetc.org 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) 62 May 2013 www.aidsetc.org 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 63 May 2013 www.aidsetc.org 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 64 May 2013 www.aidsetc.org 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 65 May 2013 www.aidsetc.org 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 66 May 2013 www.aidsetc.org