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All persons should be tested for LTBI at the time of HIV diagnosis regardless of their TB risk category (AII). Persons with negative diagnostic tests for LTBI, advanced HIV infection (CD4⁺ count <200 cells/µL), and without indications for initiating empiric LTBI treatment should be re-tested for LTBI once they start ART and attain a CD4⁺ count ≥200 cells/µL (AIII). In general, annual testing for LTBI is recommended for HIV-infected persons who are or remain in a "high-risk" category for repeated or ongoing exposure to persons with active TB, i.e., persons who are or who have been incarcerated, live in congregate settings, are active drug users, or have other sociodemographic risk factors for TB (AIII). All HIV-infected persons with a positive diagnostic test for LTBI should undergo chest radiography and clinical evaluation to rule out active TB (AI).

Diagnosis of LTBI can be accomplished with one of two approaches. The tuberculin skin test (TST), placed by the Mantoux method, is considered positive in HIV-infected persons if induration of ≥5 mm is demonstrated 48-72 hours after the intradermal placement of 0.1 mL purified protein derivative (PPD). Recently, new in vitro assays that detect IFN-g release in response to M. tuberculosis-specific peptides have been developed for diagnosing LTBI (299Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 2006;3:103-10.). Given the high risk for progression to active disease in HIV-infected persons, any HIV-infected person with reactivity on any of the current LTBI diagnostic tests should be considered infected with M. tuberculosis (Figure 1) (300Jasmer RM, Nahid P, Hopewell PC. Clinical practice: latent tuberculosis infection. N Engl J Med 2002;347:1860-6.).

Evidence suggests that the IGRAs have more consistent and higher specificity (92%-97%) compared with TST (56%-95%), better correlation with surrogate measures of exposure to M. tuberculosis, and less cross reactivity because of Bacillus Calmette-Guérin (BCG) vaccination or other nontuberculous mycobacteria exposure than the TST (299Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 2006;3:103-10., 301Menzies D, Pai M, Comstock G. New tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54.). Three IGRAs are FDA-approved and available in the United States: the QuantiFERON^®-TB Gold and the QuantiFERON^®-TB Gold In-Tube (Cellestis Limited), and the T-SPOT^™.TB test (Oxford Immunotec) is awaiting final FDA approval (Table 10). For both the TST and IGRAs, however, HIV-related immunosuppression might be associated with false-negative results (302Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR 2005;54(No. RR-15).). The frequency of false-negative and indeterminate IGRA results increases with advancing immunodeficiency (303Brock I, Ruhwald M, Lundgren B, et al. Latent tuberculosis in HIV positive, diagnosed by the M. tuberculosis specific interferon-gamma test. Respir Res 2006:1;7:56., 304Pai M, Lewinsohn DM. Interferon-gamma assays for tuberculosis: is anergy the Achilles' heel? Am J Respir Crit Care Med 2005;172:519-21.).

Results from comparative studies of TST and IGRAs in HIV-infected patients indicate that concordance between the tests is not complete (305Luetkemeyer AF, Charlebois ED, Flores LL, et al. Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals. Am J Respir Crit Care Med 2007;175:737-42., 306Chapman AL, Munkanta M, Wilkinson KA, et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells. AIDS 2002;16:2285-93.). The TST remains useful for diagnosing LTBI, particularly for patients who have not been vaccinated for BCG and in settings with cost constraints. The optimal application of IGRAs in HIV-infected persons will be better defined when the results of ongoing studies become available (301Menzies D, Pai M, Comstock G. New tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54.). IGRAs might be used in combination with TST to improve sensitivity and specificity for detection of LTBI (301Menzies D, Pai M, Comstock G. New tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54.).

Fibrotic lesions consistent with TB might be incidentally noted on a chest radiograph obtained for other reasons. Persons with fibrotic lesions should undergo diagnostic testing for LTBI and be evaluated for active disease. Unless the patient has a known history of prior adequate treatment for active TB, sputum samples for AFB smear and culture should be obtained even if the patient is asymptomatic. HIV-infected persons with CD4⁺ counts <200 cells/µL who have fibrotic lesions consistent with TB on a chest radiograph and no prior history of treatment should be considered as having M. tuberculosis infection irrespective of the results of LTBI diagnostic tests. In situations with moderate-to-high suspicion of active TB regardless of the results of LTBI tests, empiric treatment for active TB should be initiated while awaiting the results of further diagnostic tests (AII).

The evaluation of suspected HIV-related TB should include a chest radiograph regardless of the possible anatomic site of disease. Sputum samples for AFB smear and culture should be obtained from patients with pulmonary symptoms and chest radiographic abnormalities. A normal chest radiograph does not exclude the possibility of active pulmonary TB and when suspicion for disease is high, sputum samples should still be obtained (289Perlman DC, El-Sadr WM, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. Clin Infect Dis 1997;25:242-6., 307Greenberg SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115-9.). Obtaining three unique specimens, preferably in the morning of different days, increases the yield for both smear and culture (308American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95.). TST and IGRAs should not be relied upon for the diagnosis of TB disease. Approximately one fourth of HIV-infected persons with pulmonary TB disease have false-negative results (301Menzies D, Pai M, Comstock G. New tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340-54.).

HIV serostatus does not affect the yield from sputum smear and culture examinations; positive smear results are more common in cavitary pulmonary disease (309Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006;6:64-74.). The yield of AFB smear and culture of specimens from extrapulmonary sites is greater among patients with advanced immunodeficiency compared with HIV-uninfected adults (310Artenstein AW, Kim JH, Williams WJ, Chung RC. Isolated peripheral tuberculous lymphadenitis in adults: current clinical and diagnostic issues. Clin Infect Dis 1995;20:876-82., 311Golden MP. Vikram HR. Extrapulmonary tuberculosis: an overview. Am Fam Physician 2005;72:1761-8., 312Shriner KA, Mathisen GE, Goetz MB. Comparison of mycobacterial lymphadenitis among persons infected with human immunodeficiency virus and seronegative controls. Clin Infect Dis 1992;15:601-5.). Nucleic acid amplification (NAA) tests, also called "direct amplification tests," can be applied directly to clinical specimens such as sputum and help to evaluate persons with a positive AFB smear. A positive NAA result in an AFB smear-positive patient likely reflects active TB. In persons with AFB smear-negative sputum or extrapulmonary disease, however, NAA tests have lower sensitivity and negative predictive value and should be used and interpreted with caution (299Nahid P, Pai M, Hopewell PC. Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 2006;3:103-10.).

For patients with signs of extrapulmonary TB, needle aspiration or tissue biopsy of skin lesions, lymph nodes, or pleural or pericardial fluid should be performed. Mycobacterial blood cultures might be helpful for patients with signs of disseminated disease or worsening immunodeficiency.

A positive AFB smear result in any specimen (sputum, needle aspirate, tissue biopsy) represents some form of mycobacterial disease but does not always represent TB. Because TB is the most virulent mycobacterial pathogen and can be spread from person to person, patients with smear-positive results should be considered to have TB disease until definitive mycobacterial species identification is made. Automated liquid media culture systems might indicate growth of M. tuberculosis within 1-3 weeks compared with 3-8 weeks in solid media.

Drug-susceptibility testing and adjustment of the treatment regimen based on results are critical to the successful treatment of patients with TB and to curbing transmission of drug-resistant M. tuberculosis. For all patients with TB disease, testing for susceptibility to first-line agents (isoniazid [INH], rifampin [RIF], ethambutol [EMB], and pyrazinamide [PZA]) should be performed, regardless of the source of the specimen. Drug susceptibility tests should be repeated if sputum cultures remain positive for M. tuberculosis after 3 months of treatment or become positive after 1 month or longer of negative cultures (308American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-95.). Second-line drug susceptibility testing should be performed only in reference laboratories and should be limited to specimens from patients who 1) have had previous therapy, 2) are contacts of patients with drug-resistant TB disease, 3) have demonstrated resistance to RIF or to other first-line drugs, 4) have positive cultures after 3 months of treatment, or, 5) are from regions with a high prevalence of multiple drug-resistant (MDR) or extensively drug-resistant (XDR) TB (313Rich ML, Socci AR, Mitnick CD, et al. Representative drug susceptibility patterns for guiding design of retreatment regimens for MDR-TB. Int J Tuberc Lung Dis 2006;10:290-6.).

Molecular beacons, phage-based assays, and line probe assays are three methods for rapidly detecting the presence of drug resistance, specifically to INH and RIF. These assays are expensive, require sophisticated laboratory support, need further study, and are not yet FDA-approved for use in the United States. Published results on the performance of the two assays suitable for direct use on samples, the INNO-LiPA Rif.TB kit (Innogenetics, Gent, Belgium) and FASTPlaque-TB (Biotec Laboratories Ltd., Ipswich, United Kingdom), have been inconsistent. Until results of ongoing validation and field testing of these rapid tests are available, conventional laboratory methods for culture and susceptibility testing should be pursued on all suspect clinical specimens.

All patients with a diagnosis of LTBI should be counseled about risk for TB, adherence to treatment regimens, benefits and risks of treatment, interactions with other drugs, and an optimal follow-up plan. HIV-infected patients receiving treatment for LTBI also should have baseline laboratory testing, including an evaluation of hepatic function (serum aspartate aminotransferase [AST], bilirubin, and alkaline phosphatase) for patients treated with INH and a complete blood count and platelet count for patients taking RIF or rifabutin (282CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6)., 283CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6).).

Patients being treated for LTBI should be monitored at least monthly with a history and physical assessment designed to detect hepatitis and neuropathy. Patients should be advised to stop treatment and promptly seek medical evaluation if symptoms suggesting hepatitis occur, such as nausea, vomiting, jaundice, or dark urine. Clinicians in all settings should consider dispensing no more than a 1-month supply of medication (331CDC. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR 2003;52:735-9., 332Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281:1014-8.). Routine laboratory monitoring is indicated in HIV-infected patients with abnormal baseline liver-function tests, with chronic liver disease, or in those receiving treatment with ART (282CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6)., 283CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6)., 333Saukkonen JJ, Cohn DL, Jasmer RM, et al. Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52.).

A baseline evaluation and monthly follow-up consisting of clinical, bacteriologic, and periodic laboratory and radiographic evaluations are essential to ensure treatment success. Clinical history and baseline tests to evaluate hepatic function (AST, bilirubin, and alkaline phosphatase), renal function (serum creatinine), complete blood count (including platelet count), and CD4⁺ counts are recommended for all patients (277CDC. Treatment of tuberculosis. MMWR 2003;52(No. RR-11).). HIV-infected patients being treated for active TB should have a clinic-based evaluation at least monthly. For patients with extrapulmonary TB, the frequency and types of evaluations will depend on the sites involved and the ease with which specimens can be obtained. For patients with pulmonary TB, at least one sputum specimen for AFB smear and mycobacterial culture should be obtained monthly until two consecutive specimens are culture negative. Sputum specimens should be obtained after 8 weeks of treatment to inform clinical decision-making about the duration of the continuation phase. For patients with positive AFB smears at initiation of treatment, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the treatment response (277CDC. Treatment of tuberculosis. MMWR 2003;52(No. RR-11).).

For patients with positive M. tuberculosis cultures after 3 months of treatment, drug-susceptibility tests should be repeated on newly acquired sputum specimens. Patients with positive M. tuberculosis cultures after 4 months of treatment should be considered as treatment failures and managed accordingly (44U.S. Public Health Service. Guidelines for the prevention of opportunistic infections in persons infected with HIV: part I. Prevention of exposure. Am Fam Physician 2000;61:163-71.). At each visit, patients should be questioned about adherence and possible adverse effects of anti-TB medications; those taking EMB should be asked about blurred vision or scotomata and tested for visual acuity and color discrimination. Routine laboratory monitoring during treatment, even when baseline laboratory abnormalities are not present, could be considered (333Saukkonen JJ, Cohn DL, Jasmer RM, et al. Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52.).

In HIV-infected persons with active TB, serum concentrations of the first-line anti-TB drugs are frequently lower than published normal ranges (334Chideya SR, Jappero J, Peloquin C, et al. Sub-therapeutic serum concentrations of anti-tuberculosis medications and treatment-Botswana, 1997-1999. In: 56th Annual Epidemic Intelligence Service (EIS) Conference. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, April 2007.). However, routine drug-level monitoring is not recommended (277CDC. Treatment of tuberculosis. MMWR 2003;52(No. RR-11).). For those with a slow response to treatment, drug concentration measurements might provide objective information on which to base modifications of treatment (335Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002;62:2169-83.).

Although the reported frequency of anti-TB drug-related toxicity in patients with HIV infection varies, for most adverse events, rates are not different than for HIV-uninfected patients (333Saukkonen JJ, Cohn DL, Jasmer RM, et al. Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52., 336Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Am J Respir Crit Care Med 2007;175:858., 337Breen RA, Miller RF, Gorsuch T, et al. Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax 2006;61:791-4., 338Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167:1472-7.,339Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83.). Because alternative drugs often have less efficacy and more toxicities than first-line anti-TB drugs and diagnosing a drug reaction and determining the responsible agent can be difficult, the first-line drugs (especially INH, RIF, or rifabutin) should not be stopped permanently without strong evidence that the specific anti-TB drug was the cause of the reaction. In such situations, consultation with a specialist in treating LTBI or TB in persons with HIV infection is recommended (48CDC. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR 2004;53(No. RR-15).).

Gastrointestinal reactions are common with many of the anti-TB medications (340). If gastrointestinal symptoms occur, AST and bilirubin should be measured, and if the AST level is less than three times the upper limit of normal (ULN) or the baseline for the patient, the symptoms are assumed not to be caused by hepatic toxicity. Typically, gastrointestinal symptoms should be managed without discontinuing TB medications; initial approaches should include either changing the hour of administration or administering drugs with food.

Skin rashes are common with all of the anti-TB drugs. If rash is minor, affects a limited area, or causes pruritis, antihistamines should be administered for symptomatic relief and all anti-TB medications continued. If the rash is severe, all TB medications should be stopped until the rash is substantially improved, and TB drugs restarted one by one at intervals of 2-3 days. RIF or rifabutin should be restarted first (because they are least likely to cause rash and their role in treatment is critical). If the rash recurs, the last drug added should be stopped. If a petechial rash thought to be caused by thrombocytopenia occurs, the RIF or rifabutin should be stopped permanently (341Mehta YS, Jijina FF, Badakere SS, Pathare AV, Mohanty D. Rifampicin-induced immune thrombocytopenia. Tuber Lung Dis 1996;77:558-62.). If a generalized rash associated with either fever or mucous membrane involvement occurs, all drugs should be stopped immediately, the patient should be switched to alternative anti-TB agents, and LTBI or TB treatment should be managed in consultation with a specialist.

Fever in an HIV-infected patient who has been receiving effective TB therapy for several weeks might represent drug fever, a paradoxical reaction, or IRIS (342Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933-6.). If superinfection or worsening TB is excluded as a potential cause, all TB drugs should be stopped. Once the fever has resolved, the general guidelines described for restarting/stopping drugs in the presence of a rash should be followed.

An increase in AST concentration occurs in approximately 20% of patients treated with the standard four-drug anti-TB regimen (343Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465-71.). Drug-induced liver injury can be caused by INH, rifamycins, or PZA and is defined as an AST elevation to ≥3 times the ULN in the presence of symptoms, or >5 times the ULN in the absence of symptoms (344Ormerod LP. Hepatotoxicity of antituberculosis drugs. Thorax 1996;51:111-3.). In addition to AST elevation, disproportionate increases in bilirubin and alkaline phosphatase occur occasionally. This latter pattern is more consistent with rifamycin hepatotoxicity than with INH or PZA hepatotoxicity. In most patients, asymptomatic aminotransferase elevations resolve spontaneously.

In the absence of symptoms, elevations of AST <3 times ULN should not prompt changes of TB therapy, but the frequency of clinical and laboratory monitoring should be increased. If AST levels are ≥5 times the ULN regardless of symptoms, >3 times the ULN with symptoms, or if a significant increase in bilirubin and/or alkaline phosphatase occurs, hepatotoxic drugs should be stopped, and the patient should be evaluated immediately. For any substantial new transaminase or bilirubin elevation, serologic testing for hepatitis A, B, and C should be performed and the patient questioned regarding symptoms suggestive of biliary tract disease and exposures to alcohol and other hepatotoxins.

If anti-TB drugs must be stopped for hepatotoxicity, substituting ≥3 nonhepatotoxic anti-TB drugs is prudent until the specific cause of hepatotoxicity can be determined and an alternative longer-term regimen constructed. The suspected anti-TB medications should be restarted one at a time after the AST level returns to <2 times the ULN or to near baseline for patients with pre-existing abnormalities. Because the rifamycins are a critical part of the TB regimen and are less likely to cause hepatotoxicity than INH or PZA (343Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465-71.), they should be restarted first. If no increase in AST occurs after 1 week, INH may be restarted. PZA may be restarted 1 week after INH if AST does not increase. If symptoms recur or AST increases, the last drug added should be stopped. If RIF and INH are tolerated and hepatitis was severe, PZA should be assumed responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months with RIF and INH alone.

For HIV-infected patients on LTBI therapy who have hepatotoxicity, most of the general guidelines described for restarting/stopping drugs for patients on therapy for active TB apply. The ultimate decision regarding resumption of therapy with the same or a different agent for LTBI treatment should be made after weighing the risk for additional hepatic injury against the benefit of preventing progression to TB disease (333Saukkonen JJ, Cohn DL, Jasmer RM, et al. Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52.) and always in consultation with an expert in treating LTBI in persons with HIV infection.

The treatment of TB can be complicated by drug interactions with the rifamycins and overlapping toxicities associated with antiretrovirals (ARVs) and anti-TB drugs when therapy for both HIV and TB infections is concomitantly administered. Both RIF and rifabutin induce CYP3A enzymes, and although rifabutin is not as potent an inducer as RIF, it is a substrate, leading to drug interactions with the PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) when these agents are concomitantly administered with the rifamycins; such administration might result in increased metabolism and suboptimal levels of ARVs (345Burman WJ, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the treatment of human immunodeficiency virus-related tuberculosis. Clin Infect Dis 1999;28:419-29.).

Compared with PI-based regimens, NNRTI-based regimens have fewer interactions with RIF-based TB therapy (346CDC. Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Available at http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.html. 2004.). Rifabutin is an alternative to RIF and can be administered with PIs or NNRTIs with appropriate dose adjustments (346CDC. Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Available at http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.html. 2004.). Concomitant use of RIF with ritonavir-boosted PIs has been shown to result in subtherapeutic levels of the PI. Use of ritonavir-boosted saquinavir with RIF was associated with a high incidence of hepatotoxicity in a pharmacokinetic study using healthy volunteers (347Roche pharmaceuticals. Dear Health-care provider letter 7 February 2005 http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Invirase.). RIF should not be used in patients on PI-based regimens, with or without ritonavir-boosting (EII). For patients undergoing treatment for active TB, starting ART with either an efavirenz- or nevirapine-based regimen is preferred because these NNRTIs have fewer interactions with RIF (BII); dosage adjustments for these NNRTIs might be needed for persons weighing more than 60 kg (BII) (348Pedral-Sampaio DB, Alves CR, Netto EM, et al. Efficacy and safety of efavirenz in HIV patients on Rifampin for tuberculosis. Braz J Infect Dis 2004;8:211-6., 349World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access: recommendations for a public health approach 2006. Available at http://www.who.int/hiv/pub/guidelines/adult/en/index.html. 2006). Delavirdine should not be used with either RIF or rifabutin (350Borin MT, Chambers JH, Carel BJ, et al. Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients. Antiviral Res 1997;35:53-63.).

If rifabutin is used in place of RIF, dosage reduction is required with boosted-PI regimens. Efavirenz decreases the levels of rifabutin, and the dose of the latter might have to be increased. Nevirapine does not affect the levels of rifabutin sufficiently to merit adjustment of the rifabutin dose. Underdosing of ARVs or rifabutin can result in selection of HIV drug-resistant mutants or acquired rifamycin resistance, respectively, whereas overdosing of rifabutin might result in dose-related toxicities such as neutropenia and uveitis. Because interpatient variations in the degree of enzyme induction or inhibition can occur, the use of therapeutic drug monitoring for levels of rifabutin, PIs, or NNRTIs might help to adjust dosing for individual patients.

HIV nucleos(tide) analogs and the fusion inhibitor enfuvirtide are not affected by the CYP enzymes and can be used with the rifamycins. Results of ongoing drug-drug interaction studies predict that the combination of RIF (and possibly rifabutin) will result in decreased levels of maraviroc, raltegravir, and elvitegravir. Until data are available to guide dose adjustment, these drugs in combination should be avoided or used with extreme caution. Available NNRTIs and PIs do not have clinically significant drug interactions with other first- and second-line anti-TB drugs; thus, when rifamycins cannot be administered because of toxicity or resistance (MDR or XDR M. tuberculosis strains), ART regimens should be selected on the basis of other factors appropriate to the patient (AIII).

For ART-naïve, HIV-infected persons who are diagnosed with active TB, anti-TB treatment must be started immediately (AIII). The optimal timing of initiation of ART in this setting is not clear. Options include simultaneous TB and ART or treatment of TB first with delay of ART by several weeks to months. A positive aspect of starting both regimens simultaneously is the possible prevention of progressive HIV disease and reduction in morbidity or mortality associated with TB or other OIs. A negative of this approach is the possibility of overlapping toxicities, drug interactions, a high pill burden, and the possibility of developing IRIS or a paradoxical reaction. These factors must be weighed carefully when choosing the best time to start ART in individual patients.

Several randomized clinical trials are under way to address the optimal timing of initiation of ART in persons being treated for active TB, but the results will not be known for several years. Pending these results, certain specialists determine when to start ART based on the immunologic status of the patients (339Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83., 351Nelson M, Lipman M. Management of advanced HIV disease in patients with tuberculosis or hepatitis co-infection. Int J Clin Pract 2006;60:976-83., 352Pozniak AL, Miller RF, Lipman MC, et al. Treatment guidelines for tuberculosis (TB)/HIV infection. HIV Med 2005;6(Suppl 2):62-83.). For patients with a CD4⁺ count <100 cells/µL, ART should be started after ≥2 weeks of TB treatment (BII) to reduce confusion about overlapping toxicities, drug interactions (339Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83.), and the occurrence of paradoxical reactions or IRIS (353Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004;190:1670-6.). For persons with a CD4⁺ count of 100-200 cells/µL, certain specialists would delay ART until the end of the 2-month intensive phase of anti-TB treatment (BII). In those with a sustained CD4⁺ count >200 cells/µL, ART could be started during the anti-TB maintenance phase and for those with a CD4⁺ count >350 cells/µL, after finishing anti-TB treatment (BII). In one study, paradoxical reactions occurred in almost all HIV-infected patients with TB and a CD4⁺ count <100 cells/µL who started ART within the first 30 days of TB therapy (222Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335-41.). However, other studies suggest this approach might prevent HIV disease progression or death (222Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335-41., 339Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83., 353Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004;190:1670-6.). In a small, prospective, nonrandomized study of 49 HIV-infected patients from Brazil (348Pedral-Sampaio DB, Alves CR, Netto EM, et al. Efficacy and safety of efavirenz in HIV patients on Rifampin for tuberculosis. Braz J Infect Dis 2004;8:211-6.) treated with a RIF-based anti-TB regimen and efavirenz-based ART, morbidity and side effects of medications in patients who started ART 3 weeks after initiation of TB treatment were reduced, compared with those who started ART and anti-TB treatment simultaneously. Furthermore, simultaneous anti-TB and anti-HIV treatment did not reduce overall mortality.

When TB occurs in patients already on ART, treatment for TB must be started immediately (AIII), and ART should be modified to reduce the risk for drug interactions and maintain virologic suppression. When TB occurs in the setting of viro26 logic failure, ART drug-resistance testing should be performed and a new ART regimen constructed to achieve virologic suppression and avoid drug interactions with the anti-TB regimen administered (AIII).

IRIS or a paradoxical reaction occurring after the initiation of ART is thought to be the result of recovery of immune responses to previously recognized TB antigens, reconstituted by ART or by TB treatment itself (48CDC. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR 2004;53(No. RR-15).). The immune response might be an exaggerated inflammatory response during TB treatment in a patient known to have TB, referred to as paradoxical TB-associated IRIS, or might unmask previously undiagnosed TB, referred to as unmasking TB-associated IRIS.

TB-associated paradoxical reactions or IRIS usually occur in the first 1-3 months after starting ART in patients receiving TB treatment (294Shelburne SA, 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213-7.). The risk for IRIS is greater when ART is started within the first 2 months of TB therapy (222Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335-41., 354Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361-73.) and when the CD4⁺ count is <100 cells/µL (295Colebunders R, John L, Huyst V, et al. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis 2006;10:946-53., 296Manosuthi W, Kiertiburanakul S, Phoorisri T, Sangkanuparph S. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculosis and antiretroviral therapy. J Infect Dis 2006;53:357-63., 297Michailidis C, Pozniak AL, Mandalia S, Basnayake S, M.R. N, Gazzard BG. Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis. Antivir Ther 2005;10:417-22., 298French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27.). Signs of a paradoxical reaction or IRIS can include, but are not limited to, high fevers, worsening respiratory status, increase in size and inflammation of involved lymph nodes or new lymphadenopathy, breakthrough meningitis or new or expanding CNS lesions, radiologic worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical or IRIS reaction only after a thorough evaluation has excluded other possible causes, especially failure of TB therapy.

IRIS or paradoxical reactions are usually self-limited but if symptoms are severe, supportive treatment might be required, depending on the nature of the complications. Typically, a paradoxical or IRIS reaction that is not severe should be treated symptomatically with nonsteroidal anti-inflammatory agents without a change in anti-TB treatment or ART (BIII). Approaches to the management of severe reactions (e.g., high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, increased intracranial pressure [ICP], or sepsis syndrome) have not been studied but might require invasive interventions such as surgical decompression, and although no specific treatment is recommended for severe reactions, improvement has been observed with the use of prednisone or methylprednisolone used at a dose of approximately 1 mg/kg body weight gradually reduced after 1-2 weeks (BIII) (48CDC. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR 2004;53(No. RR-15).).