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Case 5: Discussion - Tuberculosis

Assessment of Risk for Tuberculosis in HIV-Infected Persons

Providers should maintain a high index of suspicion for active tuberculosis (TB) in any HIV-infected person, especially those with risk factors for acquiring Mycobacterium tuberculosis infection. These risk factors include birth or residence in an area endemic for TB infection, homelessness, injection drug use, and residence in a nursing home or correctional facility[1]. Individuals with HIV infection are more likely to develop active TB if infected, but no more likely to transmit M. tuberculosis to others. Some HIV-infected patients, especially those with more advanced immunosuppression, develop TB rapidly after becoming infected with M. tuberculosis, with 37% developing active TB within 6 months of primary TB infection[2]. In general, HIV-infected patients with a positive tuberculin test will develop active TB at a rate of approximately 8-10% per year[3].

Clinical Presentation of Pulmonary TB

In a large retrospective study of TB in HIV-infected individuals, 38% had isolated pulmonary involvement, 32% had pulmonary and extrapulmonary involvement, and 30% had disease only at extrapulmonary sites[4]. This distribution contrasts TB in HIV-negative patients, which is limited to pulmonary involvement in 85% of cases. Although TB can occur in HIV-infected patients irrespective of the degree of immunosuppression, those with more advanced HIV are more likely to have extrapulmonary involvement or other atypical features[1,4]. Among HIV-infected individuals who develop TB, common systemic symptoms include fever, weight loss, night sweats, anorexia, and malaise. Pulmonary disease usually manifests as cough, which eventually becomes productive of sputum. Hemoptysis, pleuritic pain, and dyspnea may also occur. Extrapulmonary manifestations in HIV-infected persons include lymphadenopathy, splenomegaly, mental status changes, and local pain, depending on the sites of involvement.

Tuberculin Skin Testing in Suspected Pulmonary TB

The tuberculin skin test can play a role in the evaluation of patients suspected of having active TB. A positive result supports the diagnosis of TB in a patient with a compatible clinical presentation. A negative test, however, does not rule out the possibility of TB, as up to 25% of patients with active TB have a false-negative skin test, even without HIV co-infection[5]. Such false-negative results in HIV-negative individuals are presumably due to poor immune function or compromised nutritional status caused by overwhelming TB disease. Among immunocompromised patients, including HIV-infected individuals, who are at highest risk for progression to active TB if infected with M. tuberculosis, a skin test result of 5 mm or more of induration is considered positive and indicates either latent or active infection with M. tuberculosis. In foreign-born persons from areas where TB is endemic, BCG status should be disregarded, as skin test reactions in adults who received BCG vaccine in childhood are highly variable and usually small (less than 10 mm induration)[6]. In addition, BCG vaccine does not confer reliable protection against TB for adults. Providers should consider TB in any HIV-infected patient with indolent constitutional symptoms or a chronic cough, regardless of the results of tuberculin skin testing.

Chest Radiographic Findings of Pulmonary TB

Among patients with a high CD4 cell count, TB typically presents as classic reactivation disease, with infiltrates located in the apical-posterior segment of an upper lobe or superior segment of a lower lobe; these infiltrates may be present with (Figure 1) or without cavitation (Figure 2). Pleural effusions can also occur (Figure 3). In those with advanced immunosuppression, the chest radiograph may show intrathoracic lymphadenopathy, infiltrates in any lung field, or a combination of lymphadenopathy and infiltrates (Figure 4). In addition, those with advanced immunosuppression often develop diffuse or miliary infiltrates (Figure 5 and Figure 6)[7]. These diffuse infiltrates can resemble the infiltrates seen in patients with Pneumocystis pneumonia. Infrequently, patients will develop pneumothorax caused by pulmonary TB (Figure 7). Some HIV-infected persons can also have a normal chest radiograph despite pulmonary involvement. Laboratory abnormalities can include anemia, leukocytosis, monocytosis, hyponatremia, hypoalbuminemia, elevated transaminases, and increased inflammatory markers.

Diagnostic Tests for Suspected Pulmonary TB

According to the diagnostic standards guidelines issued by the American Thoracic Society and CDC, a minimum of three sputum specimens should be collected when pulmonary TB is suspected, with induction by an ultrasonic nebulizer using hypertonic saline if expectorated samples are inadequate[3]. These sputum samples should ideally be collected at least 8 hours apart and sent for AFB smear (Figure 8) and culture (Figure 9). The sensitivity of a sputum smear for detecting acid-fast bacilli (AFB) is approximately 50-80%[3]. Smear-negative pulmonary TB is more common in HIV-infected patients with advanced immunosuppression[1,7]. Nucleic acid amplification (NAA) tests may be useful if the AFB smear is negative and clinical suspicion high[8]. The CDC has published a suggested approach for the use of NAA tests in evaluating patients with suspected TB[9]. For sputum samples, the sensitivity of NAA tests in smear-positive cases is approximately 95%, but it falls to 40-80% in AFB smear-negative cases. In both instances, the specificity of NAA is greater than 95%. The combination of a positive smear and NAA confirms the diagnosis of TB and excludes mycobacteria other than M. tuberculosis. The NAA tests are not FDA-approved for specimens other than sputum. Of note, clinicians should not use NAA tests to follow response to therapy, as the tests remain positive in the presence of dead organisms. Regardless of the results of microscopy and any molecular methods used, evaluation of all initial specimens should include culture for M. tuberculosis. Culture is more sensitive than AFB staining techniques and is required for positive species identification and drug susceptibility testing. Genotyping of cultured organisms may help rule out laboratory contamination and can be used to investigate epidemiologic links to other patients' samples. With use of liquid culture media, M. tuberculosis typically grows within 1-3 weeks instead of the 3-8 weeks required for growth on solid media.

Other specimens should be obtained if sputum fails to yield a diagnosis. Fiberoptic bronchoscopy can play an important role in obtaining additional lung specimens via bronchoalveolar lavage or transbronchial biopsy. Use of strict infection control precautions can prevent transmission to health-care personnel during these procedures. Patient preparation for bronchoscopy should minimize the use of topical anaesthetics, as these may inhibit mycobacterial growth. Although obtaining pleural fluid by thoracentesis may help diagnose active TB in some cases, the sensitivity of AFB staining and culture of pleural fluid is low. In contrast, microscopic examination and culture of three pleural biopsy specimens can yield the diagnosis in up to 90% of cases[3]. With a normal chest radiograph and negative sputum smears and culture, the evaluation may require biopsy of an extrapulmonary site, such as an enlarged lymph node.

Treatment Considerations for TB in HIV-Infected Persons

The 2004 Treatment of Opportunistic Infections Guidelines and the 2003 treatment guidelines published jointly by the American Thoracic Society, the CDC, and the Infectious Diseases Society of America recommend a 6-month multi-drug regimen for treatment of TB in HIV-infected individuals (Figure 10)[1,10,11]. Patients with drug-sensitive M. tuberculosis should initially receive 8 weeks of therapy with a 4-drug regimen that consists of isoniazid plus rifampin (or rifabutin) plus pyrazinamide plus ethambutol. This initial phase of treatment is followed by a continuation phase that consists of 18 weeks of isoniazid plus rifampin (or rifabutin). If the initial or follow-up chest radiograph shows cavitation, and the culture after completion of the initial 2-month phase remains positive, the continuation phase should be lengthened from 4 months to 7 months[1,10].

Rifampin, and to a lesser extent rifabutin, can cause significant drug-drug interactions in a patient concomitantly taking antiretroviral therapy[12]. Clinicians should carefully monitor patients for medication-related toxicity, including baseline testing of transaminases, bilirubin, alkaline phosphatase, creatinine, and platelet counts, and monthly monitoring during treatment if an abnormality is detected at baseline. If ethambutol is used, visual acuity and red-green color discrimination should be tested at baseline and monthly thereafter while on ethambutol. In addition, patients should be told to immediately report any symptom of hepatitis, namely abdominal pain, vomiting, and dark urine. Patients at higher risk for hepatotoxicity can be identified by testing for chronic hepatitis B and C and by screening for alcohol abuse. All HIV-infected patients who receive isoniazid should take pyridoxine (vitamin B6) dosed at 25-50 mg daily to prevent peripheral neuropathy[10]. Patients taking stavudine (Zerit) or didanosine (Videx EC) along with isoniazid may be at greater risk of developing neuropathy.

Adherence to therapy is of paramount importance to the success of TB treatment, and a patient-centered approach including directly observed therapy (DOT) is recommended[1]. The total number of doses determines treatment completion, and patients should take all doses of the standard 6-month regimen within 9 months of treatment initiation. Intermittent therapy with rifapentine has been associated with the development of drug resistance in HIV-infected patients receiving TB treatment, especially in patients with lower CD4 cell counts. Therefore, daily or thrice weekly DOT regimens are recommended for patients with CD4 counts less than 100 cells/mm3. Providers must report active TB to the local health department, which can help manage cases and evaluate contacts.

Monitoring Response to TB Therapy

The clinician should monitor response to treatment with sputum smears, sputum cultures, and chest radiography. As noted earlier, if the sputum culture remains positive after the 2-month intensive phase of treatment and the initial chest radiograph showed cavitation, the continuation phase of treatment course should extend for from 18 weeks to 26 weeks[1]. Susceptibility testing should be performed on all initial isolates and should be repeated on any positive culture after 3 months of treatment or if the patient has a positive culture after a period of negative cultures. If the clinician suspects drug resistance, molecular methods can rapidly detect rifampin resistance. HIV-infected patients with TB may have a higher risk for developing drug-resistant M. tuberculosis, especially resistance to rifamycins (rifampin, rifabutin, or rifapentine)[13]. If laboratory testing detects rifampin resistance, whether alone or in combination with isoniazid resistance, the medical provider should seek expert consultation.

Use of Antiretroviral Therapy in Patients with TB

Due to multiple potential drug-drug interactions with the simultaneous use of antituberculous therapy and antiretroviral therapy, most experts recommend treating TB for at least 4-8 weeks prior to initiating antiretroviral therapy whenever possible[1]. In addition, up to 36% of patients who start antiretroviral therapy soon after starting TB treatment will experience paradoxical worsening of their TB, defined as new and unexplained fever, radiographic worsening, or an increase in lymphadenopathy or other lesions[14]. The worsening clinical course usually occurs about 2 weeks after initiating antiretroviral therapy and often corresponds with skin test conversion and laboratory evidence of immune reconstitution[14]. This scenario is referred to as the immune reconstitution syndrome. In the setting of clinical worsening caused by suspected immune reconstitution, it is important to evaluate the patient for TB treatment failure and for other opportunistic infections or malignancies. If causes other than immune reconstitution are deemed unlikely, either prednisone or methylprednisolone can be used to control immune reconstitution symptoms (dosed at 0.5-1.0 mg/kg per day for several weeks, followed by a gradual taper, the speed of which is often determined by recurrence of symptoms). Mild immune reconstitution symptoms can sometimes be controlled with non-steroidal anti-inflammatory drugs. Active TB can lower the CD4 count, which often increases significantly with antituberculous therapy alone. Accordingly, some clinicians elect to defer antiretroviral therapy until they can reevaluate the CD4 count after TB therapy. On the other hand, patients who have a CD4 count less than 100 cells/mm3 have a high risk of dying from TB or from other opportunistic conditions, so many experts recommend starting antiretroviral therapy as soon as possible in this group. Antiretroviral therapy reduces the incidence of TB disease in HIV-infected persons, and it may also reduce the risk of relapse after treatment[15].

Antiretroviral Therapy Regimens in Patients with TB

Patients who are already on antiretroviral therapy when diagnosed with TB should continue antiretroviral therapy, with adjustments made as needed to avoid unwanted drug-drug interactions (Figure 11). For a more detailed discussion of these drug-drug interactions see the discussion section in Case 2 in the section Drug-Drug Interactions. Currently, the best option for antiretroviral therapy in patients on a rifamycin-containing TB regimen consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (Sustiva). When rifampin and efavirenz are combined, rifampin is given at the standard dose, but the efavirenz dose should be increased to 800 mg daily, if they can tolerate this dose. With concomitant use of rifabutin and efavirenz, the rifabutin dose should be increased to 450 mg once daily or 600 mg thrice weekly; the efavirenz dose is not adjusted. Protease inhibitors (PIs) are generally contraindicated with rifampin, because of the increased risk of hepatotoxicity and because of drug interactions that result in reduced PI levels. Most PIs can be combined with rifabutin with the appropriate dose adjustments. The inducing effect of rifampin on cytochrome P450 enzymes persists for at least 2 weeks after its discontinuation. Intolerance, toxicity, or resistance to either HIV or TB medications may necessitate a change in the other regimen. Such decisions should be made in consultation with experts in both TB and HIV care.

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    Figure 1. Chest Radiograph: Infiltrates with Cavitation

    This chest radiograph of an HIV-infected patient with tuberculosis shows extensive infiltrates with evidence of cavitation in the right upper lobe.

    Figure 1
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    Figure 2. Chest Radiograph: Infiltrates without Cavitation

    This chest radiograph of an HIV-infected patient with tuberculosis shows bilateral infiltrates (right greater than left) without evidence of cavitation.

    Figure 2
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    Figure 3. Chest Radiograph: Pleural Effusion

    This chest radiograph of an HIV-infected patient with tuberculosis shows a very large left-sided pleural effusion.

    Figure 3
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    Figure 4. Chest Radiograph: Adenopathy and Infiltrates

    This chest radiograph of an HIV-infected patient with tuberculosis shows marked right-sided paratracheal lymphadenopathy (arrow) and diffuse infiltrates.

    Figure 4
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    Figure 5. Chest Radiograph: Miliary Infiltrates

    This chest radiograph of an HIV-infected patient with advanced immunosuppression and tuberculosis shows a milary pattern.

    Figure 5
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    Figure 6. Chest Computed Tomographic Scan: Miliary Pattern

    This high resolution chest computed tomography of an HIV-infected patient with advanced immunosuppression and tuberculosis (same patient as shown in Figure 5) shows a widespread milary pattern in the lung parenchyma.

    Figure 6
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    Figure 7. Chest Radiograph: Pneumothorax

    This chest radiograph of an HIV-infected patient with tuberculosis shows a diffuse pattern and a right-sided pneumothorax.

    Figure 7
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    Figure 8. Ziehl-Nielsen Stain

    This Ziehl-Nielsen stain shows several characteristic red-staining acid-fast bacteria (M. tuberculosis).

    Figure 8
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    Figure 9. Growth of <em>Mycobacterium tuberculosis</em>

    Colonies of M. tuberculosis growing on media.

    Figure 9
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    Figure 10. Treatment of Drug-Sensitive <em>Mycobacterium   tuberculosis</em>

    *Rifampin dose may need to be adjusted with concomitant antiretroviral therapy.
    ^Rifabutin dose may need to be adjusted with concomitant antiretroviral therapy.
    In patients with delayed clinical or microbiologic response to initial therapy after 2 months or if cavitary pulmonary lesions are present, the duration of the continuation phase should extend from 18 weeks to 26 weeks.

    This table is reproduced and modified from Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. 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 Recomm Rep 2004;53(RR-15):1-112.

    Figure 10
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    Figure 11. Recommendations for Co-Administration of Antiretroviral Drugs with Antimycobacterial Drugs*

    *If CD4 count is greater than 100 cells/mm3, may consider twice-weekly administration of rifabutin with amprenavir, fosamprenavir, indinavir, nelfinavir, efavirenz, and nevirapine.

    This figure is adapted from information contained in Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR. 2004;53(02):37.<

    Figure 11