Tuberculosis Treatment in Resource-Limited Settings

Background

Tuberculosis (TB) is the most common severe opportunistic infection associated with HIV in many resource-limited areas such as sub-Saharan Africa. The enormous and increasing number of cases of TB associated with HIV infection has greatly increased the demands on TB treatment programs. TB treatment in HIV-infected patients is different in resource-limited settings than in resource-abundant settings, and treatment details may differ by country. In general, the emphasis of TB treatment and control in resource-limited areas has been on diagnosing sputum smear-positive patients (ie, those with infectious pulmonary TB) to minimize the need for expensive technology and to maximize the public health impact of treatment. The target for many national TB control programs is to diagnose 70% of new cases, and for 85% of newly diagnosed patients to complete a course of therapy. The following recommendations for diagnosis and treatment are derived from guidelines by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease.

See the Treatment of Latent Tuberculosis in Resource-Limited Settings chapter for a discussion of isoniazid preventive treatment (IPT) for HIV-infected persons.

For more information on tuberculosis, including diagnosis and treatment, see chapter Mycobacterium tuberculosis: Treatment in the United States and Other High-Income Nations.

HIV counseling and voluntary testing should be encouraged for every person diagnosed with TB. In addition, screening for TB symptoms should occur at every health care interaction with HIV-infected persons. Patients with both conditions should be referred between the TB and HIV treatment facilities in order to access both treatments appropriately. Coordination between TB and HIV treatment is crucial because of potential drug interactions, increased risk of toxicity, risk of immune reconstitution inflammatory syndrome (IRS), and increased adherence challenges. In many countries, an effort to coordinate HIV and TB care is just beginning.

Three sputum smears should be examined for acid-fast bacilli (AFB) in all patients with chronic cough. The presence of other respiratory symptoms (eg, breathlessness, chest pain, hemoptysis) or systemic symptoms (eg, fever, night sweats, weight loss, loss of appetite) increase the likelihood of pulmonary TB. For outpatients, an initial (spot) sputum specimen should be obtained on the day a patient presents for evaluation. The patient then is sent home with a sputum cup to collect a sample immediately after awakening the next morning. The patient brings the morning specimen back to the health facility the day it is collected. On that day, the patient provides a second spot specimen in the health facility, so that 3 specimens are collected in 2 days. All 3 are stained and examined microscopically for AFB.

HIV-infected patients with TB, especially those with advanced immunosuppression, often have either smear-negative pulmonary disease or extrapulmonary disease. In such cases, diagnosis relies on clinical judgment and radiographic imaging, and sometimes on aspirates and biopsies. In some locations, x-rays may be unavailable, so TB treatment may be instituted in smear-negative patients in whom pulmonary TB is suspected (eg, in patients in whom at least 1 trial of standard antibiotics has been ineffective and a medical doctor or an appropriately trained clinician has not made an alternative diagnosis). In some cases, diagnostic testing may not be available, and AIDS patients with a wasting febrile disease may be treated empirically for TB.

TB lymphadenitis often can be diagnosed on an AFB smear of a needle aspirate of a suspicious lymph node, or on the gross appearance of caseous necrosis in a biopsied lymph node. AFB smears are usually negative in pleural, pericardial, peritoneal, joint, and cerebrospinal fluids of patients with TB in those compartments. Diagnosis is based on clinical presentation and on cell counts and chemistry tests of the fluids. (Where chemistry tests are not available, the fluid may be observed for formation of protein clots over the course of several hours, indicating elevated fluid protein levels.) Liver and bone marrow biopsy may be helpful in diagnosing disseminated TB, revealing granulomas if not acid-fast organisms. If possible, these fluids and biopsied tissues should be cultured for Mycobacterium tuberculosis.

Young children do not produce sputum, and usually are treated on the basis of clinical presentation and chest x-ray findings. A point system has been used to assist in selecting children for treatment, especially where x-ray facilities are not available. However, this point system may not be very specific in HIV-infected children, who may have other illnesses unrelated to TB. Children exposed to TB in the home need to be assessed for symptoms and signs of active disease, and should receive either IPT (see the Treatment of Latent Tuberculosis in Resource-Limited Settings chapter) or empiric treatment for active TB.

Directly observed therapy--short course (DOTS) is recommended. The DOTS framework includes systems for

	Standardized short-course (6-month) chemotherapy promoting adherence and observing each dose of medication;
	Access to quality-assured sputum microscopy;
	Uninterrupted access to appropriate drugs;
	A quality-assured data and monitoring system; and
	The political will and resources to implement a national TB control program.

Therapy may be directly observed by health care workers, family members, lay community volunteers or activists, or coworkers. The treatment supporter documents the observation of doses using forms and procedures analogous to those used for this purpose by health care workers. The treatment supporter accompanies the patient to the TB treatment visits, bringing remaining medications and treatment documentation paperwork each time.

The TB treatment regimens recommended by the WHO for HIV-infected persons are shown in Table 1. Where DOTS can be assured, regimens for new patients are the same as those used in industrialized countries. Fixed-dose combination (FDC) tablets are available in some countries for both initial and continuation phases of treatment, for both adults and children, and may be available in blister packs. Use of the FDCs reduces the time demands on health care workers, ensures more accurate weight-based dosing, simplifies assessment of adherence, and eliminates the option for patients to avoid individual medications in their regimen.

Patients who are smear positive after completing TB treatment ("relapse") or return after a 2-month gap in treatment having had at least 1 month of prior exposure to TB medications ("return from default") are considered retreatment cases (Category II; see Table 1) and receive an expanded and extended regimen. If possible, sputum for culture and sensitivity is obtained at the beginning of a retreatment regimen. In some countries with high rates of multidrug resistance, these patients may be referred directly to second-line treatment (Category IV).

Ethambutol is included in regimens for HIV-infected persons. However, it may be omitted in HIV-uninfected persons with smear-negative pulmonary TB without cavities and without suspicion of drug resistance. Some countries do not include ethambutol in the treatment of young children with TB.

TB meningitis is treated with streptomycin instead of ethambutol during the initial phase of therapy.

Corticosteroids are recommended for patients with TB meningitis, pericarditis, severe or bilateral pleural effusions, TB laryngitis threatening the airway, massive TB adenopathy with dangerous pressure effects, severe IRS, and severe drug toxicity (prednisone 1 mg/kg with tapering over the course of weeks to months). For patients with adrenal insufficiency due to TB, stress-doses of corticosteroids will need to be followed by chronic replacement doses.

Thiacetazone was previously widely used in Africa as part of TB treatment. Its use is discouraged now because of a high rate of severe skin reactions including fatalities from Stevens-Johnson syndrome and toxic epidermal necrolysis, especially in HIV-infected persons.

Table 1. World Health Organization's Recommended First-Line Regimens for Tuberculosis Treatment

Table 1. World Health Organization's Recommended First-Line Regimens for Tuberculosis Treatment Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. WHO, Geneva. * Pyridoxine 10 mg daily is added to each dose of isoniazid. ** Rifampin is called rifampicin in other countries. It is recommended that every rifampin dose be supervised (directly observed therapy). Rifampin should not be used with nevirapine or protease inhibitors; rifabutin may be substituted with appropriate dosage adjustments. *** In TB meningitis, the World Health Organization recommends substituting streptomycin for ethambutol. †Isoniazid and ethambutol is expected to have a higher failure rate than isoniazid and rifampin; however, it is included for treatment when continuation-phase therapy cannot be directly supervised, to avoid the risk of promoting resistance to rifampin. # Culture and susceptibility testing (if available) should be performed at the beginning of Category II treatment. ## HIV-infected patients in Category III will take the same treatment as persons in Category I. TB Category TB Patients TB Treatment Regimens Initial Phase (daily or 3 times weekly) Continuation Phase (daily or 3 times weekly) I New smear positive; new smear negative with extensive chest x-ray abnormalities, severe HIV disease, or severe extrapulmonary TB Isoniazid,* rifampin,** pyrazinamide, ethambutol*** for 2 months Isoniazid* and rifampin** for 4 months Isoniazid and ethambutol† daily for 6 months II Previously treated smear-positive pulmonary TB# relapse return after default treatment failure Isoniazid,* rifampin,** pyrazinamide, ethambutol and streptomycin for 2 months, followed by isoniazid,* rifampin,** pyrazinamide and ethambutol for 1 month Isoniazid,* rifampin,** and ethambutol for 5 months III Smear-negative TB and extrapulmonary TB less severe than category 1## Isoniazid,* rifampin,** pyrazinamide, ethambutol for 2 months Isoniazid* and rifampin** for 2 months Isoniazid* and ethambutol† daily for 6 months IV Chronic and multidrug-resistant TB (smear positive after supervised retreatment) Multidrug-resistant or individualized regimen per country protocol

Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. WHO, Geneva. * Pyridoxine 10 mg daily is added to each dose of isoniazid. ** Rifampin is called rifampicin in other countries. It is recommended that every rifampin dose be supervised (directly observed therapy). Rifampin should not be used with nevirapine or protease inhibitors; rifabutin may be substituted with appropriate dosage adjustments. *** In TB meningitis, the World Health Organization recommends substituting streptomycin for ethambutol. †Isoniazid and ethambutol is expected to have a higher failure rate than isoniazid and rifampin; however, it is included for treatment when continuation-phase therapy cannot be directly supervised, to avoid the risk of promoting resistance to rifampin. # Culture and susceptibility testing (if available) should be performed at the beginning of Category II treatment. ## HIV-infected patients in Category III will take the same treatment as persons in Category I.

Pregnancy

The WHO considers all Category I medications to be safe in pregnancy. Avoid streptomycin (Category II treatment) if possible, as it can cause 8th cranial nerve damage to the fetus.

Breastfeeding

The WHO considers all anti-TB medications to be safe during breast-feeding.

Hepatic Disease

Pyrazinamide should be avoided in patients with preexisting liver disease. For mild-to-moderate liver disease, an initial 2-month regimen of isoniazid, rifampin, ethambutol, and streptomycin can be followed by a 6-month course of isoniazid and rifampin. For severe liver disease, 2 months of isoniazid, ethambutol, and streptomycin is followed by 10 months of isoniazid and ethambutol. If these regimens are not tolerated, or if drug resistance is suspected, consult an expert.

Renal Disease

Ethambutol should be dose-adjusted or avoided altogether in severe renal insufficiency. Streptomycin doses must be adjusted in patients with abnormal renal function.

Polydrug or Multidrug Resistance

Patients with polydrug or multidrug resistance may be treated with standardized Category IV regimens or individualized regimens, depending on the country protocol. Category IV patients should be treated according to expert advice or in specialized centers.

Monitoring for Treatment Effectiveness

Patients who are smear positive initially should be monitored by repeat sputum smears (Table 2). Young children, smear-negative pulmonary TB patients, and extrapulmonary TB patients can be followed clinically. Repeat chest x-ray is not recommended for routine follow-up and is considered a poor use of resources. Chest x-ray should be repeated only for a patient with new or progressive symptoms. Patients who were previously sputum smear-positive with 2 subsequent negative sputum smears and completion of 6-8 months of treatment are considered cured. Previously sputum smear-negative patients, or patients who cannot produce sputum, who respond clinically (cessation of cough and fever, weight gain) and complete 6-8 months of treatment are considered "completers." Successful treatment includes all cured patients and "completers." Patients who are smear positive at the end of the initial phase (2 months of Category I treatment or 3 months of Category II treatment) should continue on the initial phase for 1 additional month. Patients who are smear positive after the additional month need 2 sputum samples sent for culture and sensitivity (if available) and progress to the continuation phase for the usual 4 months (Category I) or 6 months (Category II). Patients who are smear positive at 5 months are considered treatment failures; sputum is sent for culture and sensitivity and they progress to the retreatment regimen. Those who have a gap in treatment are called "interrupters," and efforts must be made to get them back into treatment. Those who have at least a 2-month gap in treatment are "defaulters," and must be reassessed with new sputum smears.

Table 2. Timing of Sputum Smears

Table 2. Timing of Sputum Smears Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. World Health Organization, Geneva. *See text. When to Monitor Category I (6-month regimen) Category II (8-month regimen) At diagnosis 3 specimens 3 specimens End of initial phase 1 spot specimen 1 spot specimen End of additional month of initial phase, if needed* 1 spot specimen 1 spot specimen In continuation phase 1 spot specimen at end of month 5 1 spot specimen at end of month 5 During last month of treatment 1 spot specimen during month 6 1 spot specimen during month 8

Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. World Health Organization, Geneva. *See text.

(See Table 4 in chapter Mycobacterium tuberculosis: Treatment in the United States and Other High-Income Nations for information on adverse effects of TB therapy.)

Standard guidelines for anti-TB therapy in resource-limited settings do not require baseline or follow-up laboratory tests as a matter of routine. Rather, clinical assessment should be performed at least monthly and should include evaluation of symptoms or signs such as gastrointestinal intolerance, minor and major cutaneous drug reactions, joint pain, hepatitis (nausea, vomiting, abdominal pain, jaundice), peripheral neuropathy, changes in visual acuity, or development of blind spots (Table 3). Where laboratory facilities and financial resources allow, many clinicians prefer to check baseline and periodic complete blood counts with differential, alanine/aspartate aminotransferase (ALT/AST) or bilirubin, and baseline creatinine. Laboratory monitoring is more important in persons with preexisting liver disease or those on concomitant ART although TB treatment should not be withheld for lack of access to hematology or chemistry laboratory testing.

Management of severe rash includes discontinuation of TB therapy, supportive care, administration of corticosteroids for severe or life-threatening desquamation, and gradual reintroduction of escalating dosages of medications after resolution. Drugs are reintroduced in the reverse order of their likelihood of causing severe rash: isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin. Avoid thiacetazone because of high risk of severe cutaneous reactions. Seek expert advice.

Management of liver toxicity includes cessation of therapy until bilirubin and ALT return to normal levels. If laboratory testing is not available, wait until 2 weeks after the resolution of jaundice. Treat with ethambutol, streptomycin, rifampin (if tolerated), and isoniazid (if tolerated). See the discussion of hepatic disease, above, for 2 possible treatment regimens. If the TB is severe, treatment may have to be resumed early without hepatotoxic drugs (ethambutol and streptomycin), until additional drugs can be reintroduced to the regimen. Seek expert advice.

Table 3. Monitoring for Toxicity

Table 3. Monitoring for Toxicity Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. World Health Organization, Geneva. Side Effects Drugs Likely Responsible Management Minor Side Effects Anorexia, nausea, abdominal pain Rifampin Give dose last thing at night Joint pain Pyrazinamide Aspirin or nonsteroidal anti-inflammatory drugs Burning in feet, neuropathy Isoniazid Pyridoxine 50-75 mg daily Orange/red urine Rifampin Reassurance Major Side Effects Severe rash or skin itching Thiacetazone, streptomycin Stop TB therapy for severe reactions; give supportive care; after resolution of symptoms, reinstitute therapy (see text) Decreased hearing, deafness (rule out wax in ears) Streptomycin Substitute ethambutol or other Dizziness, vertigo, nystagmus Streptomycin Substitute ethambutol or other Jaundice Pyrazinamide, isoniazid, rifampin Stop TB treatment until jaundice resolves (see text) Vomiting and confusion Pyrazinamide, isoniazid, rifampin Stop TB treatment and perform liver function tests Visual impairment Ethambutol Stop ethambutol Generalized hypersensitivity reaction with shock and purpura Rifampin Stop rifampin

Source: Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual, 2nd ed. 2004. World Health Organization, Geneva.