As recommended by WHO, each dose of TB treatment should be directly observed throughout the duration of therapy. Monthly smear microscopy, in addition to clinical evaluation, is helpful in gauging treatment response. Ongoing clinical symptoms, cavitary disease, and/or a persistently positive sputum smear or culture after two months of treatment may reflect delayed treatment response and justify prolongation of four-drug therapy.^55,56 At ZL clinics, sputum-smear microscopy is performed for all smear-positive patients after two months of treatment; the use of four drugs is extended for any patient who still demonstrates persistent smear-positivity at that time. Subsequent monthly smear microscopies determine the duration of the intensive phase for these patients. Patients with a positive smear in the fourth, fifth, or sixth month of treatment should be considered TB treatment failures.

Poor clinical response to TB treatment may be the result of treatment failure, especially in the case of a persistently positive smear (either due to the presence of drug-resistant TB or poor patient adherence to anti-TB therapy); paradoxical worsening (immune reconstitution syndrome), particularly when fevers and shortness of breath become more prominent during treatment; or occurrence of an additional OI while the patient is receiving effective anti-TB therapy. All patients with poor clinical response and/or persistent positive smear microscopy after the intensive phase of treatment should be assessed for possible TB treatment failure, including evaluation of adherence; drug susceptibility testing, if available; and consideration of a TB regimen change if MDR TB is suspected.

Immune reconstitution syndrome in patients with pulmonary TB is characterized by clinical and radiographic worsening, often with high fever, dyspnea, or adenopathy. ⁵⁷ This syndrome is associated with recrudescence of CD4 T-cells and increased host response as a consequence of ART. The syndrome can occur two weeks to several months after the initiation of therapy and is more common in patients with very low CD4 counts and disseminated TB. For mild to moderate immune reconstitution reactions, provide nonsteroidal anti-inflammatory drugs (NSAIDs) and close observation. In patients with severe pulmonary symptoms, prednisone (1 mg/kg/day for one to two weeks, tapering the dose over a two- to four- week period) may be indicated, especially if the patient has TB in the central nervous system.⁵⁸

In patients with TB meningitis, intracranial tuberculosis or immune reconstitution can cause worsening of the neurologic deficits. In patients who experience worsening of neurologic deficits due to immune reconstitution, it is reasonable to stop ART and continue TB treatment and steroids until the central nervous system process is controlled. In general, HIV patients have a higher rate of adverse drug reactions to both TB and non-TB medications than do those without HIV disease.⁵⁹ Among co-infected patients, peripheral neuropathy may occur in more than 50 percent of those who are receiving H and stavudine (d4T).^60,61 (See Section 3.6.6 and Protocol 3.10 for additional discussion of peripheral neuropathy.) Pyridoxine at a dose of 50 mg/day should be administered concurrently with isoniazid to help prevent neuropathy.

Notably, a marked increased risk of severe cutaneous reactions, including Stevens-Johnson syndrome, is associated with the use of thiacetazone (THZ) in HIV-positive patients; this antituberculous drug should therefore not be used in co-infected individuals.⁶²