Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis.

BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. METHODS: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. RESULTS: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. CONCLUSION: The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Feasibility of shortening respiratory isolation with a single sputum nucleic acid amplification test.

RATIONALE: Serial smear analysis to guide respiratory isolation (RI) of patients with suspected tuberculosis (TB), the majority of whom will be found not to have TB, leads to expensive and unnecessary isolation, and may potentially result in decreased vigilance of subjects with respiratory compromise. OBJECTIVES: To compare the performance of a single first-sputum, Mycobacterium tuberculosis-specific nucleic acid amplification (NAA) test with three sputum smears for assessing the need for RI. METHODS: Prospective evaluation of 493 patients with suspected TB (74% HIV positive) admitted to RI in a major county hospital in the United States, who had at least three sputum smears and material available from the first sample for additional NAA testing. MEASUREMENTS AND MAIN RESULTS: Accuracy of the first sputum NAA result and serial smears for identifying patients with potentially infectious TB who truly require RI was determined. Forty-six patients (9.3%) had TB confirmed by culture. First-sputum NAA test detected all patients with TB who had a positive smear (n = 35), even when the first of the three specimens was smear negative. In addition, when compared with serial smears, the first-sputum NAA had a higher sensitivity (0.87; 95% confidence interval [CI], 0.74-0.95) and specificity (1.0) in the detection of subjects with positive M. tuberculosis cultures (smear sensitivity, 0.76; 95% CI, 0.61-0.87; and specificity, 0.96; 95% CI, 0.94-0.98). CONCLUSIONS: A single first-sputum NAA testing can rapidly and accurately identify the subset of patients with suspected TB who require RI according to serial sputum smears. Its potential use to shorten RI time does not preclude the need to obtain subsequent specimens for culture.

Short-course rifamycin and pyrazinamide treatment for latent tuberculosis infection in patients with HIV infection: the 2-year experience of a comprehensive community-based program in Broward County, Florida.

OBJECTIVES: To determine the completion rate and tolerability of short-course rifamycin and pyrazinamide treatment of latent tuberculosis infection (LTBI) in HIV-infected patients through a comprehensive community-based program. DESIGN: Prospective cohort, with comparison to a historical control group. PATIENTS: Of 3,118 patients with HIV infection screened for LTBI between February 1999 and March 2001, 135 patients were placed on rifamycin/pyrazinamide for 2 months under directly observed therapy and were compared to a historical group comprised of 93 HIV-infected patients who were placed on self-administered treatment of isoniazid for 12 months between 1996 and 1998. RESULTS: Of 135 patients receiving rifamycin/pyrazinamide, 124 patients (92%) completed treatment; 5 patients had to discontinue treatment due to side effects (allergic skin reactions [n = 4], hepatitis [n = 1]). The completion rate of the historical group who received isoniazid therapy was 61% (57 of 93 patients; p < 0.001); none of those who received isoniazid experienced significant side effects. CONCLUSION: In our experience, a comprehensive, community-based program of rifamycin/pyrazinamide for LTBI achieved significantly higher adherence than that of traditional isoniazid therapy, and thus may provide improved tuberculosis prevention in a community with high prevalence of HIV-infected patients.