Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations

Abstract

Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs.

Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion.

Results: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure.

Conclusion: Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950.

Figure 1.

Flow diagram shows patients excluded and treatment outcomes in patients followed up. Abbreviations: ART, antiretroviral therapy; GRF, glomerular filtration rate; HIV, human immunodeficiency virus.

Figure 2.

Association between concentrations of rifampicin, isoniazid, and pyrazinamide and tuberculosis treatment outcome. Box plots demonstrating area under the concentration-time curve (AUC) and estimated maximum concentrations (eC_max) for isoniazid, rifampicin, and pyrazinamide at weeks 2, 8 and 24 and stratified by tuberculosis treatment outcome: cured (C) and not cured (NC). The top of each box represents the 75th percentile (Q3); the bottom, the 25th percentile (Q1); and the horizontal line within each box, the 50th percentile (median) concentration. The top whisker represents Q3 + (1.5 × the interquartile range [IQR]), and the bottom whisker, Q1 − (1.5 × IQR); dots represent outliers.

Figure 3.

Association between number of drugs below the cutoff and time to sputum culture conversion in 108 patients with intensive sputum culture monitoring. Kaplan-Meier curves for these patients demonstrate the probability of remaining sputum culture positive over time, stratified by the number of drug concentrations below the lower limit of the normal reference range for rifampicin (<8 mg/L) and isoniazid (<3 mg/L). Hazard ratios (HRs) are shown with 95% confidence intervals in parentheses.