Pharmacologic and Clinical Risk Factors of Poor Tuberculosis Treatment Outcomes in Patients with Rifampicin-Susceptible Tuberculosis in Selected Hospitals in Ghana.

Abstract

Introduction: The global reduction in Tuberculosis (TB) incidence and deaths since 2015 is not progressing as rapidly as required to meet the established milestones of a 50% reduction in the 2015 incidence rate and a 75% reduction in the 2015 mortality rate. The rate of decline in the African region is even slower. However, the milestones are achievable with early diagnosis and appropriate treatment. Adequate plasma concentration of the recommended multi-drug regimen for each patient is important for treatment success. Current evidence linking plasma concentration to treatment outcomes has not been conclusive. This study sought to determine the pharmacologic and clinical risk factors of poor TB treatment outcomes in patients with rifampicin-susceptible TB in Ghana. Methods: A prospective study was conducted in four hospitals in three districts in the Ashanti Region and one hospital in the Bono East Region of Ghana. New and relapse TB patients eligible for management with the first-line anti-TB regimen were recruited and followed up monthly to the end of treatment in 6 months. The sample size was determined to be 164. Eligible participants were recruited by consecutive sampling. The primary outcome variable was treatment outcomes measured on a binary scale, unsuccessful and successful. The main exposure variables of interest were peak plasma concentrations (Cmax) of rifampicin, isoniazid, pyrazinamide, and ethambutol. Cmax was dichotomized using universally accepted thresholds. Blood samples were collected for all participants between the 4th and 8th week after treatment initiation. Validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for the determination of the drug concentrations. To determine the association between low Cmax and treatment outcomes, cross-fit partialing-out lasso for Poisson models was used. The baseline and longitudinal risk factors for bacteriologic failure were determined using generalized estimating equations with an “independent” working correlation and a logit link. Results: A total of 164 participants were selected into the study. The proportion of participants with low Cmax of rifampicin, isoniazid, pyrazinamide, and ethambutol were 94.4%, 87.0%, 31.3% and 52.2%, respectively. Low rifampicin Cmax was associated with a 19% reduced likelihood of sputum smear conversion at the end of the intensive phase of treatment (IRR = 0.81; 95% CI: 0.73, 0.89; p < 0.001). Patients with low pyrazinamide Cmax had an increased incidence of unsuccessful end-of-treatment outcomes (IRR = 5.92; 95% CI: 2.72, 12.88; p < 0.001). When those lost to follow up were excluded from the outcomes category the effect size was 9.11 (IRR = 9.11; 95% CI: 1.66, 50.07; p = 0.002). Low ethambutol Cmax increased the risk of unsuccessful outcomes by 5.74 times (IRR = 5.74; 95% CI: 1.88, 17.53; p = 0.002). Normal rifampicin Cmax perfectly predicted successful treatment outcomes at the end of the continuation phase. Patients with concurrently low Cmax in all the four anti-TB drugs were 12.40 times more likely to have unsuccessful end-of-treatment outcomes (IRR = 12.40; 95% CI: 2.20, 69.76, p = 0.004). Bacteriologic failure over the course of treatment was more likely among participants with low rifampicin Cmax than those with normal rifampicin Cmax (AOR = 2.44; 95% CI: p =0.001). Conclusion: This study showed that low rifampicin, pyrazinamide, and ethambutol plasma concentrations are risk factors for poor TB treatment outcomes. In addition, a concurrent deficiency in the plasma concentration of all the four first-line anti-TB drugs increases the susceptibility to poor treatment outcomes. Recommendation: Dose adjustment strategies for patients with rifampicin-susceptible TB must be pursued. This includes incorporating therapeutic drug monitoring into clinical practice for TB management and conducting research into the use of higher doses of rifampicin, pyrazinamide, and/or ethambutol. These will help to reduce the likelihood of unsuccessful treatment outcomes.