Models for Predicting Time to Sputum Conversion Among Multi-Drug Resistant Tuberculosis Patients in Lagos, South–West Nigeria

Background: Multi-drug resistant tuberculosis (MDR-TB) develops due to problems such as irregular drug supply, poor drug quality, inappropriate prescription, and poor adherence to treatment. These factors allow the development and subsequent transmission of resistant strains of the pathogen. However, due to the chronic nature of MDR-TB, cure models allow us to investigate the covariates that are associated with the long-term effects of time-to-sputum conversion among multi-drug resistant (MDR-TB) tuberculosis individuals. Therefore, this study was designed to develop suitable cure models that can predict time to sputum conversion among MDR-TB patients. Methods: A retrospective clinic-based cohort study was conducted on 413 records of patients who were diagnosed of MDR-TB and met inclusion criteria from April 2012 to October 2016 at the Infectious Disease Hospital, Lagos. The main outcome measure (time-to-sputum conversion) was the time from the date of MDR-TB treatment to the date of specimen collection for the first of two consecutive negative smear and culture taken 30 days apart. The predictor variables of interest include: demographic (age, gender and marital status) and clinical (registration group, number of drugs resistant to at treatment initiation, HIV status, diabetes status, and adherence with medication) characteristics. Kaplan-Meier estimates of a detailed survivorship pattern among the patients were examined using Cox regression models. Mixture Cox cure models were fitted to the main outcome variable using Log-normal, Log-logistic and Weibull models as alternatives to the violation of Proportional Hazard (PH) assumption. Akaike Information Criterion (AIC) was used for models comparison based on different distributions, while the effect of predictors of time to sputum conversion was reported as Hazard Ratio (HR) at α(0.05.) Results: Age was 36.8 ± 12.7 years, 60.8% were male and 67.6% were married. Majority of the patients (58.4%) converted to sputum negatives. Patients who were resistant to two drugs at treatment initiation had 39% rate of conversion than those resistant to at least three drugs [HR: 1.39; CI: 0.98, 1.98]. The likelihood of sputum conversion time was shorter among non-diabetic patients compared to diabetics [HR: 0.55; CI: 0.24, 0.85]. The overall median time for sputum conversion was 5.5 (IQR: 1.5–11.5). In the cure model, resistance to more drugs at the time of initiation was significantly associated with a longer time to sputum culture conversion for Log normal Cox mixture [2.06 (1.36–3.47)]; Log-logistic Cox mixture cure [2.56(1.85–4.09)]; and Weibull Cox mixture [2.81(1.94–4.19)]. Diabetic patients had a significantly higher sputum conversion rate compared to non-diabetics; Log-normal Cox mixture [2.03(1.17–3.58)]; Log-logistic Cox mixture cure [2.11(1.25–3.82)]; and Weibull Cox mixture [2.02(1.17–3.34)]. However, Log-normal PH model gave the best fit and provided the fitness statistics [(−2LogL: 519.84); (AIC: 1053.68); (BIC: 1078.04)]. The best fitting Log-normal PH model was Y = 1.00X(1)+2.06X(2)+0.98X(3)+2.03X(4)+ε where Y is time to sputum conversion and Xs are age, number of drugs, adherence, and diabetes status. Conclusion: The models confirmed the presence of some factors related with sputum conversion time in Nigeria. The quantum of drugs resistant at treatment initiation and diabetes status would aid the clinicians in predicting the rate of sputum conversion of patients.