Optimizing Tuberculosis treatment success rates in Namibia
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Date
2019
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Abstract
Tuberculosis (TB) is a leading cause of mortality globally, leading to an annual death rate of 1.8 million. In 2017, over 700 people died from TB in Namibia. Moreover, despite the scale-up of high-quality Directly Observed Treatment Short Course strategy (DOTS) to control TB in Namibia, treatment success rates (TSR) fall short of the global target of 90%. Unsuccessful treatment outcomes are a risk drug resistant TB. Consequently, the study aimed to model the population, patient and drug (pharmacokinetics and pharmacovigilance) level predictors of treatment success, cure and completion rates under the DOTS programme in Namibia.
The study was designed in four phases, population, and patient and drug level models, and an overall conceptual model to optimize TSR. Population-level modeling of the effectiveness of the community based-DOTS on TSR, cure and completion was done using interrupted time-series analysis. Three patient level models of TSR, loss to-folow-up (LTFU) and case fatality rates for a 10-year nationwide cohort, 2004-2016 were conducted using multivariate regression in R. Two drug level studies, i.e. a meta-analysis of the impact of HIV/TB co-infection on serum concentrations (Cmax) of rifampicin, isoniazid, pyrazinamide and ethambutol, as well as a systematic review on the burden of adverse effects were modeled.
First, the CB-DOTS intervention in 2005, immediately increased annual TSR by 12.9% (p <0.001) and then by 1.1%/year thereafter, but stagnated at ~85% by 2015. Secondly, the independent predictors for TSR were region of DOTS implementation (p=0.001); type of Workbased DOT supporter (p<0.001), sputum conversion at 2 months (p=0.013); cotrimoxazole prophylaxis OR= 0.4(95%CI: 0.2, 0.7, p=0.002); HIV co-infection OR=0.2(95%CI: 0.1, 0.5, p=0.001) and the DOT regimen (p<0.001). Thirdly, the annual decline in cases LTFU was significant between the first (2005-2010) and second (2010-2015) medium term plan periods for TB programme implementation (p=0.002).The independent predictors of LTFU were male sex (p=0.004), 15-24 age group (p=0.03), provider of treatment (p<0.001), intensive phase (p=0.047) and living in border/transit regions (p<0.001). Fourthly, the independent predictors of TB case-fatality under the DOTS programme were HIV coinfection OR=0.2 (95%CI: 0.1, 0.4, p=0.001) and the non-assessment of drug resistant testing using a GeneXpert, OR=3.4 (95%CI: 1.6, 7.5, p=0.003), region of DOTS implementation (p<0.001), patients age (p<0.001) and cotrimoxazole prophylaxis (p=0.013). Fifthly, the meta-analysis showed that HIV/AIDS significantly lowered Cmax of rifampicin -1.11μg/mL (95%CI: -2.18, -0.04, p=0.04, I2=0%) and ethambutol -0.75 μg/mL (95%CI: -1.38, -0.13, p=0.02, I2=0%) in the African population. Lastly, upto 69% of hospitalized patients experienced at least one adverse events, mainly of Type-A (i.e. predictable adverse drug reactions, range 9% to 69%). The frequency of adverse reactions was higher among TB patients with; HIV co-infection (78.5%, p=0.003), low baseline body weight (p=0.002), ART (76.2%, p=0.012) or cotrimoxazole prophylaxis (78%, p=0.005). A conceptual model for optimizing TSR was developed. We conclude, current DOTS programme though effective, is inadequate to optimize TSR and end TB by 2035. HIV/TB co-infection is main predictor of poor TSR at population, patient and drug level. Programmatic (i.e. access to bacteriological and drug resistance testing, quality of DOTS services by region), clinical (HIV/TB coinfection) and social-economic (quality of DOT supporter and young/middle aged males). The comprehensive integration of TB/HIV services as well as targeted programmatic, clinical and treatment interventions are required to enhance DOTS treatment success in Namibia. Further efforts are needed to individualize dosage regimens with rifampicin and ethambutol, and monitor Cmax in HIV co-infected patients in Africa to improve treatment outcomes.
Description
A research thesis submitted in fulfillment of the requirements for the award of the Degree of Doctor of Philosophy in Clinical Pharmacology
Keywords
Tuberculosis, Treatment Success, Optimize