BackgroundDiabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent.MethodsA case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants.ResultsAmong 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants.ConclusionDiabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control.

Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.

f Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. 2 ) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (؉14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (C max ) and area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 5.6 g/ml and 28.6 g · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher C max and AUC 0 -24 values of 6.4 g/ml and 31.6 g · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.)

Abstractobjective Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment.methods A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined.results There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5-month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co-infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates.conclusion Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival.