Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients.

BACKGROUND: Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population. OBJECTIVES: To compare exposure to TB drugs in Tanzanian TB patients with and without DM. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs. RESULTS: A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid. CONCLUSIONS: There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

Pharmacokinetics of first-line tuberculosis drugs in Tanzanian patients.

East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC0-24) and peak plasma concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC0-24s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. The Cmax was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the Cmaxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin Cmax below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.

Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study.

BACKGROUND: To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. METHODS: This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). RESULTS: A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported. CONCLUSIONS: Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Childhood tuberculosis in the Kilimanjaro region: lessons from and for the TB programme.

OBJECTIVE: To determine the magnitude of childhood TB and treatment outcome in Kilimanjaro region. METHODS: Retrospective review of registration-based data on TB notifications in Kilimanjaro region for the period 2002-2006. RESULTS: Between 2002 and 2006, there were 1615 patients of childhood TB in Kilimanjaro region constituting 13% of total TB burden and the average case detection rate was 147/100 000 for urban and 41.8/100 000 for rural populations. Of them, 54.2% were men and 75.2% had pulmonary TB (PTB); 24.9% were tested for acid-fast bacilli (AFB) by Ziehl-Neelsen staining showing that 5.8% of all patients with TB were AFB smear positive. The remaining 94.2% were presumptively treated for TB. Treatment success rate was 79.9%, mortality 10.9% and default rate was 7%. Unfavourable outcome was more common among unconfirmed TB patients. HIV testing was very rare but increased after 2004 (<2% before 2005, 11-16% afterwards.) CONCLUSION: The rate of childhood TB in Kilimanjaro region is among the highest in the world. Microbiological diagnosis for TB and AFB smear positivity is very low. Treatment outcome in this region is poor. These findings argue for specific TB control strategies to be designed for children such as more AFB testing using new tools such as induced sputum and laryngeal swabs, active case finding, HIV testing of all suspected TB children, promoting and monitoring adherence. Regular epidemiological studies are also needed.

The aetiology, management and clinical outcome of upper gastrointestinal bleeding among patients admitted at the Kilimanjaro Christian Medical Centre in Moshi, Tanzania.

Upper gastro-intestinal (GI) bleeding is a life-threatening emergency that results in high morbidity and mortality and therefore requires admission to hospital for urgent diagnosis and management. The aim of this study was to determine the causes of upper GI bleeding and clinical outcome of patients admitted to medical department with the diagnosis of upper GI bleeding. A retrospective study of records of all upper GI bleeding patients who were admitted to medical department, Kilimanjaro Christian Medical Centre (KCMC) from January 2007 to December 2008 was conducted. A total of 130 patients (13-96 years old) were enrolled in the study, whereby 73 (56.2%) were males. The causes of bleeding, all endoscopically diagnosed included oesophageal varices in 55 (42.3%) cases, followed by duodenal ulcers 20 (15.4%), hemorrhagic/erosive gastritis 10 (7.7%), gastric ulcer 6 (4.6%) and Mallory Weiss tear 2 (1.5%). No cause was identified in the remaining 27 % of cases. Conservative medical therapy alone was carried out in 52.3% of the patients. Endoscopic therapy was used in 61 (46.9%) of patients. Only 2 (1.5%) patients underwent surgical intervention. The overall mortality at discharge was 17%, while 107 (82%) patients were discharged improved. In conclusion, the commonest causes of upper GI bleeding are oesophageal varices and duodenal ulcer. Most cases of upper GI bleeding were successfully treated with pharmacologic and endoscopic treatment. The high mortality may be influenced by delayed presentation to health facilities, and comorbidities. There is a need for strengthening preventive programmes and conducting studies to identify predictors of outcome of upper GI bleeding to develop evidence based management protocols.