The reduction in mother-to-child transmission of HIV-1 by single-dose nevirapine given at birth onset is achieved at the expense of de novo HIV-1 resistance mutations. In the VITA1 study, single-dose carbamazepine accelerated nevirapine elimination, but the accompanying trend towards fewer de novo HIV-1 mutations was statistically non-significant. We investigated if the effect of carbamazepine was confounded by the individual variability in nevirapine metabolism and transport. Nine of 34 (26%) single-dose nevirapine-treated women had one or more nevirapine-associated resistance mutations, compared with 3 of 34 (9%) in the single-dose nevirapine/carbamazepine arm. The genetic polymorphisms in CYP2B6 and MRP7 affected neither nevirapine kinetics nor the development of HIV-1 resistance. In contrast, the reduction in HIV-1 mutations by single-dose carbamazepine reached statistical significance at P = 0.04 with an OR of 0.1 (95% CI 0.01–0.90) upon consideration of CYP3A activity, defined as the ratio of 4β-hydroxycholesterol to cholesterol, and it was more likely in women with higher CYP3A activity. These findings were in agreement with CYP3A induction in carbamazepine-treated patients. Likewise, carbamazepine induced CYP3A4, but not CYP2B6, in vitro when combined with nevirapine. The induction of nevirapine elimination reduces HIV-1 resistance mutations, but this effect is modulated by individual CYP3A activity. The study suggests that CYP3A4 activity could be monitored using an endogenous marker and, if needed, boosted to improve clinical endpoints.
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.
The increase in resistance of many pathogens to currently available antibiotics has been recognized as life-threatening problem. The development of drug resistance is promoted by irrational prescribing behavior. Inappropriate use of antibiotics is attributed by over-prescription, inadequate dosage and use for non-bacterial infections. The purpose of this study was to assess antibiotic prescribing practices in the management of diarrhoea and cough among children attending hospitals in Moshi municipal, Tanzania.We conducted a cross-sectional descriptive hospital based study, from September 2010 to March 2011. All children presenting with diarrhoea and cough, aged between one month and 5 years attended at the two hospitals were enrolled. Data were collected by a standard questionnaire. Information on the prescribed drugs was obtained from patient files.A total of 384 children were enrolled. Of these, 326 (84.9%) received antibiotics; common prescribed antibiotics were penicillins, sulphonamides, aminoglycosides and macrolides. Eighty percent of children with acute watery diarrhoea and 68.9% with common cold were given antibiotics inappropriately. Inappropriate antibiotic prescription was significantly associated with prescriber being a clinical officer and assistant medical officer, and child having diarrhoea. Inappropriate antibiotic dosage was significantly occurred when prescriber was clinical officer with reference to medical officer.This study observed a high antibiotic prescription rate by clinicians and treatment guidelines for management of patients who presented with cough and/or diarrhoea are followed. Continuing professional development programmes for clinicians on prescription would help in reducing irrational prescribing practices.
Background Despite receipt of combination antiretroviral therapy (cART) and subsequent viral suppression some 15–30% of treated HIV infected patients fail to achieve optimal CD4 T-cell reconstitution. Sub-optimal CD4 recovery has been associated with unfavourable outcomes for patients on cART. We assessed markers of immune activation, microbial translocation and patient baseline characteristics for associations with sub-optimal CD4 T-cell recovery post cART initiation. Methods This was a retrospective case control analysis of CD4 T-cell recovery from a completed (2002–2007) clinical trial, the Adult Antiretroviral Treatment and Drug Resistance (“Tshepo”) Trial, in Gaborone, Botswana. Cases (sub-optimal CD4 response) were defined as CD4 ≤ 200 cells/µl at 12 months post ART initiation, with virologic suppression achieved within 6 months. Microbial translocation (sCD14) and immune activation (interferon-gamma) markers were quantified using Enzyme Linked Immuno-Sorbent Assays on a subset of 30 cases and 30 controls gender matched baseline and 12 month plasma samples. Univariate and logistic regression analysis were used to assess predictors of sub-optimal CD4 T-cell recovery. Results Fifty-one cases (21%) from 249 virologically suppressed patients had sub-optimal CD4 recovery. The median age was 33.39 years and 69.9% were female. Baseline CD4 count < 100cells, haemoglobin and aspartate transaminase were associated with sub-optimal CD4 recovery (adjusted OR (aOR) = 3.03 95% CI [1.65, 5.57], p < 0.001; aOR = 0.81 [0.67, 0.99], p = 0.038 and aOR = 1.03 [1.00, 1.05], respectively). sCD14 levels were significantly different between cases and controls, p = 0.0011, at 12 months. Baseline Tuberculosis infection, body-mass-index, interferon-gamma, alanine transaminase and age were not associated with poor CD4 T-cell response. Conclusion Low baseline CD4 T-cell count, haemoglobin, aspartate transaminase and sCD14 levels are predictive of suboptimal CD4 T-cell recovery in this cohort of HIV-1 subtype C infected patients. These markers are potentially useful in identifying patients who need frequent clinical monitoring to minimise unfavourable outcomes associated with poor CD4 T-cell recovery.
