| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Svensson, Elin M, 1985-
(författare)
-
Pharmacometric Models to Improve Treatment of Tuberculosis
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) is the world’s most deadly infectious disease and causes enormous public health problems. The comorbidity with HIV and the rise of multidrug-resistant TB strains impede successful therapy through drug-drug interactions and the lack of efficient second-line treatments. The aim of this thesis was to support the improvement of anti-TB therapy through development of pharmacometric models, specifically focusing on the novel drug bedaquiline, pharmacokinetic interactions and methods for pooled population analyses.A population pharmacokinetic model of bedaquiline and its metabolite M2, linked to semi-mechanistic models of body weight and albumin concentrations, was developed and used for exposure-response analysis. Treatment response was quantified by measurements of mycobacterial load and early bedaquiline exposure was found to significantly impact the half-life of bacterial clearance. The analysis represents the first successful characterization of a concentration-effect relationship for bedaquiline.Single-dose Phase I studies investigating potential interactions between bedaquiline and efavirenz, nevirapine, ritonavir-boosted lopinavir, rifampicin and rifapentine were analyzed with a model-based approach. Substantial effects were detected in several cases and dose-adjustments mitigating the impact were suggested after simulations. The interaction effects of nevirapine and ritonavir-boosted lopinavir were also confirmed in patients with multidrug-resistant TB on long-term treatment combining the antiretrovirals and bedaquiline. Furthermore, the outcomes from model-based analysis were compared to results from conventional non-compartmental analysis in a simulation study. Non-compartmental analysis was found to consistently underpredict the interaction effect when most of the concentration-time profile was not observed, as commonly is the case for compounds with very long terminal half-life such as bedaquiline.To facilitate pooled analyses of individual patient data from multiple sources a structured development procedure was outlined and a fast diagnostic tool for extensions of the stochastic model components was developed. Pooled analyses of nevirapine and rifabutin pharmacokinetics were performed; the latter generating comprehensive dosing recommendations for combined administration of rifabutin and antiretroviral protease inhibitors.The work presented in this thesis demonstrates the usefulness of pharmacometric techniques to improve treatment of TB and especially contributes evidence to inform optimized dosing regimens of new and old anti-TB drugs in various clinical contexts.
|
|
| 7. |
- Wirtz, Andrea L, et al.
(författare)
-
Feasibility of a Combination HIV Prevention Program for Men Who Have Sex With Men in Blantyre, Malawi.
- 2015
-
Ingår i: Journal of Acquired Immune Deficiency Syndromes. - 1525-4135 .- 1944-7884. ; 70:2, s. 155-62
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The use of combination HIV prevention interventions (CHPI) now represent the standard of care to minimize HIV acquisition risks among men who have sex with men (MSM). There has been limited evaluation of these approaches in generalized HIV epidemics and/or where MSM are stigmatized. A peer-based CHPI program to target individual, social, and structural risks for HIV was developed for MSM in Blantyre, Malawi.METHODS: To test the feasibility of CHPI, adult MSM were followed prospectively from January 2012 to May 2013. Participants (N = 103) completed sociobehavioral surveys and HIV testing at each of the 3 follow-up study visits.RESULTS: Approximately 90% of participants attended each study visit and 93.2% (n = 96) completed the final visit. Participants met with peer educators a median of 3 times (range: 1-10) in the follow-up visits 2 and 3. Condom use at last sex improved from baseline through follow-up visit 3 with main (baseline: 62.5%, follow-up 3: 77.0%; P = 0.02) and casual male partners (baseline: 70.7%, follow-up 3: 86.3%; P = 0.01). Disclosure of sexual behaviors/orientation to family increased from 25% in follow-up 1 to 55% in follow-up 3 (P < 0.01).DISCUSSION: Participants maintained a high level of retention in the study highlighting the feasibility of leveraging community-based organizations to recruit and retain MSM in HIV prevention and treatment interventions in stigmatizing settings. Group-level changes in sexual behavior and disclosure in safe settings for MSM were noted. CHPI may represent a useful model to providing access to other HIV prevention for MSM and aiding retention in care and treatment services for MSM living with HIV in challenging environments.
|
|
