Publications by authors named "Catia Marzolini"

86 Publications

Aging does not impact drug--drug interaction magnitudes with antiretrovirals.

AIDS 2020 05;34(6):949-952

Service of Clinical Pharmacology.

: The risk of drug-drug interactions (DDIs) is elevated in aging people living with HIV (PLWH) because of highly prevalent age-related comorbidities leading to more comedications. To investigate the impact of aging on DDI magnitudes between comedications (amlodipine, atorvastatin, rosuvastatin) and boosted darunavir, we conducted a clinical trial in aging PLWH aged at least 55 years. DDI magnitudes were comparable with those reported in young individuals supporting that the clinical management of DDIs in aging PLWH can be similar.
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http://dx.doi.org/10.1097/QAD.0000000000002489DOI Listing
May 2020

The challenge of HIV treatment in an era of polypharmacy.

J Int AIDS Soc 2020 02;23(2):e25449

Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.

Introduction: The availability of potent antiretroviral therapy has transformed HIV infection into a chronic disease such that people living with HIV (PLWH) have a near normal life expectancy. However, there are continuing challenges in managing HIV infection, particularly in older patients, who often experience age-related comorbidities resulting in complex polypharmacy and an increased risk for drug-drug interactions. Furthermore, age-related physiological changes may affect the pharmacokinetics and pharmacodynamics of both antiretrovirals and comedications thereby predisposing elderly to adverse drug reactions. This review provides an overview of the therapeutic challenges when treating elderly PLWH (i.e. >65 years). Particular emphasis is placed on drug-drug interactions and other common prescribing issues (i.e. inappropriate drug use, prescribing cascade, drug-disease interaction) encountered in elderly PLWH.

Discussion: Prescribing issues are common in elderly PLWH due to the presence of age-related comorbidities, organ dysfunction and physiological changes leading to a higher risk for drug-drug interactions, drugs dosage errors and inappropriate drug use.

Conclusions: The high prevalence of prescribing issues in elderly PLWH highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. The knowledge of adverse health outcomes associated with polypharmacy and inappropriate prescribing should ensure that there are interventions to prevent harm including medication reconciliation, medication review and medication prioritization according to the risks/benefits for each patient.
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http://dx.doi.org/10.1002/jia2.25449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996317PMC
February 2020

Polypharmacy, Drug-Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV.

Open Forum Infect Dis 2019 Dec 21;6(12):ofz531. Epub 2019 Dec 21.

Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Background: Antiretroviral therapy has transformed HIV infection from a deadly into a chronic condition. Aging people with HIV (PWH) are at higher risk of polypharmacy, potential drug-drug interactions (DDIs), and potentially inappropriate medications (PIMs). This study aims to compare prescribed drugs, polypharmacy, and potential DDIs between young (<65 years old) and elderly (≥65 years old) PWH. The prevalence of PIMs was assessed in elderly.

Methods: PWH from 2 centers within the Swiss HIV Cohort Study were asked to fill in a form with all their current medications. Polypharmacy was defined as being on ≥5 non-HIV drugs. PIMs were evaluated using Beers criteria. Potential DDIs for the most prescribed therapeutic classes were screened with the Liverpool interaction database.

Results: Among the 996 PWH included, 122 were ≥65 years old. Polypharmacy was more frequent in the elderly group (44% vs 12%). Medications and potential DDIs differed according to the age group: cardiovascular drugs and related potential DDIs were more common in the elderly group (73% of forms included ≥1 cardiovascular drug; 11% of cardiovascular drugs involved potential DDIs), whereas central nervous system drugs were more prescribed and involved in potential DDIs in younger PWH (26%, 11%). Potential DDIs were mostly managed through dosage adjustments. PIMs were found in 31% of the elderly group.

Conclusions: Potential DDIs remain common, and PIMs constitute an additional burden for the elderly. It is important that prescribers develop and maintain a proactive approach for the recognition and management of DDIs and other prescribing issues frequently encountered in geriatric medicine.
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http://dx.doi.org/10.1093/ofid/ofz531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935678PMC
December 2019

Prescribing issues in older adults living with HIV: thinking beyond drug-drug interactions with antiretroviral drugs.

Ther Adv Drug Saf 2019 3;10:2042098619880122. Epub 2019 Oct 3.

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, CH-4031 Basel, Switzerland.

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http://dx.doi.org/10.1177/2042098619880122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777047PMC
October 2019

Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly.

Clin Pharmacokinet 2020 03;59(3):383-401

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Background: Medication use is highly prevalent with advanced age, but clinical studies are rarely conducted in the elderly, leading to limited knowledge regarding age-related pharmacokinetic changes.

Objective: The objective of this study was to investigate which pharmacokinetic parameters determine drug exposure changes in the elderly by conducting virtual clinical trials for ten drugs (midazolam, metoprolol, lisinopril, amlodipine, rivaroxaban, repaglinide, atorvastatin, rosuvastatin, clarithromycin and rifampicin) using our physiologically based pharmacokinetic (PBPK) framework.

Methods: PBPK models for all ten drugs were developed in young adults (20-50 years) following the best practice approach, before predicting pharmacokinetics in the elderly (≥ 65 years) without any modification of drug parameters. A descriptive relationship between age and each investigated pharmacokinetic parameter (peak concentration [C], time to C [t], area under the curve [AUC], clearance, volume of distribution, elimination-half-life) was derived using the final PBPK models, and verified with independent clinically observed data from 52 drugs.

Results: The age-related changes in drug exposure were successfully simulated for all ten drugs. Pharmacokinetic parameters were predicted within 1.25-fold (70%), 1.5-fold (86%) and 2-fold (100%) of clinical data. AUC increased progressively by 0.9% per year throughout adulthood from the age of 20 years, which was explained by decreased clearance, while C, t and volume of distribution were not affected by human aging. Additional clinical data of 52 drugs were contained within the estimated variability of the established age-dependent correlations for each pharmacokinetic parameter.

Conclusion: The progressive decrease in hepatic and renal blood flow, as well as glomerular filtration, rate led to a reduced clearance driving exposure changes in the healthy elderly, independent of the drug.
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http://dx.doi.org/10.1007/s40262-019-00822-9DOI Listing
March 2020

Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging people living with HIV.

AIDS 2020 01;34(1):103-108

Service of Clinical Pharmacology, University Hospital of Lausanne and University of Lausanne, Lausanne Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel University of Basel, Basel Institute of Pharmaceutical Sciences of Western Switzerland, Geneva Service of Infectious Diseases, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Objectives: The pharmacokinetics of antiretroviral drugs may differ in elderly people living with HIV (PLWH) because of age-related physiological changes. We aimed to assess the pharmacokinetics of several antiretroviral drugs in aging PLWH enrolled in the Swiss HIV Cohort (SHCS).

Design: Full pharmacokinetic profiling nested in a multicenter, observational, prospective cohort study. Additional collection of single point pharmacokinetic data during SHCS follow-up visits (unselected PLWH).

Methods: PLWH were eligible for the full pharmacokinetics investigation if they were over the age of 55 years, on a stable boosted darunavir-containing or dolutegravir-containing regimen. Single point measurements were prospectively collected during SHCS follow-up visits to compare antiretroviral drug exposure in aging (≥65 years) and younger (<65 years) PLWH.

Results: Nineteen PLWH with a median age of 64 years participated in the full pharmacokinetic investigations. Single point pharmacokinetic data were collected for 804 PLWH with a median age of 52 years. Boosted darunavir clearance was 40% lower in aging (≥65 years) compared with younger (<65 years) PLWH, consistent with other drugs predominantly metabolized by CYP3A. Dolutegravir exposure was similar between age groups whereas lamivudine exposure increased by 11% in aging PLWH. Median boosted darunavir, dolutegravir and lamivudine t1/2 were 148%, 45% and 32% higher in aging compared with younger PLWH.

Conclusion: Advanced age did not affect boosted darunavir exposure to a clinically significant extent despite the observed high variability in exposure. Age minimally affected dolutegravir and lamivudine exposure. Thus, dose adjustment based on age is a priori not warranted.
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http://dx.doi.org/10.1097/QAD.0000000000002372DOI Listing
January 2020

Polypharmacy and Drug-Drug Interactions in People Living With Human Immunodeficiency Virus in the Region of Madrid, Spain: A Population-Based Study.

Clin Infect Dis 2020 07;71(2):353-362

Unidad de Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón (Instituto de Investigación Sanitaria Gregorio Marañón [IiSGM]), Madrid, Spain.

Background: Drug-drug interactions (DDIs) that involve antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of comorbidity and polypharmacy.

Methods: A linkage was established between the drug dispensing registry of Madrid and the Liverpool human immunodeficiency virus (HIV) DDI database (January 2017-June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity.

Results: A total of 22 945 people living with HIV (PLWH) and 6 613 506 individuals without HIV had received medications. ARV regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was higher in PLWH (32.94%) than individuals without HIV (22.16%; P < .001); this difference was consistently observed across all age strata except for individuals ≥75 years. Polypharmacy was more common in women than men in both PLWH and individuals without HIV. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir- or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval, .60-.88; P = .001) for red-flag DDI.

Conclusions: Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The detection of contraindicated medications in PLWH suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with risk of harm from DDIs.
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http://dx.doi.org/10.1093/cid/ciz811DOI Listing
July 2020

Polypharmacy and Drug-Drug Interactions in People Living With Human Immunodeficiency Virus in the Region of Madrid, Spain: A Population-Based Study.

Clin Infect Dis 2020 07;71(2):353-362

Unidad de Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón (Instituto de Investigación Sanitaria Gregorio Marañón [IiSGM]), Madrid, Spain.

Background: Drug-drug interactions (DDIs) that involve antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of comorbidity and polypharmacy.

Methods: A linkage was established between the drug dispensing registry of Madrid and the Liverpool human immunodeficiency virus (HIV) DDI database (January 2017-June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity.

Results: A total of 22 945 people living with HIV (PLWH) and 6 613 506 individuals without HIV had received medications. ARV regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was higher in PLWH (32.94%) than individuals without HIV (22.16%; P < .001); this difference was consistently observed across all age strata except for individuals ≥75 years. Polypharmacy was more common in women than men in both PLWH and individuals without HIV. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir- or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval, .60-.88; P = .001) for red-flag DDI.

Conclusions: Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The detection of contraindicated medications in PLWH suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with risk of harm from DDIs.
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http://dx.doi.org/10.1093/cid/ciz811DOI Listing
July 2020

Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine.

Clin Pharmacokinet 2019 12;58(12):1553-1565

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug-drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1-4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug-drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.
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http://dx.doi.org/10.1007/s40262-019-00806-9DOI Listing
December 2019

UHPLC-MS/MS assay for simultaneous determination of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin with its active metabolites in human plasma, for population-scale drug-drug interactions studies in people living with HIV.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 09 25;1125:121733. Epub 2019 Jul 25.

Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Switzerland. Electronic address:

Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.
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http://dx.doi.org/10.1016/j.jchromb.2019.121733DOI Listing
September 2019

Current Challenges and Solutions in Research and Clinical Care of Older Persons Living with HIV: Findings Presented at the 9th International Workshop on HIV and Aging.

AIDS Res Hum Retroviruses 2019 Nov/Dec;35(11-12):985-998. Epub 2019 Sep 10.

Department of Psychiatry, University of California, San Diego, La Jolla, California.

In the era of effective antiretroviral therapy, the number of older people with HIV (PWH) is increasing, and those aging with HIV are experiencing an increasing burden of age-associated comorbidities. Life expectancy among older PWH is approaching that of demographically comparable HIV-uninfected (HIV-) adults. With this changing demographic of PWH come new challenges for researchers and clinicians in how to identify, address, and manage the complex interplay of treated HIV infection and aging-associated factors. In response to these challenges, the annual International Workshop on HIV and Aging was initiated in 2009 as a multidisciplinary platform for scientific discourse on the research and clinical complications arising from the aging population of PWH. The multidisciplinary nature of the workshop has resulted in a wide range of topics addressed over the past 9 years, from basic mechanisms in aging and HIV pathogenesis, to epidemiology of aging within large cohorts, interventions, and implementation of clinical programs. Herein, we summarize the key topics discussed at the 9th Annual International Workshop on HIV and Aging 2018, including "inflammaging," mitochondrial dysfunction, exercise interventions, HIV-associated neurocognitive impairment, metabolic dysfunction, menopause, and polypharmacy. In addition to recent developments in research and clinical care, we discuss open questions and future research directions required to better understand the interaction of HIV and aging.
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http://dx.doi.org/10.1089/AID.2019.0100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862962PMC
September 2020

Prescribing issues in elderly individuals living with HIV.

Expert Rev Clin Pharmacol 2019 Jul 19;12(7):643-659. Epub 2019 Jun 19.

c Service of Clinical Pharmacology, Department of Laboratories , University Hospital of Lausanne , Lausanne , Switzerland.

: Combined antiretroviral therapy has transformed HIV infection into a chronic disease thus people living with HIV (PLWH) live longer. As a result, the management of HIV infection is becoming more challenging as elderly experience age-related comorbidities leading to complex polypharmacy and a higher risk for drug-drug or drug-disease interactions. Furthermore, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing or inappropriate prescribing and consequently to adverse drug reactions and the subsequent risk of starting a prescribing cascade. : This review discusses the demographics of the aging HIV population, physiological changes and their impact on drug response as well as comorbidities. Particular emphasis is placed on common prescribing issues in elderly PLWH including drug-drug interactions with antiretroviral drugs. A PubMed search was used to compile relevant publications until February 2019. : Prescribing issues are highly prevalent in elderly PLWH thus highlighting the need for education on geriatric prescribing principles. Adverse health outcomes potentially associated with polypharmacy and inappropriate prescribing should promote interventions to prevent harm including medication reconciliation, medication review, and medication prioritization according to the risks/benefits for a given patient. A multidisciplinary team approach is recommended for the care of elderly PLWH.
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http://dx.doi.org/10.1080/17512433.2019.1627200DOI Listing
July 2019

Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug-drug interactions and probability of target attainment.

Br J Clin Pharmacol 2019 09 7;85(9):2022-2032. Epub 2019 Jul 7.

Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Aims: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug-drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen.

Methods: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)-infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under- or over-exposed, considering established therapeutic targets (15-80 ng/mL).

Results: A 1-compartment model with first-order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV-infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton-pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model-based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under-exposed.

Conclusion: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.
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http://dx.doi.org/10.1111/bcp.13994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710519PMC
September 2019

A comprehensive framework for physiologically based pharmacokinetic modelling in Matlab.

CPT Pharmacometrics Syst Pharmacol 2019 Feb 18. Epub 2019 Feb 18.

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Physiologically based pharmacokinetic (PBPK) models are useful tools to predict clinical scenarios for special populations for whom there are high hurdles to conduct clinical trials such as children or the elderly. However, coding of a PBPK model in a mathematical programming language can be challenging. This tutorial illustrates how to build a whole-body PBPK model in Matlab to answer specific pharmacological questions involving drug disposition, and magnitudes of drug-drug interactions in different patient populations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/psp4.12399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657005PMC
February 2019

Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes.

Clin Pharmacokinet 2019 04;58(4):483-501

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

Background: Aging is characterized by anatomical, physiological, and biological changes that can impact drug kinetics. The elderly are often excluded from clinical trials and knowledge about drug kinetics and drug-drug interaction magnitudes is sparse. Physiologically based pharmacokinetic modeling can overcome this clinical limitation but detailed descriptions of the population characteristics are essential to adequately inform models.

Objective: The objective of this study was to develop and verify a population database for aging Caucasians considering anatomical, physiological, and biological system parameters required to inform a physiologically based pharmacokinetic model that included population variability.

Methods: A structured literature search was performed to analyze age-dependent changes of system parameters. All collated data were carefully analyzed, and descriptive mathematical equations were derived.

Results: A total of 362 studies were found of which 318 studies were included in the analysis as they reported rich data for anthropometric parameters and specific organs (e.g., liver). Continuous functions could be derived for most system parameters describing a Caucasian population from 20 to 99 years of age with variability. Areas with sparse data were identified such as tissue composition, but knowledge gaps were filled with plausible qualified assumptions. The developed population was implemented in Matlab and estimated system parameters from 1000 virtual individuals were in accordance with independent observed data showing the robustness of the developed population.

Conclusions: The developed repository for aging subjects provides a singular specific source for key system parameters needed for physiologically based pharmacokinetic modeling and can in turn be used to investigate drug kinetics and drug-drug interaction magnitudes in the elderly.
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http://dx.doi.org/10.1007/s40262-018-0709-7DOI Listing
April 2019

Boosted darunavir, emtricitabine and tenofovir pharmacokinetics in sthe early and late postgastric bypass surgery periods.

AIDS 2018 08;32(13):1903-1905

Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine and Clinical Research, University Hospital of Basel.

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http://dx.doi.org/10.1097/QAD.0000000000001913DOI Listing
August 2018

HIV and Aging - Perhaps Not as Dramatic as We Feared?

Gerontology 2018 15;64(5):446-456. Epub 2018 Jun 15.

University Department of Medicine and Infectious Diseases Service, Kantonsspital Baselland, University of Basel, Bruderholz, Switzerland.

Ever since the introduction of highly active antiretroviral therapy (ART) in 1995, HIV infection has been linked to "metabolic" complications (insulin resistance, dyslipidemia, osteoporosis, and others). Studies suggested increased rates of myocardial infarction, renal insufficiency, neurocognitive dysfunction, and fractures in HIV-postitive patients. Even long-term suppression of HIV seemed to be accompanied by an excess of deleterious inflammation that could promote these complications. The aims of this viewpoint paper are to summarize recent data and to examine the possibility that the problem of aging-related morbidity in HIV might not be as dramatic as previously believed.
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http://dx.doi.org/10.1159/000489172DOI Listing
December 2018

Analysis of Clinical Drug-Drug Interaction Data To Predict Magnitudes of Uncharacterized Interactions between Antiretroviral Drugs and Comedications.

Antimicrob Agents Chemother 2018 07 26;62(7). Epub 2018 Jun 26.

Division of Infectious Diseases and Hospital Epidemiology Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland

Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes ( = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs.
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http://dx.doi.org/10.1128/AAC.00717-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021627PMC
July 2018

Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir.

J Antimicrob Chemother 2017 09;72(9):2574-2577

Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, Basel, Switzerland.

Objectives: Cobicistat and ritonavir have different inhibitory profiles for drug transporters that could impact the distribution of co-administered drugs. We compared darunavir concentrations in CSF when boosted by cobicistat versus ritonavir relative to plasma concentrations and with WT HIV-1 IC50 and IC90.

Methods: An open, single-arm, sequential clinical trial (NCT02503462) where paired CSF and blood samples were taken from seven HIV-infected patients presenting with HIV-associated neurocognitive disorders (HAND) and treated with a darunavir/ritonavir (800/100 mg) once-daily regimen. Ritonavir was subsequently replaced by cobicistat and paired CSF and blood samples were obtained from the same patients after treatment with the darunavir/cobicistat (800/150 mg) once-daily regimen. Darunavir concentrations at the end of the dosing interval were quantified by LC-MS/MS.

Results: The median (IQR) darunavir concentrations in CSF with ritonavir and cobicistat boosting were 16.4 ng/mL (8.6-20.3) and 15.9 ng/mL (6.7-31.6), respectively (P = 0.58). The median (IQR) darunavir CSF:plasma ratios with ritonavir and cobicistat boosting were 0.007 (0.006-0.012) and 0.011 (0.007-0.015), respectively (P = 0.16). Darunavir concentrations in CSF exceeded the darunavir IC50 and IC90 by a median of 9.2- and 6.7-fold with ritonavir boosting, and by 8.9- and 6.5-fold with cobicistat boosting, respectively. All patients had darunavir CSF concentrations above the target inhibitory concentrations and remained virologically suppressed in the CSF and plasma.

Conclusions: This small study shows that cobicistat and ritonavir give comparable effective darunavir concentrations in CSF, thus suggesting that these boosters can be used interchangeably in once-daily darunavir regimens.
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http://dx.doi.org/10.1093/jac/dkx165DOI Listing
September 2017

Free and total plasma concentrations of elvitegravir/cobicistat during pregnancy and postpartum: a case report.

Br J Clin Pharmacol 2017 12 16;83(12):2835-2838. Epub 2017 May 16.

Division of Clinical Pharmacology, Department of Laboratories, University Hospital of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1111/bcp.13310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698588PMC
December 2017

Dolutegravir plasma levels after gastric bypass surgery.

AIDS 2017 04;31(7):1052-1054

aDivision of Infectious Diseases, Department of Medicine, Cantonal Hospital of Olten, Olten bDivision of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1097/QAD.0000000000001438DOI Listing
April 2017

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection.

PLoS One 2017 23;12(3):e0173509. Epub 2017 Mar 23.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Background: In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria.

Methods And Findings: This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs.

Conclusions: There is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363796PMC
August 2017

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes.

Clin Pharmacokinet 2017 04;56(4):409-420

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Background: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously.

Methods: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data.

Results: The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism.

Conclusion: PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.
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http://dx.doi.org/10.1007/s40262-016-0447-7DOI Listing
April 2017

Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications.

J Antimicrob Chemother 2016 07 5;71(7):1755-8. Epub 2016 Mar 5.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments.
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http://dx.doi.org/10.1093/jac/dkw032DOI Listing
July 2016

Privacy-preserving genomic testing in the clinic: a model using HIV treatment.

Genet Med 2016 08 14;18(8):814-22. Epub 2016 Jan 14.

J. Craig Venter Institute, La Jolla, California, USA.

Purpose: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics.

Methods: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers.

Results: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%.

Conclusions: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.Genet Med 18 8, 814-822.
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http://dx.doi.org/10.1038/gim.2015.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985613PMC
August 2016

Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies.

Expert Opin Drug Metab Toxicol 2015 15;11(8):1203-17. Epub 2015 Apr 15.

University of Liverpool, Institute of Translational Medicine, Molecular and Clinical Pharmacology , Liverpool , UK +44 0 151 794 8211 ; +44 0 151 794 5656 ;

Introduction: The pharmacokinetic properties of anti-infective drugs are a determinant part of treatment success. Pathogen replication is inhibited if adequate drug levels are achieved in target sites, whereas excessive drug concentrations linked to toxicity are to be avoided. Anti-infective distribution can be predicted by integrating in vitro drug properties and mathematical descriptions of human anatomy in physiologically based pharmacokinetic models. This method reduces the need for animal and human studies and is used increasingly in drug development and simulation of clinical scenario such as, for instance, drug-drug interactions, dose optimization, novel formulations and pharmacokinetics in special populations.

Areas Covered: We have assessed the relevance of physiologically based pharmacokinetic modeling in the anti-infective research field, giving an overview of mechanisms involved in model design and have suggested strategies for future applications of physiologically based pharmacokinetic models.

Expert Opinion: Physiologically based pharmacokinetic modeling provides a powerful tool in anti-infective optimization, and there is now no doubt that both industry and regulatory bodies have recognized the importance of this technology. It should be acknowledged, however, that major challenges remain to be addressed and that information detailing disease group physiology and anti-infective pharmacodynamics is required if a personalized medicine approach is to be achieved.
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http://dx.doi.org/10.1517/17425255.2015.1037278DOI Listing
March 2016

Obesity Trends and Body Mass Index Changes After Starting Antiretroviral Treatment: The Swiss HIV Cohort Study.

Open Forum Infect Dis 2014 Sep 1;1(2):ofu040. Epub 2014 Jul 1.

Infectious Diseases Service , Kantonsspital Baselland, University of Basel , Bruderholz , Switzerland.

Background: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized.

Methods: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART.

Results: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir <199 cells/µL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/µL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change.

Conclusions: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited.
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http://dx.doi.org/10.1093/ofid/ofu040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281814PMC
September 2014

Impact of body weight on virological and immunological responses to efavirenz-containing regimens in HIV-infected, treatment-naive adults.

AIDS 2015 Jan;29(2):193-200

aDivision of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel, Basel, Switzerland bDepartment of Infection and Population Health, University College London, London, UK cDivision of Infectious Diseases, University Hospital of Nantes, Nantes, France dDepartment of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK eClinic of Infectious Diseases, University of Modena, Modena, Italy fUniversity Paris Descartes, Paris, France gRadboud University Medical Centre, Nijmegen, the Netherlands hHospital General of Castellon, University of Valencia and University Jaume I, Valencia, Spain iDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and University of Zurich, Zurich, Switzerland jUnit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy kDepartment of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark lDepartment of Infectious and Tropical Diseases, HIV Unit, University Hospital Pellegrin, Bordeaux, France mMedical University Innsbruck, Innsbruck, Austria nDepartment of Internal Medicine, University Hospital of Patras, Patras, Greece oDepartment of Infectious Diseases, San Raffaele Scientific Institute, Milan pClinical Department, National Institute for Infectious Diseases 'L. Spallanzani', Rome qDivision of Infectious and Tropical Diseases, University and Ospedali Civili of Brescia, Brescia, Italy rParis Descartes University, EA 7327, Necker School of Medicine, Paris and APHP, UF de Thérapeutique en Immuno-Infectiologie, Hôpital de l'Hôtel-Dieu, Paris sUniversity of Bordeaux, ISPED, Centre INSERM U897-Epidémiologie Statistique, Bordeaux, France tCopenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark. *Catia Marzolini and Caroline Sabin contributed equally to this work.

Objective: The prevalence of overweight and obesity is increasing among HIV-infected patients. Whether standard antiretroviral drug dosage is adequate in heavy individuals remains unresolved. We assessed the virological and immunological responses to initial efavirenz (EFV)-containing regimens in heavy compared to normal-weight HIV-infected patients.

Design: Observational European cohort collaboration study.

Methods: Eligible patients were antiretroviral-naïve with documented weight prior to EFV start and follow-up viral loads after treatment initiation. Cox regression analyses evaluated the association between weight and time to first undetectable viral load (<50 copies/ml) after treatment initiation, and time to viral load rebound (two consecutive viral load >50 copies/ml) after initial suppression over 5 years of follow-up. Recovery of CD4 cell count was evaluated 6 and 12 months after EFV initiation. Analyses were stratified by weight (kg) group (I - <55; II - >55, <80 (reference); III - >80, <85; IV - >85, <90; V - >90, <95; VI - >95).

Results: The study included 19,968 patients, of whom 9.1, 68.3, 9.1, 5.8, 3.5, and 4.3% were in weight groups I-VI, respectively. Overall, 81.1% patients attained virological suppression, of whom 34.1% subsequently experienced viral load rebound. After multiple adjustments, no statistical difference was observed in time to undetectable viral load and virological rebound for heavier individuals compared to their normal-weight counterparts. Although heaviest individuals had significantly higher CD4 cell count at baseline, CD4 cell recovery at 6 and 12 months after EFV initiation was comparable to normal-weight individuals.

Conclusion: Virological and immunological responses to initial EFV-containing regimens were not impaired in heavy individuals, suggesting that the standard 600 mg EFV dosage is appropriate across a wide weight range.
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http://dx.doi.org/10.1097/QAD.0000000000000530DOI Listing
January 2015

Etravirine: a good option for concomitant use with chemotherapy for Hodgkin's lymphoma.

Int J STD AIDS 2015 Mar 8;26(3):212-4. Epub 2014 May 8.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland

The treatment of malignancies in HIV patients is challenged by the issue of drug-drug interactions between antiretroviral therapy and antineoplastic agents. While protease inhibitors have been shown to increase the incidence and severity of cancer therapy-related side effects, the impact of other antiretroviral agents on the tolerability and response to chemotherapy is less well documented. We report the successful use of an etravirine-based regimen in a patient treated with BEACOPP chemotherapy for advanced Hodgkin's lymphoma. Etravirine constitutes a valuable option for concomitant use with chemotherapy due to its moderate inducing effect on drug metabolising enzymes.
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http://dx.doi.org/10.1177/0956462414533517DOI Listing
March 2015
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