Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS-163 ETRAL Study.

STUDY OBJECTIVE: The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C12h ) in blood plasma (BP) and seminal plasma (SP). DESIGN: Pharmacokinetic analysis of data from the ANRS163-ETRAL study. PATIENTS: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily. MEASUREMENTS AND MAIN RESULTS: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C12h were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC95 ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C12h (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C12h ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and < 1%, respectively, raltegravir 1.8 (1.3-3.3) and 12%, respectively, and raltegravir-glucuronide 12.0 (6.5-17.7) and > 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C12h < PBIC95 simultaneously. CONCLUSION: No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy.

Hand Hygiene, Cohorting, or Antibiotic Restriction to Control Outbreaks of Multidrug-Resistant Enterobacteriaceae.

BACKGROUND: The best strategy for controlling extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) transmission in intensive care units (ICUs) remains elusive. OBJECTIVE: We developed a stochastic transmission model to quantify the effectiveness of interventions aimed at reducing the spread of ESBL-PE in an ICU. METHODS: We modeled the evolution of an outbreak caused by the admission of a single carrier in a 10-bed ICU free of ESBL-PE. Using data obtained from recent muticenter studies, we studied 26 strategies combining different levels of the following 3 interventions: (1) increasing healthcare worker compliance with hand hygiene before and after contact with a patient; (2) cohorting; (3) reducing antibiotic prevalence at admission with or without reducing antibiotherapy duration. RESULTS: Improving hand hygiene compliance from 55% before patient contact and 60% after patient contact to 80% before and 80% after patient contact reduced the nosocomial incidence rate of ESBL-PE colonization by 91% at 90 days. Adding cohorting to hand hygiene improvement intervention decreased the proportion of ESBL-PE acquisitions by an additional 7%. Antibiotic restriction had the lowest impact on the epidemic. When combined with other interventions, it only marginally improved effectiveness, despite strong hypotheses regarding antibiotic impact on transmission. CONCLUSION: Our results suggest that hand hygiene is the most effective intervention to control ESBL-PE transmission in an ICU.

Virological outcome at week 48 of three recommended first-line regimens using ultrasensitive viral load and plasma drug assay.

OBJECTIVES: To describe the virological and pharmacological outcomes of three different recommended once-daily first-line regimens in a cross-sectional analysis within an observational cohort using ultra-sensitive HIV quantification. PATIENTS AND METHODS: We enrolled all HIV-1-infected patients who initiated tenofovir/emtricitabine with efavirenz, darunavir/ritonavir or atazanavir/ritonavir as a first-line regimen between 1 November 2010 and 30 June 2012. An ultrasensitive viral load (VL) assay was performed and plasma drug concentrations at 24 h (C24) were determined at Week (W) 4, W12, W24, W36 and W48. RESULTS: Sixty patients initiated efavirenz, 81 darunavir/ritonavir and 27 atazanavir/ritonavir. A higher proportion of patients with a VL >100 000 copies/mL received darunavir/ritonavir (P = 0.022). At W48, 89%, 85% and 88% of the patients had a VL <50 copies/mL, 69%, 73% and 79% had a VL <20 copies/mL and 45%, 48% and 54% had a VL <1 copy/mL using the ultrasensitive assay in the efavirenz, darunavir/ritonavir and atazanavir/ritonavir groups, respectively. Patients with a detectable VL signal at W48 had a higher baseline VL than those with no detectable VL signal (P = 0.0001). A total of 92%, 93% and 91% of the efavirenz, darunavir and atazanavir C24 values were above the respective effective cut-offs. CONCLUSIONS: In this observational cohort, the choice of the regimen was related to the physicians' preferences and the patients' characteristics. The proportion of patients reaching VL <1 copy/mL at W48 was similar in the three regimens and was not associated with drug concentrations.

Bone loss in patients with HIV infection.

The prognosis of HIV infection has been considerably improved by the introduction of antiretroviral drugs. However, the longer survival times are associated with the emergence of new complications including decreased bone mineral density (BMD) values and/or bone insufficiency fractures. A meta-analysis of studies published between 1966 and 2005 showed bone absorptiometry results indicating osteoporosis in 15% of HIV patients and osteopenia in 52%. Longitudinal studies found no evidence that antiretroviral drug therapy contributed to the occurrence of bone loss. Available data indicate uncoupling with increases in bone resorption markers and decreases in bone formation markers. In addition to conventional risk factors for osteoporotic fractures, factors in HIV-infected patients may include malnutrition (wasting syndrome), hypogonadism, disorders in calcium and phosphate metabolism, and HIV infection per se. In patients with established bone insufficiency, bisphosphonate therapy should be considered. Alendronate in combination with vitamin D and calcium supplementation has been found effective in improving BMD values.