To what extent do people living with HIV, people on pre-exposure prophylaxis, doctors and pharmacists endorse 90-day dispensing of antiretroviral therapy in France?

JUSTIFICATION: The WHO 95-95-95 targets for 2030 do not imply that people living with HIV (PLHIV) achieve a good quality of life. The current 30-day dispensing interval for antiretroviral (ART) burdens the healthcare system. Lengthening dispensing intervals could alleviate this burden as well as enhance patient well-being. OBJECTIVES: To capture perceptions on 90-day dispensing interval (90D) for ART from the perspective of PLHIV, people on pre-exposure prophylaxis (PrEP), doctors, and pharmacists. METHODS: Multi-centre observational survey led in France from 16 to 20 October 2020, among doctors agreeing to participate via regional coordinated care organisations for HIV, all PLHIV or people on PrEP consulting these outpatient-clinic doctors, and pharmacists doing ART dispensing. RESULTS: The survey was completed by 220 doctors who saw 1087 people (999 PLHIV; 88 on PrEP) and 176 pharmacists from 55 centres. Among the PLHIV, 855 (85.6%, 95% CI: 83.2%-87.7%) and among the patients on PrEP, 70 (79.5%, 95% CI: 69.6%-87.4%) stated they would be interested in 90D. All in all, patients who were more likely to endorse 90D are those who opt exclusively for hospital dispensing (OR 3.22 [1.57-6.58]) and who rotate between hospital and community pharmacy dispensing (OR 3.29 [1.15-9.32]). Patients who were less likely to endorse 90-D were those who consult in a city located outside the 3 French high HIV prevalence regions (OR 0.66 [0.44-0.99]), receive 2 vs 1 pill QD regimens (OR 0.53 [0.31-0.91]), and anticipate at least one vs no limitation to 90D (OR 0.27 [0.17-0.42]). 90D was perceived as possible by 152 pharmacists (86.4%), including 8 (5%) without restriction, and 219 doctors (99.6%), including 42 (19.2%) regardless of PLHIV's immunovirologic status or social conditions (health insurance coverage, access to housing or accommodation, access to rights, resources). Comparison of the benefits and limitations of a 90-day ART dispensing interval as perceived by PLHIV and people on PrEP, doctors and pharmacists shows that doctors anticipate a higher number of benefits than people on ART and/or pharmacists, chiefly that 90D would be more convenient and create less risk of drug shortages and that patients would gain autonomy and a better quality of life. Pharmacists were found to clearly perceive the economic benefits (90D would be less expensive) but anticipate more drawbacks than doctors and the people on ART themselves: more administrative burdens, more non-dispensing if doses get lost, harder to track adherence and more drug-drug interaction issues, and more work as they shall have to warn the patient of potential risks of shortages due to the cost of the stock. CONCLUSION: A clear majority of PLHIV, people on PrEP, doctors, and pharmacists endorsed 90D of ART. Most patients thought that 90D would be a good option, whereas most pharmacists and doctors thought that eligibility for 90D dispensing should depend on immunovirologic factors and social condition criteria. Moreover, pharmacists thought it would be necessary to commit regulatory resources and a better follow-up on adherence and drug-drug interactions.

Pharmacist's role in HIV care in France. Implication for clinical improvement of people living with HIV worldwide.

In France, antiretroviral (ARV) treatment can be dispensed by hospital and/or community pharmacies. Since January 2016, an online patient medication file can be used to optimize dispensing, but medication interviews have not yet been incorporated into this system. To understand both people living with HIV (PLHIV) and their pharmacists' habits and expectations of patient medication file and interviews, two consecutive national surveys were organized. The first one, carried out in October 2016 in care centers, was an anonymous questionnaire for PLHIV. The second one was an online survey for community and hospital pharmacies conducted in February 2017. A total of 1137 PLHIV (68% men, of mean age 50.2 ± 11.5 years, CD4 count 671 ± 354, 90% with undetectable HIV viral load (VL) and 64.2% reporting comorbidities) and 246 pharmacies responded. While the existence of the online medication file is known by 58% of PLHIV, only 40% of pharmacists declare it to be systematically offered. It was offered to 120/694 (17%) PLHIV and 96 (80%) accepted it. Currently, 78 (7%) PLHIV feel well taken care of because they are offered medication interviews, 343/1078 (32%) would like to take advantage of this program, mainly those with a shorter ARV duration (OR ARV duration 0.97 [0.95-0.99]), a VL less often undetectable (OR undetectable VL 0.55 [0.31-0.98]), and those who feel anxious more often (OR anxious 2.38 [1.48-3.84]). These results suggest that better implementation of medication files and interviews will strengthen current clinical pathways.

Sodium thiosulphate treatment of uraemic tumoral calcinosis.

OBJECTIVE: The objective of this study was to describe the efficacy of sodium thiosulphate (STS) in tumoral calcinosis (TC). METHODS: The methodology involved the reporting of four retrospective case reports of TC complicating end-stage renal disease (ESRD). RESULTS: We investigated STS treatment in four patients (two men; ages 46-70 years) with TC. ESRD was secondary to nephronophthisis (n = 1), membranoproliferative glomerulonephritis (n = 1), diabetic nephropathy (n = 1), and thrombotic microangiopathy (n = 1). TC developed 3-28 years after dialysis began and resulted in articular pain (n = 4) and stiffness (n = 1). It involved shoulders and hips and was diffuse in one patient. Several treatments were tried without success. STS 12.5-25 g was given intravenously after each dialysis session for 11-14 months. Pain and stiffness rapidly disappeared and TC showed partial or total regression. Side effects during infusion included increased blood pressure (n = 1), nausea (n = 1) and vomiting (n = 1). TC did not recur after treatment discontinuation with follow-up of 1.5-12 years. CONCLUSION: STS showed promising efficacy in this short series of TC. Further studies are warranted.

Flunitrazepam does not alter cerebral distribution of buprenorphine in the rat.

Deaths have been reported among heroin addicts related to combined buprenorphine and flunitrazepam use. The aim of this study was to determine the existence of a drug-drug interaction during the distribution phase of buprenorphine. Arterial blood gases were measured after intravenous administration of buprenorphine alone (30 mg/kg), flunitrazepam alone (40 mg/kg) or both drugs in rats. Buprenorphine kinetics was studied in plasma and in striatum using cerebral microdialysis, both alone and after rat pretreatment with flunitrazepam. In contrast to buprenorphine or flunitrazepam alone, buprenorphine in combination with flunitrazepam induced a significant, rapid and sustained respiratory depression. Arterial PCO2 was increased at 1.5 min (6.7+/-0.2 versus 5.4+/-0.3 and 5.5+/-0.3 kPa, respectively, P=0.04) (mean+/-S.E.M.), and arterial pH decreased (7.37+/-0.02 versus 7.45+/-0.02 and 7.45+/-0.01, respectively, P=0.03). Plasma buprenorphine kinetics was well described by a three-compartment linear model, with a distribution half-life of 7.4+/-2.7 min and an elimination half-life of 463.9+/-152.3 min. However, neither plasma nor striatal buprenorphine kinetics were significantly altered by pre-administration of flunitrazepam. The adverse interaction between flunitrazepam and buprenorphine cannot be explained by a pharmacokinetic drug-drug interaction during the distribution phase of buprenorphine.

Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats.

Benzodiazepine poisoning causes coma and respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of midazolam. A 160 mgkg(-1) single dose of midazolam was infused intravenously over 20 min in catheterized male Sprague-Dawley rats. Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis. Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection. Midazolam (160 mgkg(-1)) reproducibly induced deep coma with respiratory acidosis. Plasma midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4+/-1.8 h. The striatal dialysate concentration peaked at 50.0+/-8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma. Respiratory depression, assessed by the elevation in PaCO2, was more closely correlated with midazolam striatal dialysate rather than plasma kinetics. These results suggest a central mechanism for midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO2 and pH effects after the slow infusion of a toxic dose of midazolam in rats. The effects on arterial blood gases were better correlated with midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of benzodiazepine-induced respiratory depression in poisonings.

Improving HIV infection management using antiretroviral plasma drug levels monitoring: a clinician's point of view.

Due to genetic and environmental factors, there are wide inter-patient differences when measuring drug exposure to a standard dose. If there is a relationship between drug exposure and efficacy or toxicity, this inter-patient variability carries various risks to develop toxicity or failure. Therapeutic drug monitoring is an attempt to adjust the dose to obtain a level within a therapeutic range consisting in a minimum plasma concentration needed to be efficacious and a maximum plasma concentration not to exceed to avoid toxicity. Many studies have shown a relationship between various pharmacokinetic parameters and drug toxicity or efficacy for HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Therapeutic drug monitoring (TDM) proves to be a useful tool to assess adherence, to investigate drug-drug interactions between antiretroviral (ARV) drugs or with co-medications, to prevent some ARV drug toxicities, to adjust the dosage in particular populations, and to increase ARV efficacy of some drugs in naive patients. The integration of virological and pharmacological parameters, using inhibitory quotients, looks promising to improve therapy in ARV-experienced patients. Effective and non-toxic target concentrations will be determined for all present and future antiretroviral drugs covering the extended spectrum of naive patients to multiple failures. In this article, we review the rationale of TDM for antiretroviral drugs, the retrospective and prospective studies assessing plasma drug concentrations in relation with antiretroviral toxicity or efficacy, and the actually recommended or proposed indications for TDM. We also highlight the benefits and limits of this tool as an adjunct in the care of HIV-infected patients.

Enhanced saquinavir exposure in human immunodeficiency virus type 1-infected patients with diarrhea and/or wasting syndrome.

The protease inhibitor saquinavir was administered to 100 human immunodeficiency virus type 1 (HIV-1)-infected patients as a single 600-mg oral dose (hard gelatin capsules) with a standard breakfast, including 200 ml of grapefruit juice, during an open-label trial to assess whether diarrhea and/or wasting syndrome has consequences on its pharmacokinetics. Three groups of patients were enrolled: group 1, asymptomatic patients (n = 30); group 2, AIDS symptomatic patients without body weight loss or diarrhea (n = 37); and group 3, AIDS symptomatic patients with severe body weight loss and/or diarrhea (n = 33). Clinical and biological data (covariates) were collected. A population approach was performed with three blood samples per patient to estimate the mean population pharmacokinetic parameters (clearance [CL]/oral bioavailability [F], V/F, k(a), and lag time) and the derived ones (k(el), C(max), T(max), and area under the curve [AUC]). The relationships between groups, exposure (i.e., estimated individual post hoc AUCs), and covariates were explored by using multiple linear regressions. A significant increase in median AUCs (165, 349, and 705 ng. h. ml(-1) for groups 1, 2, and 3, respectively [P < 0.0001]) was observed. The enhancement in saquinavir exposure could be due to the destruction of the transporters in enterocytes and/or to the enlargement of their tight junctions, allowing a paracellular crossing of saquinavir as the illness spreads. Because of grapefruit juice intake by every patient, no implication of CYP3A4 could be assessed. These results strongly suggest that, despite its low intrinsic oral bioavailability, saquinavir can be considered as a relevant treatment for HIV-1-infected patients with diarrhea and/or wasting syndrome. This must be evaluated in a long-term period.

Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning.

OBJECTIVE: To test the hypothesis that plasma lactate concentrations could be of confirmatory value in patients with histories consistent with acute pure cyanide poisoning because immediate laboratory confirmation of suspected cyanide poisoning is rarely possible and because clinicians must rapidly decide whether to administer specific antidotes, which may have severe side effects. DESIGN: Retrospective clinical study. SETTING: An intensive care unit in a university-affiliated teaching hospital. PATIENTS: All acute cyanide-poisoned patients admitted to our intensive care unit, excluding fire victims, from 1988 to 1999. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven patients were studied. Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L. Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations ( =.74, =.017). Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH. During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L). The specificity was substantially improved in patients not receiving catecholamines (85%). CONCLUSIONS: The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning.