Single-electron spin resonance detection by microwave photon counting.

Electron spin resonance spectroscopy is the method of choice for characterizing paramagnetic impurities, with applications ranging from chemistry to quantum computing1,2, but it gives access only to ensemble-averaged quantities owing to its limited signal-to-noise ratio. Single-electron spin sensitivity has, however, been reached using spin-dependent photoluminescence3-5, transport measurements6-9 and scanning-probe techniques10-12. These methods are system-specific or sensitive only in a small detection volume13,14, so that practical single-spin detection remains an open challenge. Here, we demonstrate single-electron magnetic resonance by spin fluorescence detection15, using a microwave photon counter at millikelvin temperatures16. We detect individual paramagnetic erbium ions in a scheelite crystal coupled to a high-quality-factor planar superconducting resonator to enhance their radiative decay rate17, with a signal-to-noise ratio of 1.9 in one second integration time. The fluorescence signal shows anti-bunching, proving that it comes from individual emitters. Coherence times up to 3 ms are measured, limited by the spin radiative lifetime. The method has the potential to be applied to arbitrary paramagnetic species with long enough non-radiative relaxation times, and allows single-spin detection in a volume as large as the resonator magnetic mode volume (approximately 10 µm3 in the present experiment), orders of magnitude larger than other single-spin detection techniques. As such, it may find applications in magnetic resonance and quantum computing.

Microwave Fluorescence Detection of Spin Echoes.

Counting the microwave photons emitted by an ensemble of electron spins when they relax radiatively has recently been proposed as a sensitive method for electron paramagnetic resonance spectroscopy, enabled by the development of operational single microwave photon detectors at millikelvin temperature. Here, we report the detection of spin echoes in the spin fluorescence signal. The echo manifests itself as a coherent modulation of the number of photons spontaneously emitted after a π/2_{X}-τ-π_{Y}-τ-π/2_{Φ} sequence, dependent on the relative phase Φ. We demonstrate experimentally this detection method using an ensemble of Er^{3+} ion spins in a scheelite crystal of CaWO_{4}. We use fluorescence-detected echoes to measure the erbium spin coherence time, as well as the echo envelope modulation due to the coupling to the ^{183}W nuclear spins surrounding each ion. We finally compare the signal-to-noise ratio of inductively detected and fluorescence-detected echoes, and show that it is larger with the fluorescence method.

Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

Factors associated with deaths from suicide in a French nationwide HIV-infected cohort.

OBJECTIVES: People living with HIV (PLHIV) are at a higher risk of dying by suicide than the general population. Epidemiological data regarding determinants of suicide in PLHIV are scarce. The aim of this study was thus to study demographic, socio-economic, psychiatric history and immunovirological characteristics associated with death from suicide in the French multicenter Dat'AIDS cohort, from January 2000 to July 2013. METHODS: This was a nested case-control study. All deceased PLHIV during the study period who died by suicide and whose medical files could be checked were included as cases. Controls were selected using incidence density sampling. For each case, up to four controls were selected among all actively followed PLHIV at the index date (date of death of cases). Controls were matched for time from HIV diagnosis (5-year periods) and clinical centre. RESULTS: Seventy cases and 279 controls were included in the study. By multivariable analysis, the factors significantly associated with death from suicide were: not having children, active or substituted drug consumption, alcohol intake > 20 g/day or history of alcohol abuse, history of depressive disorder and/or of attempted suicide, and psychotropic drug intake. Conversely, age, gender, country of birth, positive HCV serology and HIV-related factors, such as AIDS status, use of combination antiretroviral therapy (cART), nadir and current CD4 counts and HIV viral load, were not significantly associated with the risk of death from suicide. CONCLUSIONS: In the cART era, HIV-related factors are not associated with a higher risk of suicide mortality. Suicide prevention measures should target PLHIV with the psychological morbidities observed in our cohort.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

Prevalence and Risk Factors of Sleep Disturbance in a Large HIV-Infected Adult Population.

This cross-sectional study evaluates the prevalence and factors associated with sleep disturbances in French adult HIV-infected outpatients. Patients fullfilled a self-administered questionnaire on their health behavior, sleep attitudes (Pittsburgh sleep quality index, PSQI), quality of life and depression; 1354 patients were enrolled. Median sleeping time was 7 h. Poor sleep quality was observed in 47 % of the patients, and moderate to serious depressive symptoms in 19.7 %. Factors significantly associated with sleep disturbances were depression, male gender, active employment, living single, tobacco-smoking, duration of HIV infection, nevirapine or efavirenz-including regimen. Prevalence of poor sleepers is high in this HIV adult outpatient population. Associated factors seem poorly specific to HIV infection and more related to social and psychological status. Taking care of these disturbances may prove to be an effective health management strategy.

Switching from tenofovir/emtricitabine and nevirapine to a tenofovir/emtricitabine/rilpivirine single-tablet regimen in virologically suppressed, HIV-1-infected subjects.

OBJECTIVES: Nevirapine is an inducer of hepatic metabolism. After discontinuation, nevirapine has an inductive effect on cytochrome P450 3A4, which persists for a few weeks and which, after switching to rilpivirine, may reduce rilpivirine exposures and have a negative clinical impact. This study evaluates the virological outcome, pharmacokinetics and safety of switching virologically suppressed, HIV-1-infected patients from nevirapine to rilpivirine. PATIENTS AND METHODS: This 24 week open-label single-centre study included HIV-1-infected adults with HIV-1 RNA <50 copies/mL for >6 months on tenofovir/emtricitabine and nevirapine, who were willing to simplify their regimen to tenofovir/emtricitabine/rilpivirine. Virological suppression, safety and nevirapine and rilpivirine pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 32 subjects remained virologically suppressed. One subject discontinued at week 1 for rilpivirine-associated insomnia and two patients chose to resume tenofovir/emtricitabine and nevirapine after week 12 because of rilpivirine-associated food constraint. There was no grade 3/4 laboratory abnormality. Rilpivirine trough concentrations were above the mean trough concentrations observed in Phase 3 studies by 1 week post-switch. Twenty-seven out of 32 patients had no measurable levels of nevirapine by 2 weeks post-switch. The meal accompanying tenofovir/emtricitabine/rilpivirine intake satisfied food requirements in 81% of cases. Overall general satisfaction was improved in 90% of the subjects despite food constraints. CONCLUSION: Nevirapine has a short and limited inductive effect on rilpivirine metabolism, which is not clinically significant. Tenofovir/emtricitabine/rilpivirine is an efficacious and safe option for virologically suppressed HIV-infected patients on nevirapine wishing to simplify their regimen.

Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen.

OBJECTIVES: Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. PATIENTS AND METHODS: We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, ß2-microglobulin and α1-microglobulin were measured during a routine clinical visit. RESULTS: Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. CONCLUSIONS: Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited.

High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs.

OBJECTIVES: The aim of this study was to assess 25-hydroxyvitamin D (vitamin D) status in an HIV-infected adult population and to define HIV- and antiretroviral-related factors associated with vitamin D deficiency. METHODS: Using data from a prospective cohort of HIV-infected adult patients followed in five French centres (Dat'AIDS cohort), we evaluated the prevalence of vitamin D deficiency/insufficiency (<30 ng/mL). A multiple linear regression model was used to examine risk factors for vitamin D deficiency (≤10 ng/mL). RESULTS: Vitamin D deficiency/insufficiency was observed in 86.7% of the 2994 patients, including 55.6% with vitamin D insufficiency and 31.1% with vitamin D deficiency. In multivariate analysis, factors associated with vitamin D deficiency were current smoking [adjusted OR (aOR) 1.55], estimated glomerular filtration rate ≥90 mL/min/1.73 m(2) (aOR 1.51), vitamin D measurement not performed in summer (aOR 0.27), CD4 <350 cells/mm(3) (aOR 1.37 for CD4 200 to <350 and 1.62 for CD4 <200 cells/mm(3)) and antiretroviral therapy (aOR 2.61). Gender, body mass index, age, coinfection and previous AIDS were not associated factors. In the antiretroviral-treated population (n = 2660), besides the same factors found in the whole population, efavirenz was the only drug to be significantly associated with deficiency, with an aOR of 1.89 (95% CI 1.45-2.47). CONCLUSIONS: Vitamin D deficiency is frequent in this HIV-infected population. Patients on antiretroviral therapy are at higher risk of vitamin D deficiency than antiretroviral-naive patients, with an increased risk in patients receiving efavirenz. No effect of the other antiretrovirals, including the latest (etravirine, darunavir, raltegravir), was found.

Public health issues and health rendezvous for migrants from conflict zones in Ukraine: A French practice guideline.

Given the number of people leaving the war zone in Ukraine and arriving in France, the French high council for public health (HCSP) has drawn up a number of recommendations. The experts have taken into account the vulnerability of migrant populations, which is exacerbated by (a) promiscuity that increases the risk of exposure to infectious agents; (b) the psychological consequences of conflict, family separation and exile; (c) prevalence in Ukraine of communicable diseases such as (possibly multi-resistant) tuberculosis, HIV and HCV; (d) low vaccination coverage (risk of circulation of poliovirus) and (e) the risk of spreading infectious diseases (Covid-19, measles…). Consequently, experts recommend that priority be given to: (i) Initial (immediate) reception, which will help to provide emergency care and to assess immediate needs (psychological disorders, risk of medication breakdown and risk of infection); (ii) Other priority measures (vaccination catch-up, including vaccination against SARS-CoV-2 and mandatory vaccination for children's entry into school, screening for post-traumatic stress disorder and tuberculosis) must be implemented as soon as feasible. At this stage, it is imperative: To ensure coordination and access to information throughout the country, by providing medico-social support (opening of social rights and access to care); To digitize medical data for the purposes of traceability; To use professional interpreting and/or health facilitators, or else, if necessary, digital translation tools. (iii) Finally, experts stress the need for vigilance in terms of management, conservation of social rights and continuity of care after the initial period, and organization of a "health rendezvous" within four months of a migrant's entering the country.

Quantitation using HRMS: A new tool for rapid, specific and sensitive determination of catecholamines and deconjugated methanephrines metanephrines in urine.

Urinary catecholamines and their methylated metabolites are biochemical indicators of pheochromocytoma, paraganglioma and neuroblastoma. A rapid and precise analytical method based on solid-phase extraction (SPE) and liquid chromatography separation coupled to high-resolution mass spectrometry (LC-HRMS) was developed and validated to measure urinary catecholamines (epinephrine (E), norepinephrine (NorE), dopamine (D)) and total methylated metabolites (normetanephrine (NorMN), metanephrine(MN) and 3-methoxytyramine (3-MT)) in a clinical setting. Results of 51 urine specimens measured using this LC-HRMS method were compared with a liquid chromatography assay with electrochemical detection (LC-EC). Urine samples (200 µL) were spiked with an internal standard solution followed by SPE purification. In the case of total methylated metabolites, urine was hydrolyzed before SPE purification. Separation was achieved on an Acclaim Mixed Mode WCX column, with an 8.5 min runtime. All compounds were detected in electrospray positive ionization mode with a parallel reaction monitoring acquisition and quantified with a linear regression (r2 > 0.998) between 2 and 200 µg/L (10.9-1090; 11.8-1182 nmol/L) for E and NorE respectively and between 10 and 1000 µg/L for others (65.2-6520; 50.7-5070; 54.5-5450 ; 59.8-5980 nmol/L for D, M, NorMN and 3-MT, respectively). Overall imprecision and bias did not exceed 15%. No significant matrix effect was observed. Correlation between the two assays was good except for epinephrine. Epinephrine concentrations measured by LC-EC method were slightly higher than values obtained with LC-HRMS method but without impact on clinical decision. This LC-HRMS assay provides a new tool for simultaneous quantitative catecholamine determination and was successfully applied in routine for the screening or follow up of pheochromocytoma, paraganglioma and neuroblastoma. LC-HRMS method offers significant advantages compared to LC-EC with good sensitivity, an unambiguous analyte determination and high sample throughput.

Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure.

Oral ganciclovir (GCV) was replaced by prodrug valganciclovir (vGCV) for cytomegalovirus (CMV) prophylaxis. We assessed retrospectively (2005-2007) vGCV effectiveness and safety during prophylaxis and 4 months after, in heart (HTx) and lung transplantation (LTx), including lung transplant for cystic fibrosis (CFTx). Patients with stable renal function received vGCV 900 mg daily during 3-6 and 8-12 months in HTx and LTx. Effectiveness was assessed by antigenemia (pp65Ag) and a GCV therapeutic drug monitoring to document exposure. A total of 32 patients (11 HTx, 7 LTx, and 14 CFTx) received vGCV for 106+/-67 days in HTx versus 270+/-85 days in LTx and CFTx. Doses were 700+/-225, 915+/-60, and 820+/-150 mg/24 h in HTx, LTx, and CFTx showing acceptable mean trough GCV 0.75+/-0.5 mg/L. Two of 9 cases of neutropenia were attributable to vGCV. Three CMV donor-positive/recipient-negative CFTx patients presented positive pp65Ag; 2 developed CMV disease (6%). We found that vGCV 900 mg, adapted to renal function, was effective and safe for long CMV prophylaxis together with efficient exposure in thoracic transplantation.

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis.

BACKGROUND AND OBJECTIVE: Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. METHODS: Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05. RESULTS: Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. CONCLUSION: This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

BACKGROUND: Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels. METHODS: VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data. RESULTS: The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements. CONCLUSIONS: TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Management of metabolic cytochrome P450 3A4 drug-drug interaction between everolimus and azole antifungals in a renal transplant patient.

We report a case of a 54-year-old male renal transplant patient who received antifungal azole treatment in combination with the recently introduced immunosuppressant agent everolimus to prevent post-transplantation aspergillosis reactivation. Voriconazole was withdrawn after 1 month because of elevated concentrations (5 mg/L trough plasma determination) and hepatotoxicity, and substituted by several months of treatment with posaconazole (observed concentration range 1-2 mg/L). We observed pharmacokinetic drug interactions between both voriconazole and posaconazole, and everolimus cytochrome P450 3A4 metabolism, resulting in 7.5- and 3.8-fold increase, respectively, in everolimus blood trough concentrations. Combined therapeutic drug monitoring (TDM) of both everolimus and azole inhibitors allowed for safe and convenient modification of everolimus dosage, which was tapered to maintain a target range of 5-15 ng/mL during and after antifungal treatments. While significant in their effects, these drug interactions were able to be managed safely through a careful approach to management and use of individual TDM.

[Phaeochromocytoma and paraganglioma]. / Phéochromocytome et paragangliome.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that arise from the adrenal medulla or sympathetic and parasympathetic ganglia. These tumors produce most often catecholamines in excess, causing hypertension and sometimes severe acute cardiovascular complications. The diagnosis is based on plasma or urines metanephrines measurements and on conventional and nuclear medicine imaging. Catecholamines-producing PPGL is very unlikely if levels are normal. The diagnosis of PPGL cannot be made without visualization of a tumor. Therapeutic management consists mostly of surgical excision, after drug preparation, and should be done in referral centers. About 40% of pheochromocytomas and paragangliomas occur in the context of an autosomal inherited syndrome, making genetic testing essential. The follow-up must be prolonged because a metastatic evolution or a recurrence can be observed in about 15% of the cases.

Switching from abacavir/lamivudine plus nevirapine to abacavir/lamivudine/dolutegravir in virologically controlled HIV-infected adults (SWAD study).

INTRODUCTION: The metabolic pathways of dolutegravir suggest a potential predator effect of nevirapine on dolutegravir pharmacokinetics and switching from a nevirapine- to a dolutegravir-containing regimen could lead to a lower and suboptimal exposure to dolutegravir several weeks after the switch in case of persistent inducer effect. PATIENTS AND METHOD: Prospective, pilot, single-arm, open-label, non-comparative, bicentric study to evaluate the pharmacokinetics, virologic outcomes, safety, and patient satisfaction of switching from abacavir/lamivudine and nevirapine to a single tablet of abacavir/lamivudine/dolutegravir. The primary endpoint was the maintenance of virologic suppression (HIV-1 RNA<50 copies/mL) at week 12. Secondary endpoints were virologic suppression at week 48, safety and tolerability, patient satisfaction, and pharmacokinetic interaction between nevirapine and dolutegravir. Fifty-three adults on stable abacavir/lamivudine and nevirapine regimen for a median duration of 6years and virologically suppressed for 9.6years were included. RESULTS: Dolutegravir reached steady state by week 4/week 12 when expected by day 5/day 10. All subjects maintained plasma HIV-RNA˂50 copies/mL at week 12 and week 48. Abacavir/lamivudine/dolutegravir was well-tolerated, with two cases of serious adverse events deemed unrelated to study drugs (coronary syndrome in both cases), and one discontinuation for renal impairment at week 24 with a slight improvement after dolutegravir discontinuation. Level of treatment satisfaction remained high after the switch. CONCLUSION: The transient predator effect of nevirapine on dolutegravir had no clinical consequences after switching from nevirapine to dolutegravir, neither on safety nor maintenance of virologic suppression. It also had no consequences on patient satisfaction.

Atazanavir in patients with persistent viral replication despite HAART: results from the French prospective NADIS cohort.

OBJECTIVE: To assess virological efficacy of a ritonavir-boosted atazanavir (ATV/r)-containing regimen in patients with persistent viral replication despite HAART. PATIENTS AND METHOD: Prospective cohort of French HIV-infected patients. Patients were included if pretreated and viral load (VL) >400 copies/mL at the time of ATV/r first prescription (baseline). Demographic and epidemiologic data, therapeutic history, and clinical and biological values at baseline and during follow-up were analyzed. Primary endpoint was failure of the regimen defined as either VL>400 copies/mL at Week 24 or treatment interruption before Week 24. Multivariate analysis was performed of baseline characteristics related with treatment failure. RESULTS: There were 424 patients with available data. Primary endpoint was met by 36%: 24% VL>400 copies/mL and 12% treatment interruption. Treatment interruption due to drug-related toxicity was significantly more frequent in women (20.5% vs. 8.8%, p= .001). Female gender (adjusted odds ratio [OR]=1.91), previous use of lopinavir (LPV; OR=2.76), number of new drugs and of active drugs in the regimen (OR=0.48 and 0.3, respectively), and baseline VL (OR=1.75) were independently related with treatment failure. CONCLUSION: ATV/r-containing regimens, because of low pill burden and good tolerance, can be a useful strategy as long as the patients did not suffer previous LPV failures. The issue of gender deserves further studies in larger populations.

Characteristics trends, mortality and morbidity in persons newly diagnosed HIV positive during the last decade: the profile of new HIV diagnosed people.

We analysed mortality, morbidity and trends in the characteristics, including risk factors of late testing, in 6805 the patients newly diagnosed for HIV infection between 1 January 1996 and 1 July 2006. The proportion of individuals in high risk groups of infection, as MSM, has decreased over time whereas the proportion of those in low risk of infection, as heterosexual persons in couple with children, has increased. This population is mainly diagnosed late with major consequences on morbidity and mortality.