The role of iturin A from B. amyloliquefaciens BUZ-14 in the inhibition of the most common postharvest fruit rots

The aim of this work was to elucidate the role of the secondary metabolites produced by B. amyloliquefaciens BUZ-14 against B. cinerea, M. fructicola, M. laxa, P. digitatum, P. italicum and P. expansum both in vitro and in planta. The entire cell free supernatant (CFS) and the lipopeptide fraction (LPF) showed similar antifungal activities, completely inhibiting all the fungi at dilutions of 1:24 or even lower, whereas the non-butanolic fraction (NBF) barely inhibited the fungi. However, when the LPF and CFS were applied on fruit, only brown rot in peaches and blue rot in apples was totally inhibited. The main families of metabolites in the LPF were iturin A, fengycin and surfactin with maximum concentrations of 407, 853 and 658¿µg¿mL-1, respectively. Subsequently, a TLC-bioautography revealed iturin A as the key metabolite in the inhibitions and allowed us to establish in vivo MICs of 16.9 and 33.9¿µg¿mL-1 for Monilinia species and P. expansum, respectively. The application of 24 h-old BUZ-14 cultures suppressed brown rot in peaches and also blue rot in apples but failed to inhibit the other diseases. However, BUZ-14 was only able to grow and produce iturin A in peaches so we can deduce that the amount of iturin A brought with the cultures (36¿±¿14¿µg¿mL-1) could be enough to control both diseases. The strong antifungal activity of the iturin A present in the BUZ-14 CFS suggests that it could be successfully used for postharvest disease control. However, future research is necessary to maximize the iturin A production by B. amyloliquefaciens BUZ-14 in order to optimize a commercial application

Antiretroviral Simplification with Darunavir/Ritonavir Monotherapy in Routine Clinical Practice: Safety, Effectiveness, and Impact on Lipid Profile

Simplification of antiretroviral treatment (ART) with darunavir/ritonavir (DRV/r) monotherapy has achieved sustained suppression of plasma viral load (pVL) in clinical trials; however, its effectiveness and safety profile has not been evaluated in routine clinical practice.We performed a retrospective cohort analysis of HIV-1-infected patients who initiated DRV/r monotherapy once daily with a pVL <50 copies/mL under ART and at least 1 subsequent follow-up visit in our clinic. The primary study endpoints were the percentage of patients with virological failure (VF, defined as 2 consecutive pVL>50 copies/mL) at week 48, and time to VF. Other causes of treatment discontinuation and changes in lipid profile were evaluated up to week 48. Ninety-two patients were followed for a median (IQR) of 73 (57-92) weeks. The median baseline and nadir CD4+ T-cell counts were 604 (433-837) and 238 (150-376) cells/mm3, respectively. Patients had previously received a median of 5 (3-9) ART lines and maintained a pVL<50 copies/mL for a median of 76 (32-176) weeks before initiating DRV/r monotherapy. Nine (9.8%) patients developed VF at week 48; time to VF was 47.1 (IQR: 36.1-47.8) weeks among patients with VF. Other reasons for changing ART were gastrointestinal disturbances (n = 3), rash (n = 1), and impaired CD4 recovery (n = 2). Median low-density lipoprotein cholesterol levels increased from 116.1 mg/dL at baseline to 137.3 mg/dL at 48 weeks (p = 0.001).Treatment simplification with DRV/r monotherapy seems safe and effective in routine clinical practice. Further research is needed to elucidate the effect of DRV/r monotherapy on cholesterol levels

Multi-omics in HIV: searching insights to understand immunological non-response in PLHIV

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4+ T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as “immune inadequate responders”, “immunodiscordant responders” or “immune nonresponders (INR)”. The molecular mechanisms underlying poor CD4+ T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4+ T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4+ T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection

High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors

Renal disorders are an emerging problem in HIV-infected patients. We performed a cross-sectional study of the first 1000 HIV-infected patients attended at our HIV unit who agreed to participate. We determined the frequency of renal alterations and its related risk factors. Summary statistics and logistic regression were applied. The study sample comprised 970 patients with complete data. Most were white (94%) and men (76%). Median (IQR) age was 48 (42–53) years. Hypertension was diagnosed in 19%, dyslipidemia in 27%, and diabetes mellitus in 3%. According to the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation, 29 patients (3%) had an eGFR < 60 ml/min/1.73m2; 18 of them (62%) presented altered albumin/creatinine and protein/creatinine (UPC or UAC) ratios. Of the patients with eGFR> 60mL/min, it was present in 293 (30%), 38 of whom (7.1%) had UPC> 300mg/g. Increased risk of renal abnormalities was correlated with hypertension (OR, 1.821 [95%CI, 1.292;2.564]; p = 0.001), age (OR, 1.015 [95%CI, 1.001;1.030], per one year; p = 0.040), and use of tenofovir disoproxil fumarate (TDF) plus protease inhibitor (PI), (OR, 1.401 [95%CI, 1.078;1.821]; p = 0.012). Current CD4 cell count was a protective factor (OR, 0.9995 [95%CI, 0.9991;0.9999], per one cell; p = 0.035). A considerable proportion of patients presented altered UPC or UAC ratios, despite having an eGFR > 60mL/min. CD4 cell count was a protective factor; age, hypertension, and use of TDF plus PIs were risk factors for renal abnormalities. Based on our results, screen of renal abnormalities should be considered in all HIV-infected patients to detect these alterations early

Prevalence of Ischemic Heart Disease and Management of Coronary Risk in Daily Clinical Practice: Results from a Mediterranean Cohort of HIV-Infected Patients

There are conflicting data on the prevalence of coronary events and the quality of the management of modifiable cardiovascular risk factors (CVRF) inHIV-infected patients. Methods.We performed a retrospective descriptive study to determine the prevalence of coronary events and to evaluate the management of CVRF in a Mediterranean cohort of 3760 HIV-1-infected patients from April 1983 through June 2011. Results.We identified 81 patients with a history of a coronary event (prevalence 2.15%); 83% of them suffered an acute myocardial infarction. At the time of the coronary event, CVRF were highly prevalent (60.5% hypertension, 48% dyslipidemia, and 16% diabetes mellitus).OtherCVRF, such as smoking, hypertension, lack of exercise, and body mass index, were not routinely assessed. After the coronary event, a significant decrease in total cholesterol (� = 0.025) and LDLcholesterol (� = 0.004) was observed. However, the percentage of patients whomaintained LDL-cholesterol > 100mg/dL remained stable (from 46% to 41%, � = 0.103). Patients using protease inhibitors associated with a favorable lipid profile increased over time (� = 0.028). Conclusions.The prevalence of coronary events in our cohort is low. CVRF prevalence is high and theirmanagement is far from optimal. More aggressive interventions should be implemented to diminish cardiovascular risk in HIV-infected patients

COVIDApp as an innovative strategy for the management and follow-up of COVID-19 cases in long-term care facilities in Catalonia : Implementation study

This work was supported by the Lluita contra la Sida Foundation, Barcelona, Spain.Background: The coronavirus disease (COVID-19) pandemic has caused an unprecedented worldwide public health crisis that requires new management approaches. COVIDApp is a mobile app that was adapted for the management of institutionalized individuals in long-term care facilities. Objective: The aim of this paper is to report the implementation of this innovative tool for the management of long-term care facility residents as a high-risk population, specifically for early identification and self-isolation of suspected cases, remote monitoring of mild cases, and real-time monitoring of the progression of the infection. Methods: COVIDApp was implemented in 196 care centers in collaboration with 64 primary care teams. The following parameters of COVID-19 were reported daily: signs/symptoms; diagnosis by reverse transcriptase-polymerase chain reaction; absence of symptoms for ≥14 days; total deaths; and number of health care workers isolated with suspected COVID-19. The number of at-risk centers was also described. Results: Data were recorded from 10,347 institutionalized individuals and up to 4000 health care workers between April 1 and 30, 2020. A rapid increase in suspected cases was seen until day 6 but decreased during the last two weeks (from 1084 to 282 cases). The number of confirmed cases increased from 419 (day 6) to 1293 (day 22) and remained stable during the last week. Of the 10,347 institutionalized individuals, 5,090 (49,2%) remained asymptomatic for ≥14 days. A total of 854/10,347 deaths (8.3%) were reported; 383 of these deaths (44.8%) were suspected/confirmed cases. The number of isolated health care workers remained high over the 30 days, while the number of suspected cases decreased during the last 2 weeks. The number of high-risk long-term care facilities decreased from 19/196 (9.5%) to 3/196 (1.5%). Conclusions: COVIDApp can help clinicians rapidly detect and remotely monitor suspected and confirmed cases of COVID-19 among institutionalized individuals, thus limiting the risk of spreading the virus. The platform shows the progression of infection in real time and can aid in designing new monitoring strategies

Dolutegravir Monotherapy as Maintenance Strategy: A Meta-Analysis of Individual Participant Data From Randomized Controlled Trials

Background Dolutegravir monotherapy (DTG-m) results in virological failure (VF) in some people with human immunodeficiency virus (PWH). We sought to identify the independent factors associated with the risk of VF and to explore the effect size heterogeneity between subgroups of PWH enrolled in DTG-m trials. Methods We searched for randomized clinical trials (RCTs) evaluating DTG-m versus combined antiretroviral therapy (cART) among PWH virologically controlled for at least 6 months on cART. We performed an individual participant data meta-analysis of VF risk factors and quantified their explained heterogeneity in random-effect models. Definition of VF was a confirmed plasma human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) >50 copies/mL by week 48. Results Among 416 PWH from 4 RCTs, DTG-m significantly increased the risk of VF (16 of 227 [7%] versus 0 of 189 for cART; risk difference 7%; 95% confidence interval [CI], 1%-2%; P = .02; I$^{2}$ = 51%). Among 272 participants exposed to DTG-m, VF were more likely in participants with the following: first cART initiated ≥90 days from HIV acute infection (adjusted hazard ratio [aHR], 5.16; 95% 95% CI, 1.60-16.65), CD4 T cells nadir <350/mm$^{3}$ (aHR, 12.10; 95% CI, 3.92-37.40), HIV RNA signal at baseline (aHR, 4.84; 95% CI, 3.68-6.38), and HIV-deoxyribonucleic acid (DNA) copy number at baseline ≥2.7 log/10$^{6}$ peripheral blood mononuclear cells (aHR, 3.81; 95% CI, 1.99-7.30). Among these independent risk factors, the largest effect size heterogeneity was found between HIV DNA subgroups (I$^{2}$ = 80.2%; P for interaction = .02). Conclusions Our study supports the importance of a large viral reservoir size for explaining DTG-m simplification strategy failure. Further studies are needed to link size and genetic diversity of the HIV-1 reservoir

Randomized, crossover, double-blind, placebo-controlled trial to assess the lipid lowering effect of co-formulated TDF/FTC

Abstract INTRODUCTION: Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1-3] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons. MATERIALS AND METHODS: RESULTS: 46 subjects with a median age of 43 (40-48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and HDL-cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL-cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure. CONCLUSION: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF

Análisis de Costes y de Coste/Eficacia de las Pautas Recomendadas por GESIDA/Plan Nacional sobre el Sida en 2018 Para el Tratamiento Antirretroviral Inicial en Adultos Infectados Por el VIH

[Background]: The GESIDA/National AIDS Plan expert panel recommended preferred regimens (PR), alternative regimens (AR) and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for 2018. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. [Methods]: Economic assessment of costs and efficiency (cost-effectiveness) based on decision tree analyses. Effectiveness was defined as the probability of reporting a viral load <50 copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug-resistance studies) over the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting was Spain and the costs correspond to those of 2018. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. [Results]: In the base-case scenario, the cost of initiating treatment ranges from 6788 euros for TAF/FTC/RPV (AR) to 10,649 euros for TAF/FTC + RAL (PR). The effectiveness varies from 0.82 for TAF/FTC + DRV/r (AR) to 0.91 for TAF/FTC + DTG (PR). The efficiency, in terms of cost-effectiveness, ranges from 7814 to 12,412 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TAF/FTC + RAL (PR), respectively. [Conclusion]: Considering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TAF/FTC/RPV (AR) and TAF/FTC/EVG/COBI (AR).[Introducción]: El panel de expertos de GESIDA/Plan Nacional del Sida ha recomendado pautas preferentes (PP), pautas alternativas (PA) y otras pautas (OP) para el tratamiento antirretroviral (TAR) como terapia de inicio en pacientes infectados por VIH para 2018. El objetivo de este estudio es evaluar los costes y la eficiencia de iniciar tratamiento con PP y PA. [Métodos]: Evaluación económica de costes y eficiencia (coste/eficacia) mediante construcción de árboles de decisión. Se definió eficacia como la probabilidad de tener carga viral <50 copias/ml en la semana 48 en análisis por intención de tratar. Se definió coste de iniciar tratamiento con una pauta como los costes del TAR y de todas sus consecuencias (efectos adversos, cambios de pauta y estudio de resistencias) que se producen en las siguientes 48 semanas. Se utilizó la perspectiva del Sistema Nacional de Salud, considerando solo costes directos diferenciales: TAR (a precio oficial), manejo de efectos adversos, estudios de resistencias y determinación de HLA-B*5701. El ámbito es España, con costes de 2018. Se realizó un análisis de sensibilidad determinista construyendo 3 escenarios para cada pauta: basal, más favorable y más desfavorable. [Resultados]: En el escenario basal, los costes de iniciar tratamiento oscilaron entre 6.788 para TAF/FTC/RPV (PA) y 10.649 para TAF/FTC + RAL (PP). La eficacia osciló entre 0,82 para TAF/FTC + DRV/r (PA) y 0,91 para TAF/FTC + DTG (PP). La eficiencia, en términos de coste/eficacia, osciló entre 7.814 y 12.412 por respondedor a las 48 semanas, para ABC/3TC/DTG (PP) y TAF/FTC + RAL (PP), respectivamente. [Conclusión]: Considerando el precio oficial del TAR, la pauta más eficiente fue ABC/3TC/DTG (PP), seguida de TAF/FTC/RPV (PA) y TAF/FTC/EVG/COBI (PA)

Factors associated with the number of drugs in darunavir/cobicistat regimens.

Background: Darunavir/cobicistat can be used as mono, dual, triple or more than triple therapy. Objectives: To assess factors associated with the number of drugs in darunavir/cobicistat regimens. Methods: A nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat in Spain from July 2015 to May 2017. Baseline characteristics, efficacy and safety at 48 weeks were compared according to the number of drugs used. Results: There were 761 patients (75% men, 98% were antiretroviral-experienced, 32% had prior AIDS, 84% had HIV RNA <50 copies/mL and 88% had ≥200 CD4 cells/mm3) who initiated darunavir/cobicistat as mono (n=308, 40%), dual (n=173, 23%), triple (n=253, 33%) or four-drug (n=27, 4%) therapy. Relative to monotherapy, triple therapy was more common in men aged <50 years, with prior AIDS and darunavir plus ritonavir use, and with CD4 cells <200/mm3 and with detectable viral load at initiation of darunavir/cobicistat; dual therapy was more common with previous intravenous drug use, detectable viral load at initiation of darunavir/cobicistat and no prior darunavir plus ritonavir; and four-drug therapy was more common with prior AIDS and detectable viral load at initiation of darunavir/cobicistat. Monotherapy and dual therapy showed a trend to better virological responses than triple therapy. CD4 responses and adverse effects did not differ among regimens. Discussion: Darunavir/cobicistat use in Spain has been tailored according to clinical characteristics of HIV-infected patients. Monotherapy and dual therapy have been common and preferentially addressed to older patients with a better HIV status, suggesting that health issues other than HIV infection may have been strong determinants of its prescription.The CODAR study (Gesida Study no 9316) was sponsored by Sociedad Española de Enfermedades Infecciosas y Microbiología-Grupo de Estudio del SIDA (SEIMC-GESIDA). This work was supported by Janssen Cilag S.A. and Red de Investigacion en Sida (RIS): RIS-EST29 and RD12/0017/0001, RD12/0017/0005, RD17/0017/0022 and RD17/0017/0029