Prescribing intranasal steroids in HIV-positive patients: systematic review of the literature.

BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.

Lopinavir/Ritonavir for COVID-19: a Systematic Review and Meta-Analysis.

PURPOSE: To provide the latest evidence on the efficacy and safety of lopinavir/ritonavir compared to other treatment options for COVID-19. METHODS: We searched PubMed, Cochran Library, Embase, Scopus, and Web of Science for the relevant records up to April 2021. Moreover, we scanned MedRxiv, Google Scholar, and clinical registry databases to identify additional records. We have used the Newcastle-Ottawa Scale and Cochrane risk of bias tools to assess the quality of studies. This Meta-analysis was conducted using RevMan software (version 5.3). RESULTS: Fourteen studies were included. No significant difference was observed between lopinavir/ritonavir and non-antiviral treatment groups in terms of negative rate of PCR (polymerase chain reaction) on day 7 (risk ratio [RR]: 0.83; 95% CI: 0.63 to 1.09; P=0.17), and day 14 (RR: 0.93; 95% CI: 0.81 to 1.05; P=0.25), PCR negative conversion time (mean difference [MD]: 1.09; 95% CI: -0.10 to 2.29; P=0.07), secondary outcomes, and adverse events (P>0.05). There was no significant difference between lopinavir/ritonavir and chloroquine as well as lopinavir/ritonavir and hydroxychloroquine regarding the efficacy outcomes (P>0.05). However, lopinavir/ritonavir showed better efficacy than arbidol for the same outcomes (P<0.05). Lopinavir/ritonavir plus arbidol was effective compared to arbidol alone in terms of the negative rate of PCR on day 7 (P=0.02). However, this difference was not significant regarding other efficacy outcomes (P>0.05). CONCLUSION: Lopinavir/ritonavir has no more treatment effects than other therapeutic agents used herein in COVID-19 patients.

Cardiovascular risks associated with protease inhibitors for the treatment of HIV.

Introduction: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.Areas covered: We searched for publications of randomized trials and observational studies on PubMed from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on clinicaltrials.gov as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.Expert opinion: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.

Clinical profile of acute pancreatitis following treatment with protease inhibitors: a real-world analysis of post-marketing surveillance data.

BACKGROUNDS: Acute pancreatitis (AP) has been reported in patients treated with protease inhibitors (PIs), but there are few real-world studies comparing the occurrence and characteristics of AP after different PI regimens. RESEARCH DESIGN AND METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the Food and Drug Administration's Adverse Event Reporting System (FAERS) database for suspected adverse events involving AP after PI. The times to onset and fatality rates of AP following different PI regimens were also compared. RESULTS: Based on 33,832 reports related to PIs, 285 cases were associated with AP, involving with 12 out of the 15 studied PIs. Of all the reported AP events related to PIs, 64.56% occurred in men and the median time to onset of AP was 103 (IQR: 26-408) days after the initiation of PI treatment with a fatality rate of 14.02%. Among all PI therapies, indinavir was notably associated with AP, and ritonavir and lopinavir/ritonavir-induced AP cases appeared to be associated with a higher risk of death. CONCLUSIONS: Most of PIs were associated with AP-related adverse events, among which indinavir has a stronger association with AP but there is no significant difference in fatality rates.

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV.

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.

Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem.

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.

Efeitos in vitro e in vivo dos inibidores da protease do HIV Atazanavir e Darunavir nos fatores de virulência de Candida albicans: formação de biofilme, filamentação e infecção em modelo de Galleria mellonella / In vitro and in vivo effects of the HIV Protease Inhibitors Atazanavir and Darunavir in virulence factors of Candida albicans: biofilm formation, hyphae formation and infection in Galleria mellonella model

Candida albicans é um fungo que habitualmente coloniza superfícies mucosas de humanos e pode assumir caráter patogênico a depender de fatores do hospedeiro. Portadores da Síndrome da Imunodeficiência Humana, causada pelo Vírus da Imunodeficiência Humana (HIV), são propícios a apresentar candidose nas mucosas devido a imunodeficiência celular que apresentam. A introdução da Terapia Antirretroviral (TARV), em especial o surgimento dos Inibidores da Protease do HIV (IPs-HIV), reduziu drasticamente a incidência e prevalência destas patologias ao longo dos anos. Estudos clínicos e epidemiológicos com IPs-HIV de primeira geração demostraram que tal redução não se deve exclusivamente à melhora imunológica promovida pela TARV, e pesquisas in vitro já demonstraram propriedades antifúngicas e antibiofilme de alguns IPs-HIV de primeiras gerações em C. albicans. Sendo assim, o objetivo deste estudo foi avaliar os efeitos do Atazanavir (ATV) e Darunavir (DRV), dois IPs-HIV de segunda e terceira geração respectivamente em uso clínico atual no Brasil, em diferentes fatores de virulência de C. albicans. Para isso foram realizados estudos com duas cepas clínicas de C. albicans isoladas de lesões de candidose orofaríngea de pacientes portadores de HIV para avaliar a ação in vitro das drogas na morfogênese, formação de biofilme (contagem de células viáveis e quantificação de biomassa) e na expressão dos genes de virulência BRC1 e SAP2, e in vivo no efeito protetor desses medicamentos na infecção experimental por C. albicans em modelo de Galleria mellonella. Os dados foram analisados por teste t, ANOVA, Kruskal-Wallis, Dunn e Kaplan-Meier (p<0,05). A Concentração Inibitória Mínima (CIM) para ambos os IPs-HIV testados foi 512 µg/mL. Nos biofilmes, a redução na contagem de UFC/mL de C. albicans nos grupos tratados com IPs-HIV foi de até 6,81 Log. A biomassa dos biofilmes tratados também sofreu reduções significantes para ATV (82%), DRV (81%) comparada ao grupo controle.DRV e ATV promoveram redução estatisticamente significante de expressão gênica de SAP2 e BRC1, respectivamente, quando comparados ao controle (p<0,05). Em relação à morfogênese de C. albicans, ATV e DRV inibiram significativamente a formação de hifas (p=0,0183). No estudo in vivo, o uso profilático de ATV e DRV em G. mellonella infectadas com C. albicans prolongou em até 40% a sobrevivência das larvas (p=0,0004). Conclui-se que ATV e DRV inibiram a filamentação e apresentaram atividade antifúngica, antibiofilme e na expressão de genes de fatores de virulência de C. albicans e preveniram candidose em G. mellonella(AU)

Candida albicans is a fungus that usually colonizes mucous surfaces of humans and can assume pathogenic character depending on host factors. Patients with Human Immunodeficiency Syndrome, caused by the Human Immunodeficiency Virus (HIV), are favorable to present mucous candidosis due to the cellular immunodeficiency they present. The introduction of Antiretroviral Therapy (ART), especially the emergence of HIV Protease Inhibitors (HIV-PI), has drastically reduced the incidence and prevalence of these mycosis over the years. Clinical and epidemiological studies with firstgeneration HIV-PIs have shown that this reduction is not exclusively due to the immunological improvement promoted by ART, and in vitro research has already demonstrated antifungal and antibiofilm properties of firsts-generations HIV-PIs on C. albicans. Thus, the aim of this study was to evaluate the effects of Atazanavir (ATV) and Darunavir (DRV), two HIV-PIs of second and third generation respectively currently in clinical use in Brazil, on virulence factors of C. albicans. For this purpose, studies were carried out with two clinical strains of C. albicans isolated from lesions of oropharyngeal candidosis of HIV positive patients to evaluate in vitro action of the drugs on morphogenesis, biofilm formation (number of viable cell and biomass determination) and virulence factor genes BRC1 and SAP2 expression and in vivo on the protective effect of these drugs on experimental infection by C. albicans in Galleria mellonella model. Data were analyzed by t Student, ANOVA, Kruskal-Wallis and Dunn and Kaplan-Meier (p<0.05) tests. The Minimum Inhibitory Concentration (MIC) for both tested HIV-PIs was 512 µg/mL. In biofilms, a reduction in the CFU/mL count of C. albicans in the groups treated with HIV-PIs was up to 6.81 log. The biomass of biofilms also suffered significant reductions for ATV (82%) and DRV (81%) compared to the control group. DRV and ATV statistically significantly downregulated the expression of SAP2 and BRC1 genes respectively (p<0,05). Regarding the morphogenesis of C. albicans, ATV and DRV inhibited the formation of hyphae (p = 0.0183). In the in vivo study, the prophylactic use of ATV and DRV in G. mellonella infected with C. albicans prolonged larval survival by up to 40% (p = 0.0004). We can conclude that ATV and DRV inhibited filamentation and showed antifungal activity, being able to inhibit growth, formation and virulence factors gene expression of C. albicans biofilm and prevented candidosis in G. mellonel(AU)

In utero exposure to protease inhibitor-based antiretroviral regimens delays growth and developmental milestones in mice.

Antiretroviral therapy (ART) in pregnancy has dramatically reduced HIV vertical transmission rates. Consequently, there is a growing number of children that are HIV exposed uninfected (CHEUs). Studies suggest that CHEUs exposed in utero to ART may experience developmental delays compared to their peers. We investigated the effects of in utero ART exposure on perinatal neurodevelopment in mice, through assessment of developmental milestones. Developmental milestone tests (parallel to reflex testing in human infants) are reflective of brain maturity and useful in predicting later behavioral outcomes. We hypothesized that ART in pregnancy alters the in utero environment and thereby alters developmental milestone outcomes in pups. Throughout pregnancy, dams were treated with boosted-atazanavir combined with either abacavir/lamivudine (ATV/r/ABC/3TC), or tenofovir/emtricitabine (ATV/r/TDF/FTC), or water as control. Pups were assessed daily for general somatic growth and on a battery of tests for primitive reflexes including surface-righting, negative-geotaxis, cliff-aversion, rooting, ear-twitch, auditory-reflex, forelimb-grasp, air-righting, behaviors in the neonatal open field, and olfactory test. In utero exposure to either ART regimen delayed somatic growth in offspring and evoked significant delays in the development of negative geotaxis, cliff-aversion, and ear-twitch reflexes. Exposure to ATV/r/ABC/3TC was also associated with olfactory deficits in male and forelimb grasp deficits in female pups. To explore whether delays persisted into adulthood we assessed performance in the open field test. We observed no significant differences between treatment arm for males. In females, ATV/r/TDF/FTC exposure was associated with lower total distance travelled and less ambulatory time in the centre, while ATV/r/ABC/3TC exposure was associated with higher resting times compared to controls. In utero PI-based ART exposure delays the appearance of primitive reflexes that involve vestibular and sensory-motor pathways in a mouse model. Our findings suggest that ART could be disrupting the normal progress/maturation of the underlying neurocircuits and encourage further investigation for underlying mechanisms.

The dual protease inhibitor lopinavir/ritonavir (LPV/r) exerts genotoxic stress on lung cells.

The Sub-Saharan countries, particularly South Africa has the largest number of people living with HIV, accompanied by the largest antiretroviral treatment (ART) programme in the world. The Highly Active Antiretroviral Treatment (HAART) is the most effective regimen against HIV/AIDS and has improved the lifespan and quality of life of HIV positive patients. HAART has also led to a decrease in the incidence of AIDS defining cancers (ADCs) while there is an increased incidence of the non-AIDS Defining Cancers (NADCs), such as lung cancer in the HAART era. The association between lung tumourigenesis and the use of HAART components such as the dual protease inhibitor (PI) lopinavir/ritonavir (LPV/r) is poorly understood. Using cell and molecular biological approaches, this study aimed at elucidating the effects of LPV/r on the regulation of the cell cycle related genes in normal (MRC-5) and adenocarcinoma (A549) lung cells. Initially, the nuclear integrity of these cells in response to LPV/r was determined using DAPI staining. The effect of LPV/r on cell cycle genes was evaluated through the use of a RT2 PCR gene array of 84 genes related to the cell cycle signaling pathway. The PCR array data was validated by Real-Time Quantification PCR (RT-qPCR). Ingenuity Pathway Analysis (IPA) bio-informatics tool was employed to disclose the molecular mechanism/s observed at cellular and gene expression levels. Loss of nuclear integrity and the upregulation of the p53 DNA damage response (DDR) pathway was revealed by DAPI staining, differential gene expression and IPA core analysis. Furthermore, MAD2L2 and AURKB which also play a role in the DDR pathway were shown to be differentially expressed. The activation of the CASP3 gene in response to LPV/r in A549 cells was also observed. The findings of this study suggest genotoxic properties of LPV/r in healthy normal lung fibroblasts cells and anti-tumour properties in the A549 cells.

A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV.

OBJECTIVE: Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. DESIGN: Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. METHODS: We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. RESULTS: Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. CONCLUSIONS: The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. CLINICAL TRIALS REGISTRATION: NCT02577042.

Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in HIV-infected adolescents receiving protease inhibitors.

BACKGROUND: Lipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types. METHODS: A cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type). RESULTS: Of the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01-1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01-1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01-1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00-1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (ß = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (ß = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05). CONCLUSIONS: Abnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.

Use of Darunavir-Cobicistat as a Treatment Option for Critically Ill Patients with SARS-CoV-2 Infection.

We retrospectively reviewed patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who were admitted to an intensive care unit in Daegu, South Korea. The outcomes of patients who did (cases) or did not (controls) receive darunavir-cobicistat (800-150 mg) therapy were compared. Fourteen patients received darunavir-cobicistat treatment, and 96 received other antiviral therapy (controls). Overall, the darunavir-cobicistat group comprised patients with milder illness, and the crude mortality rate of all patients in the darunavir-cobicistat group was lower than that in the controls [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.04-0.89, p=0.035]. After 1:2 propensity-score matching, there were 14 patients in the darunavir-cobicistat group, and 28 patients in the controls. In propensity score-matched analysis, the darunavir-cobicistat group had lower mortality than the controls (OR 0.07, 95% CI 0.01-0.52, p=0.009). In conclusion, darunavir-cobicistat therapy was found to be associated with a significant survival benefit in critically ill patients with SARS-CoV-2 infection.

Improved sensory properties of a nanostructured ritonavir suspension with a pediatric administration perspective.

The pediatric adherence to antiretroviral therapy is critical to therapeutic success. Ritonavir, a protease inhibitor drug, is commercially available as an oral solution containing a high amount of ethanol and propylene glycol, contraindicated in children younger than 4 years. Moreover, this medicine presents a bitter taste, which is limiting for the adherence to treatment. This study aims to develop ritonavir nanoparticles followed by polymeric coating for sensory characteristics improvement. The nanoparticles were coated with Eudragit® L 100-55 and characterized. A human sensory panel evaluated the proposed formulations regarding its bitter taste. The formulation showed nanotechnological features, with 130 and 134 nm for ritonavir nanoparticles and ritonavir coated nanoparticles, respectively. The pH, zeta potential, drug content and encapsulation efficiency results were suitable for oral administration. The coated nanoparticles were capable of decreasing the drug bitter taste as shown in the sensory analysis. The ritonavir incorporation in nanoparticles, followed by polymer coating can be a reasonable strategy to obtain alcohol free taste-masked medicines, which are promising for pediatric therapy.

Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for Potential Therapy of COVID-19.

In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by the World Health Organization (WHO). Full-length genome sequences of SARS-CoV-2 showed 79.6% sequence identity to SARS-CoV, with 96% identity to a bat coronavirus at the whole-genome level. COVID-19 has caused over 133,000 deaths and there are over 2 million total confirmed cases as of April 15th, 2020. Current treatment plans are still under investigation due to a lack of understanding of COVID-19. One potential mechanism to slow disease progression is the use of antiviral drugs to either block the entry of the virus or interfere with viral replication and maturation. Currently, antiviral drugs, including chloroquine/hydroxychloroquine, remdesivir, and lopinavir/ritonavir, have shown effective inhibition of SARS-CoV-2 in vitro. Due to the high dose needed and narrow therapeutic window, many patients are experiencing severe side effects with the above drugs. Hence, repurposing these drugs with a proper formulation is needed to improve the safety and efficacy for COVID-19 treatment. Extracellular vesicles (EVs) are a family of natural carriers in the human body. They play a critical role in cell-to-cell communications. EVs can be used as unique drug carriers to deliver protease inhibitors to treat COVID-19. EVs may provide targeted delivery of protease inhibitors, with fewer systemic side effects. More importantly, EVs are eligible for major aseptic processing and can be upscaled for mass production. Currently, the FDA is facilitating applications to treat COVID-19, which provides a very good chance to use EVs to contribute in this combat.

Iatrogenic Cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir.

Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur.

Interacciones de cobicistat y ritonavir en pacientes con VIH y sus consecuencias clínicas / Interactions of cobicistat and ritonavir in patients with HIV and its clinical consequences

INTRODUCCIÓN: La prescripción de tratamiento antirretroviral (TAR) que contiene potenciadores farmacocinéticos como ritonavir y cobicistat es frecuente. El objetivo de este estudio fue analizar las interacciones potenciales del TAR que incluyen estas moléculas en su formulación con la medicación domiciliaria del paciente, así como el manejo clínico de aquellas potencialmente graves. MÉTODOS: Estudio prospectivo en la consulta de atención farmacéutica de un hospital de tercer nivel entre enero y diciembre de 2018. Se incluyeron en el estudio aquellos pacientes VIH + con un TAR que contuviera cobicistat o ritonavir. Se analizaron las interacciones potenciales entre el TAR y la medicación concomitante en tres bases de datos (Micromedex(R), Drugs.com y Liverpool), se detallaron las intervenciones realizadas, y se analizaron las reacciones adversas encontradas. RESULTADOS: Se incluyeron 968 pacientes con un total de 2.148 prescripciones (274 principios activos diferentes). Se realizaron un total de 86 intervenciones relativas a interacciones potenciales en los pacientes. Las más frecuentes fueron sustituciones de tratamientos corticoideos, supensiones de tratamiento y monitorizaciones más estrechas. Se analizaron un total de doce sospechas de reacción adversa. El grado de concordancia en la clasificación de la gravedad de las interacciones para cobicistat y ritonavir fue buena entre las tres bases de datos. Resultó destacable Micromedex(R) como la más completa por tener más principios activos registrados. CONCLUSIÓN: Las interacciones entre el TAR con potenciadores farmacocinéticos en su composición y la medicación concomitante es frecuente y requiere de una importante variedad de intervenciones. El chequeo de interacciones en distintas bases de datos es recomendable ya que pueden ocasionar reacciones adversas a medicamentos

INTRODUCTION: The prescription of antiretroviral treatment (ART) that contains pharmacokinetic enhancers such as ritonavir and cobicistat is frequent. The objective of this stdy was to analyze the potential interactions of ART that include these molecules in their formulation with the patient's home medication, as well as the clinical management of those potentially serious. METHODS: Prospective study conducted in the pharmacy care clinic of a third level hospital between January and December of 2018. Those HIV+patients with an ART containing cobicistat or ritonavir were included in the study. Potential interactions between ART and concomitant medication were analysed in three databases (Micromedex(R), Drugs.com and Liverpool), the interventions carried out were detailed, and adverse drug reactions analysed. RESULTS: 968 patients were included with a total of 2,148 prescriptions (274 different medications). A total of 86 interventions were performed regarding potential interactions in patients. The most frequent were substitutions of corticoid treatments, treatment suspensions and closer monitoring of treatments. A total of possible adverse drug reactions were analysed. The degree of agreement in the severity classification of the interactions for cobicistat and ritonavir was good among the three databases. It was remarkable Micromedex(R) as the most complete because it has more registered medications. CONCLUSIÓN: The interactions between ART with pharmacokinetic enhancers in its composition and concomitant medication is frequent and requires a significant variety of interventions. The check of interactions in different databases is recommended since they can cause adverse drug reactions

Patient-Reported Outcomes in an Observational Cohort of HIV-1-Infected Adults on Darunavir/Cobicistat-Based Regimens: Beyond Viral Suppression.

OBJECTIVE: This prospective, multicenter, non-interventional cohort study enrolling human immunodeficiency virus (HIV)-1-infected, virally suppressed adult outpatients in Italy aimed to describe results obtained from patient-reported outcome questionnaires regarding treatment satisfaction and symptom perceptions in HIV-1-positive patients who switched to cobicistat-boosted darunavir antiretroviral regimens, coming from ritonavir-boosted protease inhibitors. METHODS: Patients entered this study between June 2016 and February 2017, once their treating physician had considered them eligible for cobicistat-boosted darunavir-based treatment as per clinical practice. Patients' satisfaction regarding regimen and current symptom burdens were assessed using two previously validated, patient-reported outcome questionnaires: HIV Treatment Satisfaction Questionnaire (HIV-TSQ) and HIV Symptoms Distress Module (HIV-SDM). These questionnaires were administered at prespecified time-points: enrollment (Visit 1), 4-8 weeks later (Visit 2), and 48 ± 6 weeks after study enrollment (Visit 4). Data of patient-reported outcome total scores for both questionnaires are presented as median with 25th-75th percentiles. Questionnaires scores were analyzed overall and stratified by gender when applicable. A p value of less than 0.05 was considered statistically significant. A sensitivity analysis was conducted to evaluate the role of lost to follow-up, using the "last observation carried forward" method. RESULTS: A total of 348 patients were enrolled in this study; 296 patients (208 male and 88 female) provided both evaluable HIV-TSQ and HIV-SDM at enrollment and at 4-8 weeks, while 250 patients (174 male and 76 female) provided questionnaire data at enrollment and at 48 ± 6 weeks. The total scores of HIV-TSQ showed improvements in patient satisfaction in the overall population both at Visit 2 and Visit 4 (p < 0.001, sign test) and also when stratified by gender throughout the study period. In addition, the overall burden of symptoms, as shown by the HIV-SDM scores, decreased. CONCLUSIONS: Switching to a cobicistat-boosted darunavir-based therapy led to overall increased patient satisfaction and reduced symptom burden when compared with previous regimens. The use of patient-reported outcomes in clinical daily practice could provide a useful tool towards achieving guideline goals to achieve "fourth 90", having 90% of virally suppressed patients with a good health-related quality of life.

Development of Darunavir proliposome powder for oral delivery by using Box-Bhenken design.

The aim of this study is to develop Darunavir (DRV) proliposome powder for oral delivery. Darunavir-loaded oral proliposome powder (OPP) was prepared by a solvent evaporation technique with varying independent variables at three different levels. Based on different levels, proliposome powder formulation was optimized by using Box-Behnken design. The formulations were analyzed for its size distribution, entrapment efficiency, and surface morphology. Optimized proliposome batch A was evaluated for physical parameter, morphological parameters, entrapment efficiency, followed by in vitro, ex vivo, and in vivo studies. Oral proliposome powder showed good micromeritic properties with angle of repose was less than 30°, Carr's index and Hausner's ratio were also less than 21 and 1.25, respectively. The mean size of the vesicles was in the range of 180-290 nm. The assay and entrapment efficiency of pro-liposome powder formulations were 79.00 ± 0.2 and 93.46 ± 0.2%, respectively. In vitro release of DRV proliposome powder was 78.17 ± 0.1% after 24 h which shows good release from the vesicle of proliposome. Ex vivo permeation study shows 58.11% enhancement which shows good permeation. The optimize batch A of proliposome powder indicated 50% enhancement in the relative bioavailability as compared to the DRV suspension. The results showed that proliposome powder containing DRV can efficiently deliver in to the blood stream. This drug delivery system has been designed as a novel platform for potential oral delivery of drugs having poor water solubility and high first-pass metabolism.

Pyromellitic dianhydride crosslinked soluble cyclodextrin polymers: Synthesis, lopinavir release from sub-micron sized particles and anti-HIV-1 activity.

We report the synthesis of water soluble cyclodextrin (CD) polymers prepared by crosslinking pyromellitic dianhydride (PMDA) with two CD derivatives (methyl-ß-CD - MßCD and (2-hydroxy)propyl-ß-CD - HPßCD) and their evaluation as functional sub-micron sized carriers in the development of antiretroviral drug delivery systems. Using the protease inhibitor lopinavir (LPV) as model drug, LPV loaded CD polymers (pHPßCD and pMßCD) were prepared and fully characterized. The physicochemical characterization and in vitro drug release confirmed the successful synthesis of pHPßCD and pMßCD, the formation of sub-micron sized particles and a 12-14 fold increase in LPV solubility. Cytotoxicity assays indicated that both pHPßCD and pMßCD were able to improve the safety profile of LPV while the viral infectivity assay revealed a concentration independent anti-HIV-1 effect for both pHPßCD and pMßCD with a maximum percentage inhibition (MPI) of 79 and 91% respectively. After LPV loading, the antiviral profile of pHPßCD was reversed to the sigmoidal dose-response profile of LPV, while pMßCD maintained its dose-independent profile followed by a LPV mediated increase in viral inhibition. Overall, both pHPßCD and pMßCD demonstrated anti-HIV-1 activity, while drug loaded pMßCD indicated its potential as functional sub-micron sized drug delivery polymers for achieving synergistic anti-HIV activity.