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Integrase strand transfer inhibitors (INSTI) are associated with neuropsychiatric adverse events (NPAEs). The aim of this study was to evaluate improvements in NPAEs after switching an INSTI-based regimen to darunavir/cobicistat (DRV/c) or doravirine (DOR). Methods: A prospective cohort study was conducted to evaluate the reversibility of NPAEs via the Patient Health Questionnaire (PHQ-9), the Insomnia Severity Index (ISI), and the Hospital Anxiety and Depression Scale (HADS-A and D) in patients who started antiretroviral therapy with dolutegravir (DTG) or bictegravir (BIC). These patients were switched to DRV/c or DOR. Scales were compared at the moment of the switch and 12 weeks later. Results: We included 1153 treatment-naïve men, 676 (58.7%) with BIC and 477 (41.3%) with DTG. A total of 32 (2.7%) experienced NPAEs that led to discontinuation. Insomnia was found in 20 patients; depression via PHQ-9 in 21 patients, via HADS-D in 5 patients, and anxiety via HADS-A in 12 patients. All of them were evaluated by a psychiatrist at the moment of the symptoms; 7 (21.8%) started psychotropic drugs. After 12 weeks of follow-up, PHQ-9, ISI, HADS-A, and HADS-D decreased, with a p-value ≤ 0.05. Conclusions: NPAEs seem to improve after switching to a DRV/c- or DOR-based regimen after the first 4 and 12 weeks.
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Cobicistat , Darunavir , Infecções por HIV , Piridonas , Humanos , Masculino , Darunavir/efeitos adversos , Darunavir/uso terapêutico , Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Cobicistat/efeitos adversos , Cobicistat/uso terapêutico , Cobicistat/administração & dosagem , Piridonas/efeitos adversos , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Inibidores de Integrase de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Substituição de Medicamentos/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Piperazinas/efeitos adversos , TriazóisRESUMO
OBJECTIVE: This study aimed to evaluate the role of pepsin inhibitors in the inflammatory response and their effects on laryngeal mucosal integrity during gastroesophageal reflux (GERD) under in vivo conditions. METHODS: A surgical model of GERD was used, in which mice were treated with pepstatin (0.3 mg/kg) or darunavir (8.6 mg/kg) for 3 days. On the third day after the experimental protocol, the laryngeal samples were collected to assess the severity of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and paracellular epithelial permeability to fluorescein). RESULTS: The surgical GERD model was reproduced. It showed features of inflammation and loss of barrier function in the laryngeal mucosa. Pepstatin and darunavir administration suppressed laryngeal inflammation and preserved laryngeal mucosal integrity. CONCLUSION: Pepsin inhibition by the administration of pepstatin and darunavir improved inflammation and protected the laryngeal mucosa in a mouse experimental model of GERD. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3080-3085, 2024.
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Modelos Animais de Doenças , Refluxo Gastroesofágico , Pepsina A , Animais , Camundongos , Refluxo Gastroesofágico/tratamento farmacológico , Pepstatinas/farmacologia , Mucosa Laríngea/efeitos dos fármacos , Mucosa Laríngea/patologia , Masculino , Inflamação/tratamento farmacológico , Inflamação/prevenção & controleRESUMO
Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 µg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.
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OBJECTIVES: To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. METHODS: We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/µL, viral load > 100 000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. RESULTS: We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. CONCLUSION: The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.
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Fármacos Anti-HIV , Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Carga ViralRESUMO
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)
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Candida albicans/imunologia , Inibidores da Protease de HIV/administração & dosagem , Fatores de Virulência/efeitos adversos , Darunavir/síntese química , Sulfato de Atazanavir/efeitos adversosRESUMO
Even though darunavir/ritonavir (DRV/r) has high potency and a greater genetic barrier, there are few studies on the long-term effectiveness of DRV/r-based salvage therapy in people living with HIV (PLWH) in low and middle-income countries. This retrospective cohort study, from São Paulo, Brazil, included ART-experienced PLWH aged ≥18 years with virological failure (VF) who had started DRV/r plus an optimized background regimen (OBR) between 2008 and 2012. The proportion of patients with viral load (VL) <50 copies/mL, the improved mean CD4+ T cell count and the factors associated with VF during the 144-week follow-up were assessed. The study included 173 patients with the following characteristics [median (interquartile range)]: age 48 (42 -53) years; CD4+ T cell count, 229 (89 -376) cells/mm3; VL, 4.26 (3.70 -4.74) log10; 6 (4 -7) previous regimens; and 100 (38 -156) months of VF. After 144 weeks, 129 (75%) patients had VL< 50 copies/mL and a mean increase in the CD4+ T cell count of 190 cells/mm3. VL>100,000 copies/mL and poor adherence were associated with VF. DRV/r plus an OBR showed high long-term virological suppression and immunological recovery. VL>100,000 copies/mL and poor adherence were associated with VF at 144 weeks.
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Terapia Antirretroviral de Alta Atividade , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Ritonavir/uso terapêutico , Terapia de Salvação , Adulto , Fármacos Anti-HIV/uso terapêutico , Brasil , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Sobreviventes de Longo Prazo ao HIV , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Estudos Retrospectivos , Resultado do Tratamento , Carga ViralRESUMO
Introduction. Cryptococcus species are pathogens commonly associated with cases of meningoencephalitis in individuals who are immunosuppressed due to AIDS.Aim. The aim was to evaluate the effects of the antiretroviral darunavir alone or associated with fluconazole, 5-flucytosine and amphotericin B against planktonic cells and biofilms of Cryptococcus species.Methodology. Susceptibility testing of darunavir and the common antifungals against 12 members of the Cryptococcus neoformans/Cryptococcus gattii species complex was evaluated by broth microdilution. The interaction between darunavir and antifungals against planktonic cells was tested by a checkerboard assay. The effects of darunavir against biofilm metabolic activity and biomass were evaluated by the XTT reduction assay and crystal violet staining, respectively.Results. Darunavir combined with amphotericin B showed a synergistic interaction against planktonic cells. No antagonistic interaction was observed between darunavir and the antifungals used. All Cryptococcus species strains were strong biofilm producers. Darunavir alone reduced biofilm metabolic activity and biomass when added during and after biofilm formation (P<0.05). The combination of darunavir with antifungals caused a significant reduction in biofilm metabolic activity and biomass when compared to darunavir alone (P<0.05).Conclusion. Darunavir presents antifungal activity against planktonic cells of Cryptococcus species and synergism with amphotericin B. In addition, darunavir led to reduced biofilm formation and showed activity against mature biofilms of Cryptococcus species. Activity of the antifungals against mature biofilms was enhanced in the presence of darunavir.
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Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Darunavir/farmacologia , Anfotericina B/farmacologia , Células Cultivadas , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana/métodos , Plâncton/microbiologiaRESUMO
OBJECTIVE: We evaluated the effectiveness of darunavir (DRV) treatment plus an optimized background regimen in 120 HIV-1 treatment-experienced patients. DESIGN: Retrospective cohort, multicenter study. METHODS: Adults >16 years with virological treatment failure starting therapy with a DRV-containing regimen were included. Effectiveness was evaluated as the percentage of patients with an undetectable HIV-1 RNA viral load (<50 and <200 copies/mL) after 48 weeks, and changes in CD4+ cell counts. We evaluated the risk factors associated with treatment failure. RESULTS: Of the cohort, 83 % were men with a median age of 45 years (interquartile range, IQR 40-51). They had experienced treatment for a median of 13 years (IQR 9-17) with a median of six previous regimens (IQR 4-7), all using protease inhibitors. After treatment, 82 % (95 % confidence interval, CI 74-88 %) of patients had an HIV-1 RNA viral load <200 copies/mL and 69 % (95 % CI 60-76 %) had <50 copies/mL. The CD4+ cell count increased by 378 cells/µL (IQR 252-559; P < 0.001 vs. baseline). Risk factors associated with poor outcome were age >40 years [odds ratio, OR 0.15 (95 % CI 0.10-0.78); P = 0.015], use of raltegravir in the regimen [OR 0.37 (95 % CI 0.10-0.97); P = 0.046], and baseline CD4+ cell count <200 cells/µL [OR 2.79 (95 % CI 1.11-6.97); P = 0.028]. CONCLUSION: In this Mexican cohort Darunavir was metabolically safe, well tolerated and achieved high rates of virological suppression in highly treatment-experienced patients infected with HIV-1.
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Darunavir is a synthetic non-peptidic protease inhibitor that has been shown to be extremely potent against wild-type HIV, and it is an important component of highly active antiretroviral treatment (HAART), which is considered as one of the most significant advances in the field of HIV therapy. However, there are some concerns about darunavir quality control. Darunavir shows pseudo-polymorphism: in different ambient conditions one pseudo-polymorphic form can change to another. This behavior of darunavir is problematic because the dosage form is exposed to different ambient conditions around the world, since HIV/AIDS is prevalent globally. Issues around differences in the solubility and effects that different forms of darunavir can cause are of concern, and a more stable form is preferable. Important investigations of darunavir such as dissolution behavior, polymorphism, stability and degradation studies, and the impact of that on the quality of the product are being conducted by our working group. A cure for HIV/AIDS remains a long-term commitment, and there is much yet to achieve. This article discusses, by a critical review of the literature, the impact of the use of darunavir in the treatment of HIV-infected patients, its physical-chemical properties, the analytical methods to determine it, and challenges that remain in order to ensure the quality and stability of darunavir.
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Inibidores da Protease de HIV , Sulfonamidas , Darunavir , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/análise , Inibidores da Protease de HIV/química , Humanos , Controle de Qualidade , Sulfonamidas/administração & dosagem , Sulfonamidas/análise , Sulfonamidas/químicaRESUMO
In this work, we investigated for the first time the conjugation of gluconolactone to a poly(ethylene oxide)-poly(propylene oxide) block copolymer by a microwave-assisted ring opening reaction. The glucosylated copolymer was obtained with high yield (90%). A conjugation extent of approximately 100% was achieved within 15 min. The modification reduced the critical micellar concentration and increased the size of the micelles. The agglutination of the modified polymeric micelles by a soluble lectin that binds glucose confirmed the recognizability of the modified nanocarrier. Finally, the solubilization of darunavir, an anti-HIV protease inhibitor, showed a sharp increase of the aqueous solubility from 91 microgram/mL to 14.2 and 18.9 mg/mL for 10% w/v pristine and glucosylated polymeric micelles, respectively.