HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway.

HIV-associated neurocognitive disorder (HAND) is prevalent in people living with HIV, despite the use of antiretroviral therapy (ART). Although several risk factors have been proposed to be related to HAND, substantial effort has been made to explore the neurotoxic effects of ART on HAND. HIV protease inhibitor (PI), an essential component of ART, has neurotoxicity in vivo and in vitro, which can contribute to the development of HAND. However, the pathogenesis of PI-associated neurotoxicity remains unclear. Here, we explored whether PI treatment is a potential pathogenic factor for HAND and elucidated its potential mechanisms. In our study, U87 cells were exposed to PIs, including lopinavir (LPV), ritonavir (RTV), darunavir, indinavir, and saquinavir at different concentrations, we found that LPV, LPV/RTV, and saquinavir attenuated autophagy in U87 cells, the results of Western blot showed that the expression of p62 dramatically was elevated and the level of LC3II/LC3I was decreased. Moreover, comparative transcriptomics revealed the involvement of the inflammatory response in the physiological activities of U87 cells exposed to LPV, with differential genes significantly enriched in the p38 MAPK signaling pathway. In the following study, we verified the results from RNA-sequence using the liquid chip technique, qRT-PCR, Elisa, and western blots, which suggested that LPV induced inflammatory response and the p38 MAPK pathway was involved in this process. Collectively, we demonstrated that PIs attenuated the involvement of astrocyte autophagy in inflammation via the p38 MAPK pathway, providing new insights into the mechanism of HAND.

Protease and gag diversity and drug resistance mutations among treatment-naive Mexican people living with HIV.

INTRODUCTION: In Mexico, HIV genotyping is performed in people living with HIV (PLWH) failing their first-line antiretroviral (ARV) regimen; it is not routinely done for all treatment-naive PLWH before ARV initiation. The first nationally representative survey published in 2016 reported that the prevalence of pretreatment drug mutations in treatment-naive Mexican PLWH was 15.5% to any antiretroviral drug and 10.6% to non-nucleoside reverse transcriptase inhibitors (NNRTIs) using conventional Sanger sequencing. Most reports in Mexico focus on HIV pol gene and nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI) drug resistance mutations (DRMs) prevalence, using Sanger sequencing, next-generation sequencing (NGS) or both. To our knowledge, NGS has not be used to detect pretreatment drug resistance mutations (DRMs) in the HIV protease (PR) gene and its substrate the Gag polyprotein. METHODS: Treatment-naive adult Mexican PLWH were recruited between 2016 and 2019. HIV Gag and protease sequences were obtained by NGS and DRMs were identified using the WHO surveillance drug resistance mutation (SDRM) list. RESULTS: One hundred PLWH attending a public national reference hospital were included. The median age was 28 years-old, and most were male. The median HIV viral load was 4.99 [4.39-5.40] log copies/mL and median CD4 cell count was 150 [68.0-355.78] cells/mm3. As expected, most sequences clustered with HIV-1 subtype B (97.9%). Major PI resistance mutations were detected: 8 (8.3%) of 96 patients at a detection threshold of 1% and 3 (3.1%) at a detection threshold of 20%. A total of 1184 mutations in Gag were detected, of which 51 have been associated with resistance to PI, most of them were detected at a threshold of 20%. Follow-up clinical data was available for 79 PLWH at 6 months post-ART initiation, seven PLWH failed their first ART regimen; however no major PI mutations were identified in these individuals at baseline. CONCLUSIONS: The frequency of DRM in the HIV protease was 7.3% at a detection threshold of 1% and 3.1% at a detection threshold of 20%. NGS-based HIV drug resistance genotyping provide improved detection of DRMs. Viral load was used to monitor ARV response and treatment failure was 8.9%.

In silico evaluation of atazanavir as a potential HIV main protease inhibitor and its comparison with new designed analogs.

Starting three decades ago and spreading rapidly around the world, acquired immunodeficiency syndrome (AIDS) is an infectious disease distinct from other contagious diseases by its unique ways of transmission. Over the past few decades, research into new drug compounds has been accompanied by extensive advances, and the design and manufacture of drugs that inhibit virus enzymes is one way to combat the AIDS virus. Since blocking enzyme activity can kill a pathogen or correct a metabolic imbalance, the design and use of enzyme inhibitors is a new approach against viruses. We carried out an in-depth analysis of the efficacy of atazanavir and its newly designed analogs as human immunodeficiency virus (HIV) protease inhibitors using molecular docking. The best-designed analogs were then compared with atazanavir by the molecular dynamics simulation. The most promising results were ultimately found based on the docking analysis for HIV protease. Several exhibited an estimated free binding energy lower than -9.45 kcal/mol, indicating better prediction results than the atazanavir. ATV7 inhibitor with antiviral action may be more beneficial for infected patients with HIV. Molecular dynamics analysis and binding energy also showed that the ATV7 drug had more inhibitory ability than the atazanavir drug.

Interacciones graves o potencialmente letales entre antirretrovirales y otros medicamentos / Severe or life-threatening interactions between antiretrovirals and non-HIV drugs

El tratamiento antirretroviral de gran actividad (TARGA) ha permitido un buen control de la infección por VIH, y por lo tanto la población afectada envejece progresivamente y la esperanza de vida va siendo parecida a la de la población general. Por otro lado, se sabe que la infección por VIH predispone, incluso en pacientes con TARGA efectivo, a un mayor riesgo cardiovascular y a una mayor incidencia de algunas neoplasias. Por todo ello, la mayor parte de pacientes infectados por el VIH reciben diversos medicamentos (pautados por el facultativo o autoadministrados) además de los antirretrovirales. Este artículo revisa las interacciones que pueden provocar daños importantes o incluso poner en peligro la vida de los pacientes y que los clínicos —sobre todo los que no manejan directamente pacientes infectados por el VIH— tendrían que conocer. También se revisan las implicaciones de las interacciones entre antirretrovirales y otros fármacos en situaciones especiales, como la administración concomitante de citostáticos, inmuno-supresores utilizados en el trasplante de órganos sólidos o pacientes que reciben los nuevos tratamientos para el virus de la hepatitis C. En general, las pautas con 2 inhibidores nucleós(t)idos de la transcriptasa inversa con raltegravir o dolutegravir son las que tienen menos potencial de interacciones clínicamente significativas (AU)

Highly active antiretroviral therapy has helped to improved control of the HIV infection, and has led to a progressively older population with the infection having a life expectancy quite similar to that of the general population. On the other hand, it is also known that HIV infection, even in patients with undetectable viral loads and good immunity, carries an increased cardiovascular risk, as well as an increased incidence of certain cancers. Therefore, the majority of HIV-infected patients receive several drugs (either prescribed by the physician or self-administered) combined with antiretrovirals. This article reviews the interactions between antiretrovirals and other drugs that can cause significant damage to patients, or even be life-threatening and of whom clinicians, especially those not directly treating HIV-infected patients, should be aware. A review is also presented on the implications of interactions between antiretrovirals and other drugs in special situations, such as the co-administration with cytostatics, immunesuppressants used in solid organ transplantation, or patients receiving new treatments for hepatitis C. Generally, combinations with two nucleos(t)ide reverse transcriptase inhibitors and raltegravir (or in the near future, dolutegravir) are those with less potential for clinically significant interactions (AU)

Evolución de la fibrosis hepática en reclusos coinfectados por VIH y VHC que inician tratamiento con inhibidores de la proteasa potenciados / The progression of liver fibrosis in prison inmates co-infected by HIV and HCV who started on boosted protease inhibitor therapy

Objetivos: Analizar la evolución de la fibrosis hepática medida por elastografía y pruebas bioquímicas en reclusos coinfectados por VIH y VHC que han iniciado tratamiento antirretroviral con lopinavir/ritonavir u otros inhibidores de la proteasa potenciados con ritonavir. Métodos: Estudio prospectivo, observacional y multicéntrico. Se comprobó durante 48 semanas la evolución de la fibrosis hepática medida mediante elastografía de transición (FibroScan) y pruebas bioquímicas en población penitenciaria española coinfectada por VIH y VHC. Resultados: De los 94 pacientes incluidos, 54 (57,4%) fueron seguidos durante 48 semanas. En la semana 48, no hubo cambios significativos en el grado de fibrosis medida mediante FibroScan (8,1 Kpa vs 8,3; p=0.20) o índice de FORNS (5,6 vs 5,1; p=0,50), aunque sí con el índice APRI (0.7 vs 0.6; p=0.05) y el índice FIB-4 (p=0,02). Cuando la medición se realizó en función del grado de fibrosis basal, se observó que el tratamiento redujo el porcentaje de pacientes con fibrosis basal de grado 3/4 (50% vs 15%; p=0,001), pero no hubo cambios en los que ya tenían basalmente grado 4 (20,4% vs 20,4%). Conclusión: Los reclusos coinfectados por VIH y VHC que inician tratamiento antirretroviral con lopinavir/ritonavir muestran una estabilización de la fibrosis hepática medida con FibroScan® tras un año de seguimiento. En conjunto, el tratamiento mejoró la fibrosis cuando la referencia de medición fue el índice APRI y el FIB-4, pero no con el índice FORNS o la elastografía (AU)

Objectives: To analyse the progression of liver fibrosis as measured by elastography and biochemical testing in prison inmates co-infected by HIV and HCVwho started on ritonavir-boosted protease inhibitor (PI) therapy. Methods: A prospective, observational and multi-centre study. The progression of liver fibrosis as measured by transient elastography (FibroScan) and biochemical testing was monitored for 48 weeks in a Spanish prison population co-infected with HIV and HCV. Results: Of the 94 patients included, 54 (57.4%) were followed-up for 48 weeks. At week 48, no significant changes were seen in the grade of fibrosis measured using FibroScan (8.1 kPa vs. 8.3 kPa; p=0.20) or the Forns index (5.6 vs. 5.1; p=0.50), although significant changes were detected using the APRI (0.7 vs. 0.6; p=0.05) and the FIB-4 indexes (p= 0.02).When measurement was done compared to baseline fibrosis, it was seen that therapy reduced the percentage of patients with fibrosis ≥3 but <4 (50% vs. 15%; p=0.001), but no change was seen in those found to have grade 4 fibrosis at baseline (20.4% vs. 20.4%). Conclusion: The inmates co-infected with HIV and HCV who were started on antiretroviral therapy with the boosted protease inhibitor (PI) showed stasterilizationbilisation of the liver fibrosis as measured with FibroScan after one year of follow-up. Overall, the therapy improved fibrosis when measured using the APRI or FIB-4 indexes, but not when using the Forns index or elastography (AU)

Prevalence of HIV-1 drug resistance mutations among Spanish prison inmates.

The aim of this cross-sectional study was to analyse the prevalence of HIV-1 drug-resistance mutations among HIV-1-infected prison inmates in Spain. Treatment-naive and treatment-experienced patients with an HIV RNA viral load of >/=2,000 copies/ml were included. To ensure that the study population was representative of the entire HIV-infected Spanish inmate population, a two-stage conglomerate for selection of the sample was used. In the first stage, 15 prisons were randomly selected, and in the second stage, 38 patients (30 treatment-experienced and 8 treatment-naive) per centre were randomly selected. Genotyping was performed by automatic sequencing. Resistance testing was performed on viral strains from 184 inmates from 12 prisons. Valid sequences were obtained from 133 inmates (90 treatment-experienced and 43 treatment-naive inmates). Most (92.5%) were men and had acquired HIV infection by intravenous drug use (91%); their mean age was 35 years. One or more key resistance mutations were detected in 5 (11.6%) treatment-naive and in 35 (38.6%) treatment-experienced patients. Among treatment-naive and treatment-experienced patients, resistance to nucleoside reverse transcriptase inhibitors was found in 3 (6.9%) and in 20 (22.2%) patients, respectively, resistance to non-nucleoside reverse transcriptase inhibitors in 3 (6.9%) and in 21 (23.3%) patients, and resistance to protease inhibitors in 3 (6.9%) and in 14 (15.5%) patients. Multidrug resistance was detected in 1 of the 43 (2.3%) treatment-naive patients. These findings support the use of resistance testing in HIV-infected inmates who must begin antiretroviral therapy, given the high rate of primary resistance to drugs frequently included in the initial treatment regimens.