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2.
Arch Virol ; 165(1): 115-125, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31741096

RESUMEN

The latest class of antiretrovirals (ARVs), including integrase strand transfer inhibitors (INSTIs), has been demonstrated to be effective for antiretroviral therapy (ART). Despite all the distinguishing characteristics of these drugs, including a high genetic barrier to resistance and lower toxicity than other ARVs, unfortunately, INSTI drug resistance mutations (DRMs) have occasionally been observed. The aim of this study was to investigate the presence of DRMs associated with INSTIs among treatment-experienced HIV-1-infected patients. From June 2012 to December 2018, a total of 655 treatment-experienced HIV-1-infected patients enrolled in this cross-sectional survey. Following amplification and sequencing of the HIV-1 integrase region of the pol gene, DRM and phylogenetic analysis were successfully carried out on the plasma samples of patients who had a viral load over 1,000 IU/ml after at least 6 months of ART. Out of the 655 patients evaluated, 62 (9.5%) had a viral load higher than 1,000 IU/ml after at least 6 months of ART. Phylogenetic analysis showed that all of the 62 HIV-1 patients experiencing treatment failure were infected with CRF35_AD, and one of these patients (1.6%) was infected with HIV-1 variants with DRMs. The DRMs that were identified belonged to the INSTI class, including E138K, G140A, S147G, and Q148R. This survey shows that DRMs belonging to the INSTI class were detected in an Iranian HIV patient who has experienced treatment failure. Therefore, regarding the presence of DRMs to INSTIs in ART-experienced patients, it seems better to perform drug resistance mutation testing in HIV patients experiencing treatment failure before changing the ART regimen and prescribing this class of medication.


Asunto(s)
Farmacorresistencia Viral , Infecciones por VIH/virología , Integrasa de VIH/genética , VIH-1/clasificación , Mutación , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios Transversales , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/enzimología , VIH-1/genética , Humanos , Lactante , Irán , Masculino , Persona de Mediana Edad , Filogenia , Análisis de Secuencia de ARN , Adulto Joven
4.
Pol J Microbiol ; 68(3): 317-322, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31880877

RESUMEN

Mutations associated with the pol and the S gene can emerge as a consequence of the high replication capacity and proofreading deficiencies of hepatitis B virus during replication. The current study was constructed to evaluate primary, partial, compensatory and the escape mutations in chronic hepatitis B patients in Northern Cyprus. The samples of HBsAg positive treatment naïve 100 patients were involved in this study. HBV pol gene region was sequenced, amplified and HBV pol/S gene mutations were determined. The samples of thirty-two patients were excluded because of their low viral load (HBV < 1000 iu/ml). Among the sequenced 68 samples, there was a partial mutation (1.5%) and 36.7% displayed a resistance profile to lamivudine, adevofir, and telbivudine. Immune response escape, vaccine escape, HBIg and diagnosis escape mutations were determined in 24%, 10%, 6%, and 4% samples of the patients, respectively. Additionally, there were six different combined mutations. These data underscored that there is no concern for primary mutations in Northern Cyprus, however, we have identified a compensatory mutation (rtV173M) that may have primary mutation characteristics by combining with other mutation patterns. Additionally, HBsAg escape mutants demonstrated that detection of the S gene together with the pol gene mutations might be beneficial and important to monitor the surveillance of S variants.Mutations associated with the pol and the S gene can emerge as a consequence of the high replication capacity and proofreading deficiencies of hepatitis B virus during replication. The current study was constructed to evaluate primary, partial, compensatory and the escape mutations in chronic hepatitis B patients in Northern Cyprus. The samples of HBsAg positive treatment naïve 100 patients were involved in this study. HBV pol gene region was sequenced, amplified and HBV pol/S gene mutations were determined. The samples of thirty-two patients were excluded because of their low viral load (HBV < 1000 iu/ml). Among the sequenced 68 samples, there was a partial mutation (1.5%) and 36.7% displayed a resistance profile to lamivudine, adevofir, and telbivudine. Immune response escape, vaccine escape, HBIg and diagnosis escape mutations were determined in 24%, 10%, 6%, and 4% samples of the patients, respectively. Additionally, there were six different combined mutations. These data underscored that there is no concern for primary mutations in Northern Cyprus, however, we have identified a compensatory mutation (rtV173M) that may have primary mutation characteristics by combining with other mutation patterns. Additionally, HBsAg escape mutants demonstrated that detection of the S gene together with the pol gene mutations might be beneficial and important to monitor the surveillance of S variants.


Asunto(s)
Evolución Molecular , Productos del Gen pol/genética , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Adulto , Anciano , Antivirales/farmacología , Chipre , Farmacorresistencia Viral , Femenino , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Lamivudine/farmacología , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven
5.
Comput Biol Chem ; 83: 107154, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31751885

RESUMEN

Hepatitis C virus (HCV) NS3/4A protease is an attractive target for the development of antiviral therapy. However, the evolution of antiviral drug resistance is a major problem for treatment of HCV infected patients. Understanding of drug-resistance mechanisms at molecular level is therefore very important for the guidance of further design of antiviral drugs with high efficiency and specificity. Paritaprevir is a potent inhibitor against HCV NS3/4A protease genotype 1a. Unfortunately, this compound is highly susceptible to the substitution at D168 in the protease. In this work, molecular dynamics simulations of paritaprevir complexed with wild-type (WT) and two mutated strains (D168 N and D168Y) were carried out. Due to such mutations, the inhibitor-protein hydrogen bonding between them was weakened and the salt-bridge network among residues R123, R155 and D168 responsible for inhibitor binding was disrupted. Moreover, the per-residue free energy decomposition suggested that the main contributions from key residues such as Q80, V132, K136, G137 and R155 were lost in the D168 N/Y mutations. These lead to a lower binding affinity of paritaprevir for D168 N/Y variants of the HCV NS3/4A protease, consistent with the experimental data. This detailed information could be useful for further design of high potency anti-HCV NS3/4A inhibitors.


Asunto(s)
Antivirales/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Simulación de Dinámica Molecular , Mutación , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Farmacorresistencia Viral/efectos de los fármacos , Enlaces de Hidrógeno , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Compuestos Macrocíclicos/química , Termodinámica , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo
6.
Pan Afr Med J ; 33: 222, 2019.
Artículo en Francés | MEDLINE | ID: mdl-31692792

RESUMEN

Introduction: HIV-2, endemic in West Africa, has a natural resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) which makes it difficult to treat it in developing countries. Methods: We conducted a descriptive, longitudinal, prospective study over the period November 2005-June 2017. Virologic failure has been defined as any viral load greater than 50 copies/ml after 6 months of ARV treatment administered twice. Assays for detecting drug-resistance mutations was performed in the protease-coding region and in the reverse transcriptase-coding region. Results: Data from a total of 110 patients were collected. The patients had a median age of 46 years (ranging from 18 to 67) with a sex-ratio F/M of 2.54. At inclusion, viral load could be assessed in 44% of cases with a median of 935cp/ml (ranging from 17 to 144038). Antiretroviral regimen consisted of a combination of 2 NRTIs and 1IP in 94% of cases. The median follow-up was 1200 days (ranging from 1 to 3840); 94 then 76 patients completed their 12-month and 24-month assessments respectively. At 24-month follow-up, 39 patients had virologic failure, reflecting a prevalence of 39% estimated at 33% at 12-month follow-up and at 11% at 24-month follow-up; NRTIs resistance was observed in 45% of patients, IP resistance in 41% of patients while multi-NRTIs resistance and multi-IP resistance in 30% of patients. Conclusion: Currently, there is an urgent need to make available the new therapeutic classes of ARV for second line ART for patients living with HIV-2 with therapeutic failure in resource-limited settings.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , VIH-2/aislamiento & purificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adolescente , Adulto , Anciano , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-2/efectos de los fármacos , VIH-2/genética , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de la Transcriptasa Inversa/farmacología , Senegal/epidemiología , Carga Viral , Adulto Joven
7.
Mikrobiyol Bul ; 53(4): 374-387, 2019 Oct.
Artículo en Turco | MEDLINE | ID: mdl-31709935

RESUMEN

Human immunodeficiency virus (HIV) comprises two genotypes, namely HIV-1 (group M, N, O and P) and HIV-2 (group A to H), which differ in their envelope glycoproteins and other antigenic epitopes despite their morphological and biological resemblance.Group M of HIV-1 responsible for 95% of HIV infections worldwide is composed of nine subgroups. In addition to subgroups, group M contains also two recombinant forms, known as circulating recombinant form (CRF) and unique recombinant form (URF). The first case of HIV/acquired immun deficiency virus (AIDS) in Turkey was reported in 1985 and the current number of cases reached a total of 18.557 including 1736 with AIDS based upon the surveillance data of Ministry of Health between October 1985 and November 2018. The aim of this study was to determine the prevalence of HIV-1 strains isolated from HIV positive autopsy cases detected by HIV polymerase chain reaction (PCR) and determine drug resistance. Twenty eight cases [17 males, 11 female: age ranged between 3 months and 66 years (median: 35 years)] found to be HIV positive among the autopsy cases sent for HIV1 PCR study and serological screening between 2011-2017 were recruited in the study. For identification of subtypes in HIV-1 isolates, most-preferred analysis tool was used [HIVdb Stanford University Genotypic Resistance Interpretation Algorithm (www.hivdb.stanford.edu)]. Phylogenetic tree was made according to direct sequencing of HIV-1 reverse transcriptase (pol) region and phylogenetic analysis was evaluated in 23 cases. Los Alamos National Laboratory were trimmed from full-length genomes. Phylogenetic analysis of the 870 base pair of the pol gene region was performed using CLC Sequence Viewer v8.0 (Qiagen Aarhus A/S, www.qiagenbioinformatics.com) software. The phylogenetic tree was obtained according to the neighbor-joining method and the Jukes-Cantor nucleotide distance scale and bootstrap value was set at 1000. In our study, subtype B was found to be most frequent type (39.3%; 11/28). Subtype A (17.9%; 5/28), CRF02_AG (14.3%; 4/28), subtype C (10.7%; 3/28), B+CRF02_AG recombinant (3.6%; 1/28), CRF01_AE (3.6%; 1/28), subtype D (3.6%; 1/28), as well as subtype F (3.6%; 1/28) and subtype G (3.6%; 1/28) strains were also detected in the circulation. Analysis of our results showed that 32.1% (9/28) of the samples exhibited resistance mutations. Detected mutations were as follows: M41L, T215C, K65R, M184V, responsible for nucleoside reverse transcriptase inhibitor (NRTI) resistance; K103N, Y181C, G190A, responsible for non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance; D30N, M46I, responsible for protease inhibitor (PI) resistance. NRTI, NNRTI and PI mutation rates in the samples were found as 21.4%, 7.1% and 3.6%, respectively. Although number of samples analyzed in our study is low, we can propose that they resemble the strains circulating in Turkey. The results of our study; although the subtype B is still dominant in our country, it supports other studies reporting that there are non-B subtypes and an increase in CRF rates in recent years. Phylogenetic analysis is widely regarded as the gold standard technique to determine the subtypes of HIV-1. Molecular epidemiologic studies related to HIV may be important in monitoring HIV subtype patterns and spreading pathways in that country. As a result; the opportunity to collect postmortem HIV sequences in a database appears to have occurred, and as this database expands, its usability is available. Therefore, it is thought that HIV subtypes and mutation information may be useful.


Asunto(s)
Infecciones por VIH , VIH-1 , Epidemiología Molecular , Adolescente , Adulto , Anciano , Antivirales/farmacología , Autopsia , Niño , Preescolar , Farmacorresistencia Viral , Femenino , Genotipo , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/efectos de los fármacos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Filogenia , Turquia/epidemiología
8.
BMC Infect Dis ; 19(1): 875, 2019 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-31640596

RESUMEN

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana. METHODS: This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis. RESULTS: Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations - K10Q and R70Q - were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments. CONCLUSION: Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.


Asunto(s)
Hepacivirus/genética , Hepatitis C/virología , Mutación , Filogenia , Adulto , Antivirales/uso terapéutico , Botswana , Carcinoma Hepatocelular/virología , Estudios Transversales , Farmacorresistencia Viral , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/aislamiento & purificación , Hepatitis C/tratamiento farmacológico , Humanos , Interferón-alfa/uso terapéutico , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Retrospectivos , Ribavirina/uso terapéutico
9.
Medicine (Baltimore) ; 98(43): e17585, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31651864

RESUMEN

This study sought to examine the human immunodeficiency virus type 1 (HIV-1) genetic diversity on drug resistance among men who have sex with men (MSM) with virologic failure in antiretroviral therapy (ART), and investigate linking-associated factors for genetic transmission networks.Seven hundred and thirty-four HIV-positive MSM with virologic failure in ART were recruited into our study from 2011 to 2017. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The drug resistance mutations were determined using the Stanford University HIV Drug Resistance Database. The genetic transmission networks were analyzed for CRF01_AE and CRF07_BC sequences by the genetic distance-based method.Of 734 subjects, 372 (50.68%) showed drug resistance, in which CRF01_AE and CRF07_BC were the predominating subtypes. Drug resistance more frequently occurred in non-nucleoside reverse transcriptase inhibitors (NNRTIs) treatment (48.64%), and followed by nucleoside reverse transcriptase inhibitors (NRTIs) (36.51%) and PIs (4.03%). The most common drug resistance-associated mutations in protease inhibitors (PIs), NRTIs and NNRTIs were K20I/R, M184V/I and K103N/KN, respectively. For 283CRF01_AE sequences, 64 (22.61%) fell into clusters at a genetic distance of 0.011, resulting in 17 clusters ranging in size from 2 to 16 individuals. For 230 CRF07_BC sequences, 66 (28.69%) were connected to at least one other sequence with 0.005 genetic distances, resulting in 8 clusters ranging in size from 2 to 52 individuals. Individuals who showed drug resistance to ART were less likely to fall into clusters than those who did not. The genetic linkage was robust by the exclusion of sites associated with drug resistance.CRF01_AE and CRF07_BC were the main strains among MSM with virologic failure in ART, and the drug resistance more frequently occurred in NNRTIs, followed by NRTIs and PIs. Genetic transmission networks revealed a complexity of transmission pattern, suggesting early-diagnosis and in-time intervention among MSM.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Inhibidores de la Transcriptasa Inversa/efectos adversos , Adolescente , Adulto , China , Homosexualidad Masculina , Humanos , Masculino , Minorías Sexuales y de Género/estadística & datos numéricos , Insuficiencia del Tratamiento , Adulto Joven
10.
MMWR Morb Mortal Wkly Rep ; 68(40): 880-884, 2019 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-31600182

RESUMEN

During May 19-September 28, 2019,* low levels of influenza activity were reported in the United States, with cocirculation of influenza A and influenza B viruses. In the Southern Hemisphere seasonal influenza viruses circulated widely, with influenza A(H3) predominating in many regions; however, influenza A(H1N1)pdm09 and influenza B viruses were predominant in some countries. In late September, the World Health Organization (WHO) recommended components for the 2020 Southern Hemisphere influenza vaccine and included an update to the A(H3N2) and B/Victoria-lineage components. Annual influenza vaccination is the best means for preventing influenza illness and its complications, and vaccination before influenza activity increases is optimal. Health care providers should recommend vaccination for all persons aged ≥6 months who do not have contraindications to vaccination (1).


Asunto(s)
Salud Global/estadística & datos numéricos , Vacunas contra la Influenza/química , Gripe Humana/epidemiología , Vigilancia de la Población , Farmacorresistencia Viral , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza B/efectos de los fármacos , Virus de la Influenza B/genética , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/virología , Estaciones del Año , Estados Unidos/epidemiología
11.
Arch Virol ; 164(12): 3081-3087, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31576459

RESUMEN

Owing to consistent genetic mutation and recombination, various escape mutants and/or drug-resistant mutants of human immunodeficiency virus (HIV-1) are now emerging worldwide. Therefore, an understanding of the genetic characteristics of prevailing strains, particularly with regard to drug-resistance-associated substitutions, is essential for devising and implementing treatments and disease control interventions in endemic settings such as Pakistan. We processed a total of 130 plasma samples originating from HIV-treatment centers in selected districts of Punjab province, Pakistan. The samples were first screened using an HIV-1 Ag/Ab Combo test followed by amplification of the pol gene (1084 bp) from samples that were positive either for the antigen or for both the antigen and antibodies simultaneously. Screening revealed that a total of 45 samples were positive (34.62%; 95% CI: 26.99-43.13) for either antigen or both antigen and antibodies (n = 18, 40%; 95% CI: 27.02-54.55) or for antibodies alone (n = 27, 60%; 95% CI: 45.45-72.98). A largest number of positive samples was from the district of Lahore (n = 19/43, 44.18%; 95% CI: 30.44-58.9) followed by Faisalabad (n= 12/36, 33.33%; 95% CI: 20.21-49.66), Gujranwala (n = 05/23, 21.7%; 95% CI: 9.66-41.9) and Sargodha (n = 09/28, 32.1%; 95% CI: 17.93-50.66). The probability of occurrence of HIV infection was significantly associated with individuals having a history of injecting drug use (68.08%; OR = 11.15; 95% CI: 53.84-79.61, p = 0.0001). Phylogenetic analysis based on the pol gene showed that the sequences from this study clustered into three distinct clades representing recombinant form 02_AG (n = 14, 77.0%; 95% CI: 54.79-91.00), and subtypes A (n = 2, 11.1%; 95% CI: 3.1-32.8) and G (n = 2, 11.1%; 95% CI: 3.1-32.8). Although we screened 18 samples for drug-resistance-associated mutations, except for an accessory mutation (M46K) in the protease (PR) region in one subject, we found a lack of drug-resistance-associated substitutions in the PR region. On the other hand, we found two subjects (2/18) carrying a resistance-associated mutation (V106I) conferring a low level of resistance against non-nucleoside reverse transcriptase inhibitors. The present study shows that multiple subtypes of HIV-1 are present in the affected population. Continuous disease surveillance coupled with evaluation of drug resistance at higher resolution should be done in future studies.


Asunto(s)
Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/aislamiento & purificación , Adulto , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Femenino , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pakistán/epidemiología , Filogenia , Adulto Joven , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética
12.
Expert Opin Drug Metab Toxicol ; 15(10): 813-829, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31556749

RESUMEN

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy against HIV-1 infections. Here, we provide a comprehensive overview of approved and emerging NNRTIs. Areas covered: This review covers the latest trend of NNRTIs regarding their pharmacodynamics, pharmacokinetics, mechanisms of drug action, drug resistance as well as new applications such as two-drug regimens and long-acting formulations. Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. The latter three compounds with favorable pharmacodynamic profiles and minimal adverse effects are often combined with one integrase inhibitor or two NRTIs in once-daily fixed-dose tablets. NNRTI-anchored regimens have been approved as initial therapies in treatment-naïve patients (efficacy: 72% to 86%) or maintaining therapies in virologically-suppressed patients (efficacy: 91% to 95%). Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Terapia Antirretroviral Altamente Activa/métodos , Preparaciones de Acción Retardada , Farmacorresistencia Viral , VIH-1/efectos de los fármacos , Humanos , Cumplimiento de la Medicación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética
13.
BMC Infect Dis ; 19(Suppl 1): 787, 2019 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-31526373

RESUMEN

BACKGROUND: South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. METHODS: Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. RESULTS: Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. CONCLUSIONS: These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/inmunología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Lactancia Materna , Recuento de Linfocito CD4 , Preescolar , Estudios Transversales , Pruebas con Sangre Seca , Femenino , Infecciones por VIH/diagnóstico , Seropositividad para VIH , VIH-1/aislamiento & purificación , Humanos , Lactante , Recién Nacido , Lactancia , Madres , Periodo Posparto , Embarazo , Prevalencia , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Autoinforme , Sudáfrica/epidemiología
14.
Molecules ; 24(18)2019 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-31489889

RESUMEN

HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed.


Asunto(s)
Farmacorresistencia Viral , VIH-1/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/química , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Diseño de Drogas , Proteasa del VIH/genética , Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Modelos Moleculares , Mutación , Conformación Proteica , Relación Estructura-Actividad
15.
Vet Microbiol ; 236: 108395, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31500730

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically significant pathogen that has been recognized for its genetic variation, rapid evolution, and immune suppression. Type I interferons (IFNs) play an important role in host defense against viral infection by inducing many antiviral effectors, which might be a selective pressure driving viral evolution towards IFN resistance. To investigate the IFN resistance-related variation of PRRSV genome under IFN selective pressure and explore the molecular mechanism of IFN sensitivity changes, PRRSV strain JXwn06 was serially propagated in porcine pulmonary alveolar macrophages (PAMs) with IFNα treatment for 45 passages and 3 rounds of purification. Four mutant strains named JX-αP51n (n = 1, 2, 3 and 4) with reduced IFNα sensitivity were selected; the strains showed a 100-fold higher titer than the passaging-control strain JX-P51 in IFNα-treated PAMs. IFNα-resistant strains were found to antagonize the IFNα-activated JAK-STAT signaling pathway to a greater extent than the nonresistant strain by down-regulating the expression level of IFNα-activated pJAK1 through interfering with phosphatase. Furthermore, the PRRSV genetic variations interacting with IFNα were identified by full genomic sequencing and alignment. Among these mutations, amino acid substitutions in nsp1ß (E87 G), GP3 (F143 L) and GP5 (Y136 H) were found to correlate with increased IFNα resistance by enhancing the suppression effect on pJAK1, which could be further increased if these three substitution sites were combined. These findings provide some novel evidence for understanding PRRSV genetic variation under host selective pressure and viral evolution strategies to evade the host innate immune response.


Asunto(s)
Farmacorresistencia Viral/genética , Interferón-alfa/farmacología , Mutación , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , Proteínas Virales/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Regulación de la Expresión Génica , Haplorrinos , Fosforilación , Virus del Síndrome Respiratorio y Reproductivo Porcino/efectos de los fármacos , ARN Viral , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/metabolismo , Transducción de Señal , Porcinos , Proteínas Virales/genética
16.
Nat Med ; 25(9): 1377-1384, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31501601

RESUMEN

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.


Asunto(s)
Fármacos Anti-VIH/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Indazoles/farmacología , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Fármacos Anti-VIH/uso terapéutico , Cápside/efectos de los fármacos , Cápside/metabolismo , Proteínas de la Cápside/genética , ADN Viral/efectos de los fármacos , Preparaciones de Acción Retardada , Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/genética , VIH-1/patogenicidad , VIH-2/efectos de los fármacos , VIH-2/patogenicidad , Humanos , Indazoles/uso terapéutico , Cumplimiento de la Medicación , Ratones , Piridinas/uso terapéutico
17.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 982-987, 2019 Aug 10.
Artículo en Chino | MEDLINE | ID: mdl-31484265

RESUMEN

Objective: To understand the distribution of HIV-1 genotypes and the status of drug resistance among people living with HIV who had prepared to initiate antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefecture (Dehong). Methods: A total of 170 adults with HIV were recruited in Dehong from January to June 2017, before initiating ART. HIV-1 pol genes were amplified and used to analyze the HIV-1 genotypes and drug resistance. Results: A total of 147 samples were successfully sequenced. Based on the phylogenetic analysis, 12 HIV-1 genotypes were found among the subjects, including three predominant genotypes such as subtype C (29.9%, 44/147), unique recombinant forms (URFs) (27.2%, 40/147) and CRF01_AE (19.7%, 29/147). Circulating recombinant forms (CRFs) which were newly identified in this area in recent years were also found among these subjects, including CRF62_BC, CRF64_BC, CRF86_BC and CRF96_cpx. The distribution of HIV-1 genotypes between heterosexual transmission or intravenous drug use, showed statistical difference. Surveillance drug resistance mutations (SDRMs) were found among 8.8% (13/147) of the subjects. Proportion of drug resistant strains among injecting drug users (25.0%, 8/32) was higher than that among those heterosexual transmitted individuals (4.6%, 5/109, χ(2)=10.166, P=0.002). Conclusions: Among people living with HIV-1 who had prepared to initiate ART, their HIV-1 genetics were highly complicated, with moderate prevalence rate of HIV-1 drug-resistant strains.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Adulto , Análisis del Polimorfismo de Longitud de Fragmentos Amplificados , Fármacos Anti-VIH/farmacología , Terapia Antirretroviral Altamente Activa , China/epidemiología , Genes pol , Genotipo , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , Humanos , Filogenia
18.
Pediatrics ; 144(4)2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31477606

RESUMEN

This statement updates the recommendations of the American Academy of Pediatrics for the routine use of influenza vaccines and antiviral medications in the prevention and treatment of influenza in children during the 2019-2020 season. The American Academy of Pediatrics continues to recommend routine influenza immunization of all children without medical contraindications, starting at 6 months of age. Any licensed, recommended, age-appropriate vaccine available can be administered, without preference of one product or formulation over another. Antiviral treatment of influenza with any licensed, recommended, age-appropriate influenza antiviral medication continues to be recommended for children with suspected or confirmed influenza, particularly those who are hospitalized, have severe or progressive disease, or have underlying conditions that increase their risk of complications of influenza.


Asunto(s)
Antivirales/administración & dosificación , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Adolescente , Factores de Edad , Antivirales/efectos adversos , Lactancia Materna , Causas de Muerte , Niño , Niño Hospitalizado , Preescolar , Contraindicaciones , Progresión de la Enfermedad , Farmacorresistencia Viral , Hipersensibilidad al Huevo , Femenino , Humanos , Huésped Inmunocomprometido , Lactante , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/efectos adversos , Gripe Humana/complicaciones , Gripe Humana/epidemiología , Pediatría , Embarazo , Estados Unidos/epidemiología , Vacunas de Productos Inactivados/administración & dosificación
19.
Infect Dis Poverty ; 8(1): 63, 2019 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-31370888

RESUMEN

BACKGROUND: Over 90% of Human Immunodeficiency Virus (HIV) infected individuals will be on treatment by 2020 under UNAIDS 90-90-90 global targets. Under World Health Organisation (WHO) "Treat All" approach, this number will be approximately 36.4 million people with over 98% in low-income countries (LICs). MAIN BODY: Pretreatment drug resistance (PDR) largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine, has been increasing with roll-out of combined antiretroviral therapy (cART) with 29% annual increase in some LICs countries. PDR has exceeded 10% in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations. If no change in regimens is enforced in LICs, it's estimated that over 16% of total deaths, 9% of new infections, and 8% of total cART costs will be contributed by HIV drug resistance by 2030. Less than optimal adherence, and adverse side effects associated with currently available drug regimens, all pose a great threat to achievement of 90% viral suppression and elimination of AIDS as a public health threat by 2030. This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide. CONCLUSIONS: The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance, better safety, and tolerability profiles. It's also imperative to strengthen quality service delivery in terms of retention of patients to treatment, support for adherence to cART, patient follow up and adequate drug stocks to help achieve a free AIDS generation.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Antirretrovirales/análisis , Países en Desarrollo/estadística & datos numéricos , Desarrollo de Medicamentos , Antirretrovirales/provisión & distribución , Antirretrovirales/uso terapéutico , Farmacorresistencia Viral , Humanos
20.
Nat Commun ; 10(1): 3468, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31371704

RESUMEN

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.


Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antivirales/química , Línea Celular Tumoral , Diseño de Drogas , Farmacorresistencia Viral/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Hepacivirus/efectos de los fármacos , Hepacivirus/metabolismo , Hepatitis C/tratamiento farmacológico , Hepatitis C/genética , Hepatitis C/virología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Modelos Moleculares , Oligopéptidos/química , Oligopéptidos/farmacología , Prueba de Estudio Conceptual , Inhibidores de Proteasas/química , Proteolisis/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas no Estructurales Virales/metabolismo
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