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2.
Lancet HIV ; 8(4): e185-e196, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794181

RESUMEN

BACKGROUND: There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. METHODS: FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. FINDINGS: Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. INTERPRETATION: The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. FUNDING: ViiV Healthcare and Janssen Research and Development.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridonas/administración & dosificación , Rilpivirina/administración & dosificación , Adulto , Fármacos Anti-VIH/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Piridonas/efectos adversos , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Rilpivirina/efectos adversos , Resultado del Tratamiento , Carga Viral/efectos de los fármacos
3.
Lancet HIV ; 8(4): e197-e205, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794182

RESUMEN

BACKGROUND: DNA methylation-based estimators of biological age are reliable biomarkers of the ageing process. We aimed to investigate a range of epigenetic ageing biomarkers in a substudy of the NEAT001/ANRS143 clinical trial, which compared ritonavir-boosted darunavir with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in antiretroviral therapy (ART)-naive adults. METHODS: We analysed frozen whole blood samples from 168 ART-naive participants with HIV from the NEAT001/ANRS143 trial, before ART initiation and after 2 years of ART (84 participants on ritonavir-boosted darunavir with raltegravir and 84 participants on ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine). We also included 44 participants without HIV with a similar age and sex distribution. We analysed DNA methylation. Epigenetic age estimators (Horvath's clock, Hannum's clock, GrimAge, and PhenoAge) and estimated leucocyte compositions were generated using Horvath's New Online Methylation Age Calculator and Houseman's method. We calculated epigenetic age acceleration measures for each estimator of epigenetic age. The NEAT001/ANRS143 trial is registered with ClinicalTrials.gov, NCT01066962. FINDINGS: Compared with the HIV-uninfected group, ART-naive participants with HIV showed higher epigenetic age acceleration (EAA) according to all EAA estimators (mean 2·5 years, 95% CI 1·89-3·22 for Horvath-EAA; 1·4 years, 0·74-1·99 for Hannum-EAA; 2·8 years, 1·97-3·68 for GrimAge-EAA; and 7·3 years, 6·40-8·13 for PhenoAge-EAA), with all differences being statistically significant except for Hannum-EAA (Horvath-EAA p=0·0008; Hannum-EAA p=0·059; GrimAge-EAA p=0·0021; and PhenoAge-EAA p<0·0001). Epigenetic ageing was more pronounced in participants who had CD4 counts less than 200 cells per µL (significant for PhenoAge and Hannum's clock, p=0·0015 and p=0·034, respectively) or viral loads over 100 000 copies per mL at baseline (significant for PhenoAge, p=0·017). After 2 years of ART, epigenetic age acceleration was reduced, although PhenoAge and GrimAge remained significantly higher in participants with HIV compared with participants without HIV (mean difference 3·69 years, 95% CI 1·77-5·61; p=0·0002 and 2·2 years, 0·47-3·99; p=0·013, respectively). There were no significant differences in the ART effect on epigenetic ageing between treatment regimens. At baseline, participants with HIV showed dysregulation of DNA methylation-based estimated leucocyte subsets towards more differentiated T-cell phenotypes and proinflammatory leucocytes, which was also partly restored with ART. INTERPRETATION: ART initiation partly reversed epigenetic ageing associated with untreated HIV infection. Further studies are needed to understand the long-term dynamics and clinical relevance of epigenetic ageing biomarkers in people with HIV. FUNDING: NEAT-ID Foundation.


Asunto(s)
Envejecimiento/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Adulto , Envejecimiento/genética , Biomarcadores/análisis , Recuento de Linfocito CD4 , Metilación de ADN , Quimioterapia Combinada , Femenino , Infecciones por VIH/genética , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Carga Viral
4.
Nat Commun ; 12(1): 2147, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846309

RESUMEN

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).


Asunto(s)
Canal Anal/citología , Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Genitales/citología , VIH-1/fisiología , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Monocitos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Forma de la Célula , Colagenasas/metabolismo , Dermis/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Receptores de Lipopolisacáridos/metabolismo , Membrana Mucosa/metabolismo , Fagocitos/metabolismo , Fenotipo , Receptores CCR5/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Transcripción Genética
5.
Nat Commun ; 12(1): 1474, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674572

RESUMEN

The establishment of a long-lived viral reservoir is the key obstacle for achieving an HIV-1 cure. However, the anatomic, virologic, and immunologic features of the viral reservoir in tissues during antiretroviral therapy (ART) remain poorly understood. Here we present a comprehensive necroscopic analysis of the SIV/SHIV viral reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Viral DNA is observed broadly in multiple tissues and is comparable in animals that had initiated ART at week 1 or week 52 of infection. In contrast, viral RNA is restricted primarily to lymph nodes. Ongoing viral RNA transcription is not the result of unsuppressed viral replication, as single-genome amplification and subsequent phylogenetic analysis do not show evidence of viral evolution. Gag-specific CD8+ T cell responses are predominantly observed in secondary lymphoid organs in animals chronically infected prior to ART and these responses are dominated by CD69+ populations. Overall, we observe that the viral reservoir in rhesus macaques is widely distributed across multiple tissue sites and that lymphoid tissues act as a site of persistent viral RNA transcription under conditions of long-term ART suppression.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/virología , Ganglios Linfáticos/virología , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Linfocitos T CD8-positivos , ADN Viral , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Ganglios Linfáticos/inmunología , Tejido Linfoide/virología , Macaca mulatta , Filogenia , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/genética , Carga Viral , Replicación Viral
6.
Medicine (Baltimore) ; 100(10): e25140, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725916

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN. METHODS: Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data. RESULTS: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. CONCLUSION: This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN. PROSPERO REGISTRATION NUMBER: CRD42020210994.


Asunto(s)
Terapia por Acupuntura/efectos adversos , Infecciones por VIH/complicaciones , Neuralgia/terapia , Parestesia/terapia , Polineuropatías/terapia , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Metaanálisis como Asunto , Neuralgia/diagnóstico , Neuralgia/inmunología , Neuralgia/virología , Dimensión del Dolor , Parestesia/diagnóstico , Parestesia/inmunología , Parestesia/virología , Polineuropatías/diagnóstico , Polineuropatías/inmunología , Polineuropatías/virología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Revisiones Sistemáticas como Asunto , Resultado del Tratamiento
7.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669351

RESUMEN

HIV-2 infection is frequently neglected in HIV/AIDS campaigns. However, a special emphasis must be given to HIV-2 as an untreated infection that also leads to AIDS and death, and for which the efficacy of most available drugs is limited against HIV-2. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry. Here, we developed and optimized a computer-assisted drug design approach of an important HIV-2 glycoprotein that allows us to explore and gain further insights at the molecular level into protein structures and interactions crucial for the inhibition of HIV-2 cell entry. The 3D structure of a key HIV-2ROD gp125 region was generated by a homology modeling campaign. To disclose the importance of the main structural features and compare them with experimental results, 3D-models of six mutants were also generated. These mutations revealed the selective impact on the behavior of the protein. Furthermore, molecular dynamics simulations were performed to optimize the models, and the dynamic behavior was tackled to account for structure flexibility and interactions network formation. Structurally, the mutations studied lead to a loss of aromatic features, which is very important for the establishment of π-π interactions and could induce a structural preference by a specific coreceptor. These new insights into the structure-function relationship of HIV-2 gp125 V3 and surrounding regions will help in the design of better models and the design of new small molecules capable to inhibit the attachment and binding of HIV with host cells.


Asunto(s)
Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/química , Infecciones por VIH/metabolismo , VIH-2/metabolismo , Dominios Proteicos , Secuencia de Aminoácidos , Antígenos CD4/química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/metabolismo , Humanos , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Internalización del Virus/efectos de los fármacos
8.
Lancet Glob Health ; 9(4): e479-e488, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33740409

RESUMEN

BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa. METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed. FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery. INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens. FUNDING: US National Institutes of Health. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Coinfección/tratamiento farmacológico , Diarilquinolinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/psicología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Coinfección/microbiología , Coinfección/psicología , Consejo , Quimioterapia Combinada/métodos , Quimioterapia Combinada/psicología , Femenino , Grupos Focales , Infecciones por VIH/psicología , Infecciones por VIH/virología , Humanos , Estudios Longitudinales , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Estudios Prospectivos , Investigación Cualitativa , Resiliencia Psicológica , Sudáfrica , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/psicología , Adulto Joven
9.
Arch Virol ; 166(5): 1283-1296, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33606110

RESUMEN

The lack of progress in finding an efficient vaccine for a human immunodeficiency virus (HIV) is daunting. In fact, this search has spanned nearly four decades without much success. There are several objective reasons for such a failure, which include the highly glycosylated nature of HIV-1, the presence of neotopes, and high mutation rates. This article argues that the presence of highly flexible and intrinsically disordered regions in both human anti-HIV-1 antibodies and the major HIV-1immunogen, its surface glycoprotein gp120, represent one of the major causes for the lack of success in utilization of structure-based reverse vaccinology.


Asunto(s)
Vacunas contra el SIDA/química , VIH-1/inmunología , Proteínas Intrínsecamente Desordenadas/química , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/inmunología , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/química , Humanos , Inmunoglobulina G/química , Inmunoglobulina G/inmunología , Proteínas Intrínsecamente Desordenadas/inmunología
11.
Lancet HIV ; 8(2): e87-e95, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539762

RESUMEN

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Dispositivos Anticonceptivos Femeninos , Infecciones por VIH/prevención & control , Pirimidinas/uso terapéutico , Tenofovir/uso terapéutico , Administración Intravaginal , Adulto , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Malaui , Cooperación del Paciente/estadística & datos numéricos , Seguridad del Paciente , Seroconversión , Sudáfrica , Resultado del Tratamiento , Uganda , Zimbabwe
12.
BMC Infect Dis ; 21(1): 214, 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33632139

RESUMEN

BACKGROUND: HIV-1C has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors (bPIs), a component of second-line combination antiretroviral therapy (cART) in South Africa. This study entailed an evaluation of HIV-1 drug resistance-associated mutations (RAMs) among minor viral populations through high-throughput sequencing genotypic resistance testing (HTS-GRT) in patients on the South African national second-line cART regimen receiving bPIs. METHODS: During 2017 and 2018, 67 patient samples were sequenced using high-throughput sequencing (HTS), of which 56 samples were included in the final analysis because the patient's treatment regimen was available at the time of sampling. All patients were receiving bPIs as part of their cART. Viral RNA was extracted, and complete pol genes were amplified and sequenced using Illumina HiSeq2500, followed by bioinformatics analysis to quantify the RAMs according to the Stanford HIV Drug Resistance Database. RESULTS: Statistically significantly higher PI RAMs were observed in minor viral quasispecies (25%; 14/56) compared to non-nucleoside reverse transcriptase inhibitors (9%; 5/56; p = 0.042) and integrase inhibitor RAM (4%; 2/56; p = 0.002). The majority of the drug resistance mutations in the minor viral quasispecies were observed in the V82A mutation (n = 13) in protease and K65R (n = 5), K103N (n = 7) and M184V (n = 5) in reverse transcriptase. CONCLUSIONS: HTS-GRT improved the identification of PI and reverse transcriptase inhibitor (RTI) RAMs in second-line cART patients from South Africa compared to the conventional GRT with ≥20% used in Sanger-based sequencing. Several RTI RAMs, such as K65R, M184V or K103N and PI RAM V82A, were identified in < 20% of the population. Deep sequencing could be of greater value in detecting acquired resistance mutations early.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Cuasiespecies/efectos de los fármacos , Antirretrovirales/uso terapéutico , Farmacorresistencia Viral/efectos de los fármacos , Genes pol/genética , Genotipo , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Mutación , Cuasiespecies/genética , ARN Viral/genética , Sudáfrica/epidemiología
13.
Viruses ; 13(2)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557210

RESUMEN

HIV-1 infection elicits a complex dynamic of the expression various host genes. High throughput sequencing added an expressive amount of information regarding HIV-1 infections and pathogenesis. RNA sequencing (RNA-Seq) is currently the tool of choice to investigate gene expression in a several range of experimental setting. This study aims at performing a meta-analysis of RNA-Seq expression profiles in samples of HIV-1 infected CD4+ T cells compared to uninfected cells to assess consistently differentially expressed genes in the context of HIV-1 infection. We selected two studies (22 samples: 15 experimentally infected and 7 mock-infected). We found 208 differentially expressed genes in infected cells when compared to uninfected/mock-infected cells. This result had moderate overlap when compared to previous studies of HIV-1 infection transcriptomics, but we identified 64 genes already known to interact with HIV-1 according to the HIV-1 Human Interaction Database. A gene ontology (GO) analysis revealed enrichment of several pathways involved in immune response, cell adhesion, cell migration, inflammation, apoptosis, Wnt, Notch and ERK/MAPK signaling.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/virología , VIH-1/fisiología , Transcriptoma , Linfocitos T CD4-Positivos/virología , Perfilación de la Expresión Génica , Ontología de Genes , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Interacciones Huésped-Patógeno , Humanos
14.
Viruses ; 13(2)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557422

RESUMEN

Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200-250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.


Asunto(s)
Antivirales/metabolismo , Cápside/metabolismo , Infecciones por VIH/metabolismo , VIH-1/metabolismo , Animales , Antivirales/química , Antivirales/farmacología , Cápside/química , Proteínas de la Cápside/química , Proteínas de la Cápside/metabolismo , Infecciones por VIH/virología , VIH-1/química , VIH-1/efectos de los fármacos , VIH-1/fisiología , Interacciones Huésped-Patógeno , Humanos , Unión Proteica , Replicación Viral/efectos de los fármacos
15.
Viruses ; 13(2)2021 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-33573241

RESUMEN

During the last two decades, progresses in bioimaging and the development of various strategies to fluorescently label the viral components opened a wide range of possibilities to visualize the early phase of Human Immunodeficiency Virus 1 (HIV-1) life cycle directly in infected cells. After fusion of the viral envelope with the cell membrane, the viral core is released into the cytoplasm and the viral RNA (vRNA) is retro-transcribed into DNA by the reverse transcriptase. During this process, the RNA-based viral complex transforms into a pre-integration complex (PIC), composed of the viral genomic DNA (vDNA) coated with viral and host cellular proteins. The protective capsid shell disassembles during a process called uncoating. The viral genome is transported into the cell nucleus and integrates into the host cell chromatin. Unlike biochemical approaches that provide global data about the whole population of viral particles, imaging techniques enable following individual viruses on a single particle level. In this context, quantitative microscopy has brought original data shedding light on the dynamics of the viral entry into the host cell, the cytoplasmic transport, the nuclear import, and the selection of the integration site. In parallel, multi-color imaging studies have elucidated the mechanism of action of host cell factors implicated in HIV-1 viral cycle progression. In this review, we describe the labeling strategies used for HIV-1 fluorescence imaging and report on the main advancements that imaging studies have brought in the understanding of the infection mechanisms from the viral entry into the host cell until the provirus integration step.


Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Internalización del Virus , Animales , Núcleo Celular/virología , VIH-1/química , VIH-1/genética , Humanos , Microscopía Fluorescente , Integración Viral
16.
Lancet HIV ; 8(2): e67-e76, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539760

RESUMEN

BACKGROUND: UNAIDS recommends integrating methadone or buprenorphine treatment of opioid use disorder with HIV care to improve HIV outcomes, but buprenorphine adoption remains limited in many countries. We aimed to assess whether HIV clinic-based buprenorphine plus naloxone treatment for opioid use disorder was non-inferior to referral for methadone maintenance therapy in achieving HIV viral suppression in Vietnam. METHODS: In an open-label, non-inferiority trial (BRAVO), we randomly assigned people with HIV and opioid use disorder (1:1) by computer-generated random number sequence, in blocks of ten and stratified by site, to receive HIV clinic-based buprenorphine plus naloxone treatment or referral for methadone maintenance therapy in six HIV clinics in Vietnam. The primary outcome was HIV viral suppression at 12 months (HIV-1 RNA ≤200 copies per mL on PCR) by intention to treat (absolute risk difference [RD] margin ≤13%), compared by use of generalised estimating equations. Research staff actively queried treatment-emergent adverse events during quarterly study visits and passively collected adverse events reported during HIV clinic visits. This study is registered with ClinicalTrials.gov, NCT01936857, and is completed. FINDINGS: Between July 27, 2015, and Feb 12, 2018, we enrolled 281 patients. At baseline, 272 (97%) participants were male, mean age was 38·3 years (SD 6·1), and mean CD4 count was 405 cells per µL (SD 224). Viral suppression improved between baseline and 12 months for both HIV clinic-based buprenorphine plus naloxone (from 97 [69%] of 140 patients to 74 [81%] of 91 patients) and referral for methadone maintenance therapy (from 92 [66%] of 140 to 99 [93%] of 107). Buprenorphine plus naloxone did not demonstrate non-inferiority to methadone maintenance therapy in achieving viral suppression at 12 months (RD -0·11, 95% CI -0·20 to -0·02). Retention on medication at 12 months was lower for buprenorphine plus naloxone than for methadone maintenance therapy (40% vs 65%; RD -0·53, 95% CI -0·75 to -0·31). Participants assigned to buprenorphine plus naloxone more frequently experienced serious adverse events (ten [7%] of 141 vs four of 140 [3%] assigned to methadone maintenance therapy) and deaths (seven of 141 [5%] vs three of 141 [2%]). Serious adverse events and deaths typically occurred in people no longer taking ART or opioid use disorder medications. INTERPRETATION: Although integrated buprenorphine and HIV care may potentially increase access to treatment for opioid use disorder, scale-up in middle-income countries might require enhanced support for buprenorphine adherence to improve HIV viral suppression. The strength of our study as a multisite randomised trial was offset by low retention of patients on buprenorphine. FUNDING: National Institute on Drug Abuse (US National Institutes of Health).


Asunto(s)
Buprenorfina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Metadona/uso terapéutico , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/virología , Cooperación del Paciente/estadística & datos numéricos , ARN Viral/sangre , Distribución Aleatoria , Resultado del Tratamiento , Vietnam , Carga Viral/efectos de los fármacos
17.
Expert Opin Drug Saf ; 20(4): 397-409, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33557651

RESUMEN

Introduction: Despite the efficacy and safety of antiretroviral therapy, new treatment options are needed to address the concerns of patients and physicians regarding long-term toxicities, costs, and convenience of lifelong antiretroviral therapy. To achieve this goal, one strategy is to reduce the number of drugs in the antiretroviral regimen.Areas covered: We review the recent evidence on the efficacy and safety of reduced drug regimens and their potential risks and benefits. There is currently strong evidence showing that some two-drug regimens have a comparable efficacy and short-term safety compared to standard three-drug regimens. The fixed-dose combination of dolutegravir/lamivudine is already an alternative for many treatment-naïve and virologically suppressed HIV-1 infected adults supported by large randomized clinical trials. The co-formulation dolutegravir plus rilpivirine is also a switch strategy for maintenance therapy. Long-acting injectable cabotegravir plus rilpivirine has already regulatory approval, and islatravir plus doravirine is an expected option in the near future. Some two-drug regimens have not been as successful.Expert opinion: Long-term safety issues of these two-drug regimens remain to be determined, but with the overwhelming evidence available in virological control and short-term safety, the potential benefits of some of these two-drug regimens appear to outweigh the risks.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Combinación de Medicamentos , Quimioterapia Combinada , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
18.
Science ; 371(6535)2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33542150

RESUMEN

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Infecciones por VIH/virología , Proteasa del VIH/metabolismo , VIH-1/fisiología , Inflamasomas/metabolismo , Proteínas de Neoplasias/metabolismo , Piroptosis , Alquinos/farmacología , Fármacos Anti-VIH/farmacología , Benzoxazinas/farmacología , Proteínas Adaptadoras de Señalización CARD/química , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD4-Positivos/virología , Caspasa 1/metabolismo , Ciclopropanos/farmacología , Activación Enzimática , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Humanos , Macrófagos/fisiología , Macrófagos/virología , Proteínas de Neoplasias/química , Inhibidores de la Transcriptasa Inversa/farmacología , Rilpivirina/farmacología , Células THP-1 , Latencia del Virus
19.
AIDS Patient Care STDS ; 35(2): 39-46, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33571047

RESUMEN

Viral suppression and postpartum retention in care have far-reaching health implications for pregnant women living with HIV and their children, yet remain public health challenges. Prenatal care presents a unique opportunity to engage pregnant women in care. The purpose of this study is to evaluate whether group prenatal care is effective in impacting these outcomes for pregnant women living with HIV. A retrospective cohort study was performed of all women living with HIV who obtained prenatal care from a community-based health center between 2013 and 2019. Women who spoke English or Spanish, remained within the system, and had not participated in group prenatal care previously were included. Women self-selected a prenatal care model: 85 selected group care and 109 elected individual care. Group prenatal care followed a standard Centering Pregnancy® curriculum with the addition of HIV-related topics. The primary outcomes of the study were viral suppression (viral load <20 copies/mL) and postpartum retention in care (attending at least one or two visits with HIV primary care within 12 months postpartum). After adjusting for potential confounding factors, women who participated in group prenatal care were significantly more likely to have at least one HIV primary care visit postpartum {adjusted odds ratio (aOR) = 2.71 [95% confidence interval (CI 1.14-6.46)]; p = 0.024}, and had a trend for achieving viral suppression by the time of delivery [aOR = 2.29 (95% CI 0.94-5.55); p = 0.068]. We have demonstrated that group prenatal care for pregnant women living with HIV is feasible and effective, with positive impacts on retention in care and viral suppression, factors that affect long-term outcomes from patients living with HIV.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Servicios de Salud Comunitaria/organización & administración , Infecciones por VIH/tratamiento farmacológico , Aceptación de la Atención de Salud/estadística & datos numéricos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Retención en el Cuidado , Adulto , Niño , Estudios de Cohortes , Centros Comunitarios de Salud , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Atención Posnatal , Periodo Posparto , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Mujeres Embarazadas , Atención Prenatal , Estudios Retrospectivos , Respuesta Virológica Sostenida , Texas/epidemiología , Carga Viral
20.
AIDS Patient Care STDS ; 35(2): 33-38, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33571048

RESUMEN

Breastfeeding (BF) in mothers living with HIV (MLWH) is still discussed controversially in resource-rich settings. In Germany, where formula feeding is recommended for MLWH single BF cases have been reported, but no systematic data collection and analysis are available so far. This study, titled HELENE, aims to fill this data gap. A questionnaire covering the course of BF was distributed by a graduate student visiting each study site. Information was collected from patient files and by personal communication with the health care provider. Primary study objectives were the duration of BF and the maternal antiretroviral treatment (ART). Fifteen treatment centers across Germany contributed a total of 42 BF cases, observed from May 2009 to July 2020. There was an increasing number of BF cases over time. The median duration of BF was 20 weeks varying from single BF of colostrum to 104 weeks. All BF women except one elite controller received ART: 39% non-nucleoside reverse transcriptase inhibitor-, 37% INSTI-, 29% protease inhibitor-based regimens; one woman was on maraviroc. Thirty-nine percent of the ART regimens included drugs that were not recommended by the German-Austrian pregnancy guidelines. Our findings highlight the diversity of BF cases in Germany in terms of duration, maternal ART, and monitoring. Since the number of BF cases is increasing, guidelines are obliged to implement more detailed recommendations on BF, the monitoring of BF mothers, and the follow-up of the infants. There is an urgent need for prospective national and European data collections to further improve HIV prevention of mother-to-child transmission (PMTCT) in the setting of BF.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Lactancia Materna/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Fármacos Anti-VIH/administración & dosificación , Niño , Femenino , Alemania , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , Lactante , Embarazo , Complicaciones Infecciosas del Embarazo/prevención & control , Estudios Prospectivos , Carga Viral
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