RESUMEN
OBJECTIVES: Resistance associated mutations (RAMs) are archived in the HIV reservoir and can re-emerge with an inappropriate ART use limiting treatment options. However, recent studies, using ultra-deep sequencing (UDS), showed a decrease of quasispecies harbouring RAMs, suggesting that recycling some antiretrovirals could be considered. The aim of this study was to characterize, in HIV treated PLWHIV, the M184V mutation decrease kinetics in proviral DNA and associated factors of M184V mutation clearance over time. METHODS: UDS was performed on HIV-DNA from blood cells at different time points to quantify the percentage of M184V positive quasispecies. The sequence reads were analysed with a minimum coverage set at 50 and an ambiguity filter at 5% or 2%. RESULTS: At 2.5â years after the first time point, the M184V lost was observed in 50% of PLWHIV. Moreover, univariate analyses highlight that a higher nadir CD4 count and a lower zenith HIV1 RNA viral load were correlated with a faster clearance of the mutation. In multivariate analysis, a higher zenith was negatively associated with the M184V clearance at the 5% threshold. Interestingly, lamivudine/emtricitabine presence in the ART therapy regiment during the 5 years was not associated with the persistence of the M184V. CONCLUSIONS: Our study provides new information concerning the clearance speed of M184V mutation over time in PLWHIV with fully suppressed viremia, opens the discussion about the duration needed to consider a lamivudine/emtricitabine recycling and reinforces the association of the nadir and zenith values with the M184V mutation clearance.
Asunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Mutación , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Farmacorresistencia Viral/genética , VIH-1/genética , VIH-1/efectos de los fármacos , Recuento de Linfocito CD4 , Masculino , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Femenino , Adulto , Persona de Mediana Edad , Provirus/genética , Secuenciación de Nucleótidos de Alto Rendimiento , ADN Viral/genética , ADN Viral/sangre , Transcriptasa Inversa del VIH/genética , Terapia Antirretroviral Altamente ActivaRESUMEN
Immunoblots remain the gold standard for HIV-1/HIV-2 infection confirmation. However, their ability to differentiate HIV-1 from HIV-2 infection on an antigenically diversified HIV-1 and HIV-2 panel remain uncommon. We performed a multicenter study on 116 serum samples accounting for most of the diversity of HIV-1 (9 different subtypes in group M, 17 circulating recombinant forms (CRFs), and 3 group O) and HIV-2 (groups A and B), evaluating seven confirmatory assays (six commercially available assays and one in-house assay) with genotyping as the reference. The assays were INNO-LIA HIV I/II score, HIV-2 blot 1.2, HIV blot 2.2, New Lav blot I and II, Geenius, and an in-house serotyping enzyme-linked immunosorbent assay (ELISA). Among the HIV-1 samples, INNO-LIA, HIV blot 2.2, New Lav blot I, Geenius, and serotyping had comparable high sensitivities, from 98% to 100%, whereas HIV-2 blot 1.2 and New Lav blot II had high rates of "undetermined" results (85% and 95%, respectively). HIV-2 blot 1.2 and New Lav blot II misclassified 7% and 5% of HIV-1 samples as HIV-2, respectively, and HIV-2 blot 1.2 had an 8% false-negative rate. Among the HIV-2 samples, INNO-LIA, New Lav blot II, HIV-2 blot 1.2, and serotyping had high sensitivities, from 96% to 100%. HIV blot 2.2 misclassified 17% of HIV-2 samples as HIV-1/HIV-2 dual infections. New Lav blot I misclassified 19% of HIV-2 samples as HIV-1 with a high (81%) undetermined rate, and Geenius misclassified 2% as HIV-1 and 7% as untypeable HIV positive. For HIV-1/HIV-2 dual infection, the results were less sensitive, with at most 87.5% for INNO-LIA and Geenius and 75% for HIV blot 2.2 and serotyping. Overall, confirmatory assays remain useful for most cases, with the exception of HIV-1/HIV-2 dual-infection suspicion.
Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , VIH-2/genética , Sensibilidad y Especificidad , Infecciones por VIH/diagnóstico , Anticuerpos Anti-VIHRESUMEN
BACKGROUND: We aimed to assess the kinetics of drug-resistant viral variants (DRVs) harboring the M184V mutation in proviral DNA of long-term virally suppressed patients, and factors associated with DRV persistence. METHODS: Human immunodeficiency virus (HIV) DNA from blood cells stored in 2016 and 2019 was sequenced using Sanger and ultradeep sequencing (SS and UDS; detection threshold 1%) in antiretroviral therapy (ART)-treated patients with HIV RNAâ <â 50 copies/mL for at least 5 years, with past M184V mutation documented in HIV RNA. RESULTS: Among 79 patients, by combining SS and UDS, M184V was found to be absent in 26/79 (33%) patients and persistent in 53/79 (67%). M184V-positive patients had a longer history of ART, lower CD4 nadir, and higher pretherapeutic HIV RNA. Among 37 patients with viral sequences assessed by UDS, the proportion of M184V-positive DRVs significantly decreased between 2016 and 2019 (40% vs 14%, Pâ =â .005). The persistence of M184V was associated with duration and level of HIV RNA replication under lamivudine/emtricitabine (3TC/FTC; Pâ =â .0009 and Pâ =â .009, respectively). CONCLUSIONS: While it decreased over time in HIV DNA, M184V mutation was more frequently persistent in HIV DNA of more treatment-experienced patients with longer past replication under 3TC/FTC.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , ADN/farmacología , Farmacorresistencia Viral/genética , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Cinética , Lamivudine/uso terapéutico , Mutación , ARNRESUMEN
There are concerns about neutralizing antibodies' (NAbs') potency against severe acute respiratory syndrome coronavirus 2 variants. Despite decreased NAb titers elicited by BNT162b2 vaccine against VOC202012/01 and 501Y.V2 strains, 28/29 healthcare workers (HCWs) had an NAb titer ≥1:10. In contrast, 6 months after coronavirus disease 2019 mild forms, only 9/15 (60%) of HCWs displayed detectable NAbs against 501Y.V2 strain.
Asunto(s)
COVID-19 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Personal de Salud , Humanos , SARS-CoV-2/genética , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Target-detected (TD) results or low-level viraemia (LLV) can be observed in HIV-1 patients on ART, which regularly raises questions. OBJECTIVES: We describe here the impact on HIV-1 RNA quantification of switching from the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) to the Cobas 6800 system (C6800), based on analyses of viraemia close to the lower limit of quantification (LLoQ). PATIENTS AND METHODS: We retrospectively selected two groups of patients: 200 individuals whose viral loads (VLs) were consistently <50â copies/mL with CAP/CTM for at least 3â years before switching to C6800 (group 1), and 35 other patients with confirmed LLV when C6800 was in use (group 2). In both groups, we compared several consecutive VL results performed before and after the change of quantification assay. Analyses were performed with McNemar's paired tests or Fisher's exact tests. RESULTS: In group 1, the frequency of TD results (below or above the LLoQ) increased significantly after the switch to C6800 for patients with <25% of results being TD for VLs performed with CAP/CTM (Pâ<â0.0001). Significantly more patients had at least one VL ≥20 or ≥50â copies/mL with C6800, in both group 1 (37.0% versus 18.5%; Pâ<â0.0001 and 6.5% versus 0%; Pâ=â0.0009, respectively) and group 2 (100% versus 66%; Pâ=â0.0015 and 97% versus 40%; Pâ<â0.0001, respectively). CONCLUSIONS: C6800 revealed residual or low-level HIV-1 RNA that was not detected with CAP/CTM, resulting in twice as many patients being found to have a VL ≥20â copies/mL. Physicians and patients should be aware of possible differences in results between assays, and it is crucial to specify the quantitative assay used in studies.
Asunto(s)
Infecciones por VIH , VIH-1 , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , ARN Viral/genética , Estudios Retrospectivos , Sensibilidad y Especificidad , Carga Viral/métodos , ViremiaRESUMEN
BACKGROUND: Little is known about HIV-1 integrase inhibitor resistance in the CNS. OBJECTIVES: This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. METHODS: HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. RESULTS: Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85-5.80) and 3.59 (2.16-4.50) log10 copies/mL versus 4.79 (3.56-5.25) and 3.80 (2.68-4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, nâ=â3; L74I/M, nâ=â1; T97A, nâ=â1; E157Q, nâ=â4) and ARV-treated (L74I, nâ=â6; L74M, nâ=â1; T97A, nâ=â1; N155H, nâ=â1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. CONCLUSIONS: This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.
Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/genética , Humanos , MutaciónRESUMEN
OBJECTIVES: APOBEC3 editing activity contributes to sequences variation and viral diversification. We aimed to characterize virological and clinical factors associated with G-to-A mutations and stop codons in the HIV-1 reservoir, markers of APOBEC3 footprints, in order to better understand HIV-1 diversity among virologically suppressed HIV-1-infected patients. METHODS: Immuno-virological and clinical factors were compared between 92 patients harbouring G-to-A mutations and stop codons (APOBEC+) in the reverse transcriptase gene and 92 patients without G-to-A mutations (APOBEC-) and stop codons in their DNA genotypes. RESULTS: Patients were predominantly men (74.5%) and were mostly infected by B-subtype (69.0%), with 44.1% and 55.9% in APOBEC+ and APOBEC- groups, respectively. At time of HIV DNA genotypes, the total cell-associated HIV-1 DNA load was 2.34 log10 copies/106 cells (IQR 1.85-2.67) and 33.2% of them had a detectable ultrasensitive plasma viral load. Hypermutated sequences were identified in 28.2% of the APOBEC+ group. The median total cell-associated HIV-1 DNA level was significantly lower in APOBEC+ than APOBEC- group: 2.13 log10 copies/106 cells (IQR 1.60-2.60) versus 2.52 log10 copies/106 cells (IQR 2.19-2.71) (P < 0.001), respectively. Presence of G-to-A mutations and stop codon was independently associated with HIV-1 subtype non-B (P = 0.017). CONCLUSIONS: These results show an independent association between the presence of G-to-A mutations and stop codons with HIV-1 subtype non-B and low proviral DNA that could be explained by the APOBEC3 footprints and restriction of DNA synthesis and integration. However, further investigations are needed to study the contribution of Vif amino acid variability among HIV-1 subtypes.
Asunto(s)
Desaminasas APOBEC/genética , Infecciones por VIH , VIH-1 , VIH-1/genética , Humanos , Masculino , Mutación , Provirus , Carga ViralRESUMEN
BACKGROUND: Multivariable baseline factor analysis across cabotegravirâ+ârilpivirine clinical trials showed that HIV-1 subtypes A6/A1 and the presence of rilpivirine resistance-associated mutations (RAMs) were associated with an increased risk of virological failure of this dual therapy. The aim of this study was to describe the prevalence of genotypic baseline risk factors for cabotegravirâ+ârilpivirine failure among ARV-naive patients. PATIENTS AND METHODS: From 2010 to 2020, 4212 sequences from ARV-naive patients were collected from three large Parisian academic hospital genotypic databases. Cabotegravir and rilpivirine RAMs were defined according to the ANRS algorithm. RESULTS: Among 4212 ARV-naive patients, 38.6% were infected with subtype B, 32.4% with CRF02_AG (32.4%) and 5.1% with subtype A (85.5% being A6/A1 subtype). Overall, the presence of at least one cabotegravir or rilpivirine RAM was 16.2% and 14.3%, respectively. Considering genotypic resistance interpretation, using the ANRS algorithm, 0.74% (nâ=â31), 6.2% (nâ=â261) and 0.09% (nâ=â4) of sequences were resistant to cabotegravir, rilpivirine or both, respectively. The overall prevalence of L74I in integrase and E138A in RT was 13.0% and 3.2%, respectively, and stable over the decade. Thus, adding 183 subtype A6/A1 sequences to 244 sequences interpreted as resistant to rilpivirine led to 427 (10.1%) sequences combining both baseline virological risk factors for cabotegravirâ+ârilpivirine dual-therapy failure. CONCLUSIONS: Among large sequence databases, when adding prevalence of rilpivirine-resistant viruses and HIV-1 subtype A6/A1 sequences, 10.1% of patients would not be eligible for cabotegravirâ+ârilpivirine dual therapy. These data re-emphasize the need for a pre-therapeutic genotypic resistance test to detect polymorphisms and transmitted drug resistance and to define HIV-1 subtype.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/genética , Humanos , Prevalencia , Piridonas , Rilpivirina/uso terapéutico , Factores de RiesgoRESUMEN
OBJECTIVES: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks. METHODS: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia. RESULTS: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period. CONCLUSIONS: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Preparaciones Farmacéuticas , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Carga ViralRESUMEN
BACKGROUND: M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I. OBJECTIVES: We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors. PATIENTS AND METHODS: A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50â copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12â months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia. RESULTS: During the 12â months of follow-up, three patients had a blip of VL (53, 62 and 106â copies/mL) at Month 3 followed by a subsequent VL <50â copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up. CONCLUSIONS: M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12â months.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Didesoxinucleósidos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Lamivudine/uso terapéutico , Oxazinas , Piperazinas , Piridonas , Estudios Retrospectivos , Carga ViralRESUMEN
OBJECTIVES: Patients with primary HIV-1 infection (PHI) are a particular population, giving important insight about ongoing evolution of transmitted drug resistance-associated mutation (TDRAM) prevalence, HIV diversity and clustering patterns. We describe these evolutions of PHI patients diagnosed in France from 2014 to 2016. METHODS: A total of 1121 PHI patients were included. TDRAMs were characterized using the 2009 Stanford list and the French ANRS algorithm. Viral subtypes and recent transmission clusters (RTCs) were also determined. RESULTS: Patients were mainly MSM (70%) living in the Paris area (42%). TDRAMs were identified among 10.8% of patients and rose to 18.6% when including etravirine and rilpivirine TDRAMs. Prevalences of PI-, NRTI-, first-generation NNRTI-, second-generation NNRTI- and integrase inhibitor-associated TDRAMs were 2.9%, 5.0%, 4.0%, 9.4% and 5.4%, respectively. In a multivariable analysis, age >40 years and non-R5 tropic viruses were associated with a >2-fold increased risk of TDRAMs. Regarding HIV diversity, subtype B and CRF02_AG (where CRF stands for circulating recombinant form) were the two main lineages (56% and 20%, respectively). CRF02_AG was associated with higher viral load than subtype B (5.83 versus 5.40 log10 copies/mL, P=0.004). We identified 138 RTCs ranging from 2 to 14 patients and including overall 41% from the global population. Patients in RTCs were younger, more frequently born in France and more frequently MSM. CONCLUSIONS: Since 2007, the proportion of TDRAMs has been stable among French PHI patients. Non-B lineages are increasing and may be associated with more virulent CRF02_AG strains. The presence of large RTCs highlights the need for real-time cluster identification to trigger specific prevention action to achieve better control of the epidemic.
Asunto(s)
Farmacorresistencia Viral/genética , Monitoreo Epidemiológico , Variación Genética , Infecciones por VIH/epidemiología , VIH-1/genética , Adulto , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Evolución Molecular , Femenino , Francia/epidemiología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Filogenia , Análisis de Secuencia de ADN , Minorías Sexuales y de Género , Carga Viral , VirulenciaRESUMEN
OBJECTIVES: In a context of life-long therapy, we asked whether it could be possible to reduce the number of antiretroviral drugs without jeopardizing viral suppression. METHODS: ECOVIR was a prospective study aiming to assess whether in patients on combination ART with ≥4 antiretrovirals for ≥24 weeks and virally suppressed for ≥48 weeks, a drug-reduced (DR) regimen could be proposed. The intervention consisted of discontinuing genotypically less susceptible drugs to reach a DR regimen with ≤3 antiretrovirals. The primary endpoint was the proportion of patients maintaining viral suppression at week (W) 24. RESULTS: From 89 eligible individuals for the study, a DR regimen was proposed in 86 (97%) patients, of whom 71 were switched to a DR regimen. Baseline characteristics [median (IQR)] were: age 58 (53-65) years, duration of treatment 24 (21-26) years and viral suppression 8 (6-11) years. The cumulative resistance profile showed full resistance to lamivudine/emtricitabine (91%), abacavir (74%), efavirenz/nevirapine (70%), rilpivirine (56%), darunavir (q24h/q12h) (42%/29%), lopinavir (69%), atazanavir (71%) and raltegravir (24%). The final DR regimen consisted of a two-drug or three-drug regimen in 54 patients (76%) and in 17 patients (24%), respectively. The success rate of a DR regimen at W24 was 93.9% (95% CI 84.4-97.6, Kaplan-Meier estimate). Four patients experienced virological failure (at W4, W8 and W12), all with plasma viral load (pVL) <600 copies/mL and no emergence of resistance mutations. The DR strategy allowed a monthly cost saving of 36%. CONCLUSIONS: In experienced patients with high-level resistance, individualized strategies based on expert advice can offer DR regimen options with fewer drug-drug interactions and a significant economic impact while ensuring virological success.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Adulto , Anciano , Fármacos Anti-VIH/farmacología , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Farmacorresistencia Viral , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
OBJECTIVES: To further characterize HIV-1 viruses of patients experiencing unexplained virological failure (VF) on PI-containing regimens, ultradeep sequencing was performed on protease, gag and gp41 genes in patients failing a first-line treatment. METHODS: All naive patients initiating an antiretroviral treatment based on boosted darunavir, atazanavir or lopinavir and experiencing VF without any transmitted drug resistance mutation detected by Sanger sequencing on protease and reverse transcriptase genes were selected. Ultradeep sequencing (IlluminaTM Nextera®) was performed on protease, gag and gp41 genes in plasma before initiation of treatment and at VF to identify emergent mutations. RESULTS: Among the 32 patients included in the study, emergent and previously undescribed mutations in the viral protease gene were identified in five patients at VF: 64M (1 CRF02_AG), 64M/70R with mutation 15V (2 CRF02_AG), 79A (1 CRF06_cpx) and 79A with mutation 15V (1 CRF02_AG). Two patients showed the emergence of R286K in the gag region, outside of cleavage sites (2 CRF02_AG). In the gp41 region, the V321I mutation emerged inside the cytoplasmic tail (1 subtype A and 1 subtype B). All these patients were treated with a darunavir/ritonavir-based regimen. CONCLUSIONS: In some cases of VF to PIs, we observed the emergence of protease, Gag or Gp41 mutations that had not previously been associated with VF or PI resistance. These mutations should be further studied, in particular the 15V/64M/70R pattern in the protease gene identified among CRF02_AG viruses.
Asunto(s)
Farmacorresistencia Viral , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Adulto , Femenino , Proteína gp41 de Envoltorio del VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Carga Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
OBJECTIVES: We estimated the prevalence of transmitted-drug-resistance-associated mutations (TDRAMs) in antiretroviral-naive chronically HIV-1-infected patients. PATIENTS AND METHODS: TDRAMs were sought in samples from 660 diagnosed HIV-1-infected individuals in 2015/2016 in 33 HIV clinical centres. Weighted analyses, considering the number of patients followed in each centre, were used to derive representative estimates of the percentage of individuals with TDRAMs. Results were compared with those of the 2010/2011 survey (nâ=â661) using the same methodology. RESULTS: At inclusion, median CD4 cell counts and plasma HIV-1 RNA were 394 and 350/mm3 (Pâ=â0.056) and 4.6 and 4.6 log10 copies/mL (Pâ=â0.360) in the 2010/2011 survey and the 2015/2016 survey, respectively. The frequency of non-B subtypes increased from 42.9% in 2010/2011 to 54.8% in 2015/2016 (P < 0.001), including 23.4% and 30.6% of CRF02_AG (Pâ=â0.004). The prevalence of virus with protease or reverse-transcriptase TDRAMs was 9.0% (95% CIâ=â6.8-11.2) in 2010/2011 and 10.8% (95% CIâ=â8.4-13.2) in 2015/2016 (Pâ=â0.269). No significant increase was observed in integrase inhibitor TDRAMs (6.7% versus 9.2%, Pâ=â0.146). Multivariable analysis showed that men infected with the B subtype were the group with the highest risk of being infected with a resistant virus compared with others (adjusted ORâ=â2.2, 95% CIâ=â1.3-3.9). CONCLUSIONS: In France in 2015/2016, the overall prevalence of TDRAMs was 10.8% and stable compared with 9.0% in the 2010/2011 survey. Non-B subtypes dramatically increased after 2010. Men infected with B subtype were the group with the highest risk of being infected with a resistant virus, highlighting the need to re-emphasize safe sex messages.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/transmisión , VIH-1/genética , Mutación , Adulto , Recuento de Linfocito CD4 , Enfermedad Crónica/epidemiología , Femenino , Francia/epidemiología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Seropositividad para VIH/epidemiología , VIH-1/clasificación , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , ARN Viral/sangreRESUMEN
BackgroundEnding the HIV pandemic must involve new tools to rapidly identify and control local outbreaks and prevent the emergence of recombinant strains with epidemiological advantages.AimThis observational study aimed to investigate in France a cluster of HIV-1 cases related to a new circulating recombinant form (CRF). The confirmation this CRF's novelty as well as measures to control its spread are presented.MethodsPhylogenetic analyses of HIV sequences routinely generated for drug resistance genotyping before 2018 in French laboratories were employed to detect the transmission chain. The CRF involved was characterised by almost full-length viral sequencing for six cases. Cases' clinical data were reviewed. Where possible, epidemiological information was collected with a questionnaire.ResultsThe transmission cluster comprised 49 cases, mostly diagnosed in 2016-2017 (n = 37). All were infected with a new CRF, CRF94_cpx. The molecular proximity of this CRF to X4 strains and the high median viraemia, exceeding 5.0 log10 copies/mL, at diagnosis, even in chronic infection, raise concerns of enhanced virulence. Overall, 41 cases were diagnosed in the Ile-de-France region and 45 were men who have sex with men. Among 24 cases with available information, 20 reported finding partners through a geosocial networking app. Prevention activities in the area and population affected were undertaken.ConclusionWe advocate the systematic use of routinely generated HIV molecular data by a dedicated reactive network, to improve and accelerate targeted prevention interventions. Geosocial networking apps can play a role in the spread of outbreaks, but could also deliver local targeted preventive alerts.
Asunto(s)
Infecciones por VIH/transmisión , VIH-1/clasificación , VIH-1/genética , Filogenia , Recombinación Genética , Adulto , Análisis por Conglomerados , ADN Viral/genética , Brotes de Enfermedades/prevención & control , Farmacorresistencia Viral/genética , Francia/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Masculino , Redes Sociales en Línea , Filogeografía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Minorías Sexuales y de Género/estadística & datos numéricos , Carga Viral , Viremia/virología , Virulencia , Secuenciación Completa del GenomaRESUMEN
OBJECTIVES: Characterization of the conditions favouring HIV-1 low-level viraemia (LLV) during treatment is required to guide strategies for prevention and cure. METHODS: The characteristics and treatments of 171 patients experiencing a confirmed LLV of 50-1000 copies/mL (PLLVs) were compared with those of 146 patients with persistently controlled viraemia. We analysed the risk factors for LLV, the parameters affecting the level of viraemia and the presence of resistance-associated mutations (RAMs). We compared outcomes for PLLVs on fully effective HAART as a function of treatment modifications. RESULTS: LLV was <500 copies/mL in at least 90% of cases. A higher zenith viral load (VL) (5.27 versus 4.91 log10 copies/mL, OR 2.23; Pâ=â0.0003), a shorter time on continuous HAART (4.3 versus 6.8 years, OR 0.88; Pâ=â0.0003) and previously detected RAMs (43% versus 23%, OR 2.42; Pâ=â0.0033) were independent predictors of LLV. NNRTIs were less frequently used in PLLVs and were associated with more stable treatment. The presence of any RAM during LLV was associated with a lower zenith VL and a higher LLV. In the absence of resistance, virological success was achieved in similar proportions of patients with and without treatment modification. CONCLUSIONS: Viraemia >500 copies/mL should no longer be considered to be LLV. In patients with a high zenith VL, several years on continuous HAART may be required to decrease the HIV reservoir and prevent LLV. Resistance testing is useful to detect RAMs, leading if necessary to treatment modifications. In the absence of resistance, treatment changes seemed dispensable.
Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Carga Viral , Viremia , Adulto , Farmacorresistencia Viral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: Resistant minority variants present before ART can be a source of virological failure. This has been shown for NRTIs, NNRTIs and CCR5 inhibitors. However, very few data are available for the detection of such minority resistant variants that could be selected at virological failure and not detected using classical Sanger sequencing. METHODS: We studied 26 patients treated with tenofovir, emtricitabine and efavirenz with their first virological failure (defined as two consecutive viral loads >50 copies/mL). We performed standard Sanger sequencing and ultradeep sequencing (UDS; Roche 454(®) Life Sciences) in plasma at failure. For UDS, mutations >1% were considered. We compared the presence of reverse transcriptase mutations between the two techniques, using the latest ANRS algorithm. RESULTS: UDS detected more resistance mutations in 38.5% of cases (10/26 patients) and the genotypic sensitivity score (GSS) was reduced for 6 of them (23.1%). The GSS was impacted more often for NRTIs than for NNRTIs, for which most mutations were already detected by Sanger sequencing. Resistant minority variants were detected even in patients with low viral load at failure. CONCLUSIONS: These results strongly argue for the use of next-generation sequencing in patients failing on an NRTI+NNRTI regimen, as UDS has the potential to modify the choice of the subsequent regimen.
Asunto(s)
Fármacos Anti-VIH/farmacología , Benzoxazinas/farmacología , Farmacorresistencia Viral , Emtricitabina/farmacología , VIH/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Tenofovir/farmacología , Alquinos , Ciclopropanos , Técnicas de Genotipaje/métodos , VIH/genética , Infecciones por VIH/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Plasma/virología , Insuficiencia del TratamientoRESUMEN
OBJECTIVES: HIV-1 integration can be efficiently inhibited by strand-transfer inhibitors such as raltegravir, elvitegravir or dolutegravir. Three pathways conferring raltegravir/elvitegravir cross-resistance (involving integrase residues Q148, N155 and Y143) were identified. Dolutegravir, belonging to the second generation of strand-transfer compounds, inhibits the Y143 and N155 pathways, but is less efficient at inhibiting the Q148 pathway. The aim of this study was to characterize the combination of two pathways involved in raltegravir resistance described in one patient failing a dolutegravir regimen for their propensity to confer dolutegravir resistance. METHODS: In this study, a patient first failing a regimen including raltegravir was treated with dolutegravir and showed an increase in viruses carrying a combination of two pathways (N155 and Q148). Impacts of these mutations on integrase activity and resistance to strand-transfer inhibitors were characterized using both in vitro and virological assays. RESULTS: Our data showed that the combination of N155H, G140S and Q148H mutations led to strong resistance to dolutegravir. CONCLUSIONS: Combination of N155H, G140S and Q148H mutations originating from two distinct resistance pathways to raltegravir or elvitegravir led to a high level of dolutegravir resistance. Due to its high genetic barrier of resistance, it would be reasonable to use dolutegravir in first-line therapy before emergence of raltegravir or elvitegravir resistance.