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1.
Antivir Ther ; 28(6): 13596535231220754, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38085652

RESUMEN

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks. METHODS: The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52. RESULTS: Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence. CONCLUSION: The gag sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.


Asunto(s)
Fármacos Anti-VIH , Inhibidores de Fusión de VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Maraviroc/uso terapéutico , Farmacorresistencia Viral/genética
2.
J Infect Dis ; 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38060982

RESUMEN

The activity of lenacapavir against HIV-1 has been extensively evaluated in vitro, but comparable data for HIV-2 are scarce. We determined the anti-HIV-2 activity of lenacapavir using single-cycle infections of MAGIC-5A cells and multicycle infections of a T cell line. Lenacapavir exhibited low-nanomolar activity against HIV-2, but was 11- to 14-fold less potent against HIV-2 in comparison to HIV-1. Mutations in HIV-2 that confer resistance to other antiretrovirals did not confer cross-resistance to lenacapavir. Although lenacapavir-containing regimens might be considered for appropriate patients with HIV-2, more frequent viral load and/or CD4 testing may be needed to assess clinical response.

3.
J Med Virol ; 95(12): e29292, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38063404

RESUMEN

Human immunodeficiency virus (HIV) capsid is one of the most recent viral proteins successfully targeted for the development of antiretrovirals. Lenacapavir is a first in class HIV-1 capsid inhibitor that was recently approved for the treatment of highly treatment-experienced people with HIV in combination with other anti-HIV drugs. Owing to the novelty of the viral target, methods to characterize the potential resistance-associated mutations present in capsid upon treatment failure have not been fully established yet. Here, we describe a rapid and simple method to amplify capsid fragments and to determine their sequence from various clinical samples including diverse HIV-1 subtypes. These methods could easily be implemented in laboratories, including hospital laboratories often caring for this patient population.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Cápside/metabolismo , VIH-1/genética , Genotipo , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Mutación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico
4.
Lancet HIV ; 10(8): e497-e505, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37451297

RESUMEN

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Infecciones por VIH/tratamiento farmacológico , Cápside , Piridonas/efectos adversos , Fármacos Anti-VIH/efectos adversos , ARN/uso terapéutico , Carga Viral
5.
J Med Virol ; 95(4): e28723, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37185867

RESUMEN

Tenofovir alafenamide (TAF) is a prodrug of the nucleoside reverse transcriptase (RT) inhibitor tenofovir (TFV). Compared to the earlier TFV prodrug, TFV disoproxil fumarate (TDF), TAF achieves more than fourfold-higher intracellular levels of its active metabolite TFV diphosphate (TFV-DP) in clinical studies, while achieving a significant reduction of TFV systemic exposure. Resistance to TFV has been well established, with the K65R mutation in RT as the signature mutation. Here we evaluated the in vitro activity of TAF and TDF in patient-derived HIV-1 isolates harboring the K65R mutation. Clinical isolates containing K65R were cloned into the pXXLAI construct (n = 42). In vitro phenotypic susceptibility of the constructs to TAF and TDF was evaluated in an MT-2 cell HIV assay and in viral breakthrough assays modeling physiological concentrations of TAF and TDF. TAF and TDF susceptibility were highly correlated in K65R-containing mutants, ranging from 2.7- to 3.0-fold (K65R alone) and 1.2- to 27.6-fold (K65R+ other RT mutations) relative to wild-type. In viral breakthrough assays mimicking differences in physiological concentrations, TAF inhibited breakthrough of 40 of 42 clinical isolates, while the TDF equivalent only inhibited 32 of 42 isolates tested. TAF displayed a higher barrier to resistance than TDF in this panel of K65R-containing clinical isolates.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Profármacos , Humanos , VIH-1/genética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Profármacos/farmacología , Tenofovir/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Alanina/farmacología , Alanina/uso terapéutico
6.
J Infect Dis ; 226(11): 1985-1991, 2022 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-36082606

RESUMEN

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. METHODS: CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. RESULTS: At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. CONCLUSIONS: LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Farmacorresistencia Viral/genética , Cápside , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , VIH-1/genética , Antirretrovirales/uso terapéutico
7.
N Engl J Med ; 386(19): 1793-1803, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35544387

RESUMEN

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).


Asunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral Múltiple , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Cápside , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , ARN Viral , Carga Viral
8.
J Antimicrob Chemother ; 77(4): 989-995, 2022 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-35028668

RESUMEN

BACKGROUND: Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility. OBJECTIVES: To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resistance analyses conducted in a Phase 1b study of lenacapavir (Study 4072) in people with HIV (PWH). METHODS: Mutations were inserted in a proviral DNA clone by site-directed mutagenesis, and viruses (n = 12) were generated by transfection. Sequences were used to generate single-cycle (SC) test vectors that were evaluated in a Gag-Pro assay, and replicative viruses were tested in a multicycle (MC) MT-2 assay to determine lenacapavir susceptibility. Study 4072 was a Phase 1b, double-blinded, placebo-controlled, dose-ranging, randomized study of lenacapavir in untreated PWH. Participants received a single dose of lenacapavir (up to 750 mg) or placebo (10 day monotherapy). CA resistance was characterized using genotypic and/or phenotypic assays. RESULTS: Lenacapavir susceptibility in the SC assay showed an inverse relationship between replication capacity and resistance. In Study 4072, all 29 participants receiving lenacapavir showed a robust virological response with no rebound. At baseline, no participant had resistance mutations to lenacapavir, and all had WT susceptibility to lenacapavir. Post-monotherapy analyses revealed the emergence of CA mutation Q67H at Day 10 in two participants. CONCLUSIONS: In vitro assays confirmed that increased resistance to lenacapavir was associated with decreased replication capacity of mutant viruses. In the clinical study no pre-existing lenacapavir resistance was detected. Emergence of Q67H occurred at exposures below the dose used in current Phase 2/3 studies. These results support development of lenacapavir as an antiretroviral agent.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Mutación
9.
AIDS ; 36(2): 205-214, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34586088

RESUMEN

OBJECTIVE: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. METHODS: Four cohorts with participants who initiated ART during acute infection or during chronic infection were enrolled in a cross-sectional, noninterventional study. Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIV DNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. RESULTS: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. CONCLUSION: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.


Asunto(s)
Infecciones por VIH , VIH-1 , Antirretrovirales/uso terapéutico , Anticuerpos ampliamente neutralizantes , Estudios Transversales , VIH-1/genética , Humanos , Carga Viral
10.
J Acquir Immune Defic Syndr ; 86(4): 490-495, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33315694

RESUMEN

BACKGROUND: The ability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) to maintain virologic suppression in participants with M184V and/or M184I resistance mutations from historical genotypic reports when switching from a tenofovir disoproxil fumarate-based or abacavir (ABC)-based regimen was investigated. SETTING: Phase IIIb, 48-week, open-label, single-arm, multicenter, clinical trial (NCT02616029). METHODS: Virologically suppressed adults with HIV and documented M184V/I on historical genotypic records switched to E/C/F/TAF from a tenofovir disoproxil fumarate-based or ABC-based regimen. The primary end point was HIV-1 RNA of <50 copies per milliliter at week 12 using pure virologic response (PVR). Secondary end points included HIV-1 RNA of <50 copies per milliliter at weeks 24/48 (PVR) and at weeks 12, 24, and 48 (Food and Drug Administration snapshot algorithm), and change in CD4+ count at weeks 12, 24, and 48. RESULTS: M184V alone was reported in 82.8% of 64 participants; 9.4% and 7.8% had M184I and M184V/I, respectively, and 43.8% had archived M184V/I (baseline DNA). All (62/62 with available data, 100%, 95% confidence interval 94.2% to 100%) participants maintained PVR at weeks 12, 24, and 48. By Food and Drug Administration snapshot algorithm, one participant had HIV-1 RNA of ≥50 copies per milliliter (week 12); confirmatory HIV-1 RNA was <50 copies per milliliter. No significant changes were observed in CD4+ cell count. Drug-related adverse events (AEs) were reported by 10 (15.6%) participants. Six (9.4%) and 5 (7.8%) participants had grade 3-4 AEs or serious AEs, respectively (none drug related). CONCLUSIONS: The presence of the resistance mutations M184V/I did not jeopardize the efficacy of switching to E/C/F/TAF in virologically suppressed adults. High rates of virologic suppression were maintained throughout 48 weeks of therapy and treatment was well tolerated.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Adulto , Anciano , Alanina/administración & dosificación , Alanina/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Cobicistat/administración & dosificación , Cobicistat/uso terapéutico , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , Femenino , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Quinolonas/administración & dosificación , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Tenofovir/uso terapéutico , Adulto Joven
11.
Artículo en Inglés | MEDLINE | ID: mdl-33288639

RESUMEN

Lenacapavir (LEN; GS-6207) is a potent first-in-class inhibitor of HIV-1 capsid with long-acting properties and the potential for subcutaneous dosing every 3 months or longer. In the clinic, a single subcutaneous LEN injection (20 mg to 750 mg) in people with HIV (PWH) induced a strong antiviral response, with a >2.3 mean log10 decrease in HIV-1 RNA at day 10. HIV-1 Gag mutations near protease (PR) cleavage sites have emerged with the use of protease inhibitors (PIs). Here, we have characterized the activity of LEN in mutants with Gag cleavage site mutations (GCSMs) and mutants resistant to other drug classes. HIV mutations were inserted into the pXXLAI clone, and the resulting mutants (n = 70) were evaluated using a 5-day antiviral assay. LEN EC50 fold change versus the wild type ranged from 0.4 to 1.9 in these mutants, similar to that for the control drug. In contrast, reduced susceptibility to PIs and maturation inhibitors (MIs) was observed. Testing of isolates with resistance against the 4 main classes of drugs (n = 40) indicated wild-type susceptibility to LEN (fold change ranging from 0.3 to 1.1), while reduced susceptibility was observed for control drugs. HIV GCSMs did not impact the activity of LEN, while some conferred resistance to MIs and PIs. Similarly, LEN activity was not affected by naturally occurring variations in HIV Gag, in contrast to the reduced susceptibility observed for MIs. Finally, the activity of LEN was not affected by the presence of resistance mutations to the 4 main antiretroviral (ARV) drug classes. These data support the evaluation of LEN in PWH with multiclass resistance.


Asunto(s)
Infecciones por VIH , Inhibidores de la Proteasa del VIH , VIH-1 , Preparaciones Farmacéuticas , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Humanos , Mutación , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética
12.
J Antimicrob Chemother ; 75(8): 2249-2252, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32413134

RESUMEN

BACKGROUND: The M184V/I reverse transcriptase mutation, which confers major resistance to lamivudine and emtricitabine, is still quite frequent in people living with HIV. The underlying presence of the M184V/I mutation may undermine virological outcomes of ART, particularly in the context of proposed treatment with two-drug combinations that include drugs affected by M184V, such as lamivudine. In suppressed patients for whom historical data are seldom available, resistance assays evaluating integrated viral DNA can help select a fully active switch regimen. OBJECTIVES: To compare detectability of M184V/I in historical HIV-1 RNA analyses versus HIV-1 DNA sequencing. METHODS: We analysed the detection of the M184V/I mutation in a prospective study and compared HIV historical genotypes (plasma) versus integrated HIV DNA (PBMCs) obtained via a validated commercial proviral HIV DNA assay. Eligible participants had HIV-1 RNA <50 copies/mL for ≥6 consecutive months prior to screening. A plasma historical genotypic report (HGR) showing the presence of M184V/I was required for all participants and proviral HIV DNA analysis was conducted prior to enrolment. RESULTS: All 84 participants had evidence of M184V or M184I in their HGR (100%), whereas the mutation was detected in only 40/84 participants by proviral HIV DNA sequencing analysis (48%). Differential detection of M184V/I was not associated with timing differences between the HGR and proviral HIV DNA sampling, the overall duration of ART, or CD4 cell counts and HIV-1 viral load at baseline. CONCLUSIONS: Our results suggest that undetected M184V/I should be considered when switching virologically suppressed patients to new regimens, particularly two-drug lamivudine- or emtricitabine-containing combinations.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Preparaciones Farmacéuticas , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Genotipo , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Lamivudine/uso terapéutico , Mutación , Estudios Prospectivos , Carga Viral
13.
Antivir Ther ; 25(3): 163-169, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32420906

RESUMEN

BACKGROUND: Vesatolimod (VES; GS-9620) is a Toll-like receptor 7 (TLR7) agonist that directly activates human plasmacytoid dendritic cells (pDCs) and B lymphocytes resulting in direct and indirect production of cytokines and immune activation. VES is being evaluated in HIV-1-infected people as part of an HIV remission strategy. Here we investigated the potential of VES to trigger indirect activation of HIV-specific CD8+ T-cells using immune cell cultures derived from HIV+ donors. METHODS: Peripheral blood mononuclear cell (PBMC) cultures derived from HIV+ donors virologically suppressed on stable antiretroviral therapy (n=31) were isolated and treated with VES or vehicle for 24 h. Cells were stained with surface and intracellular fluorescent conjugated antibodies and HIV-specific pentamers, and analysed by flow cytometry. RESULTS: Treatment of PBMCs with VES resulted in all 31 donors demonstrating a concentration dependent increase in CD8+ T-cell activation (CD69+) of up to 88%. Of these donors, 20 of 31 donors displayed a concentration-dependent increase in HIV-specific CD8+ T-cell activation due to VES with a maximum of 20.8%. Intracellular staining was performed in a subset of donors (n=14), 5 of which displayed VES-induced activation of functional HIV-specific CD8+ T-cells as assessed by CD107a and/or tumour necrosis factor (TNF)-α upregulation. CONCLUSIONS: This study demonstrates that VES treatment can induce the activation of functional HIV-specific CD8+ T-cells in donor derived PBMCs. These data support the potential use of VES to activate functional HIV-specific CD8+ T-cells as part of an HIV remission strategy.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Pteridinas/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Relación Dosis-Respuesta a Droga , Citometría de Flujo , VIH/inmunología , Infecciones por VIH/inmunología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos
14.
J Antimicrob Chemother ; 75(6): 1588-1590, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32154864

RESUMEN

BACKGROUND: GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207. OBJECTIVES: To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH). METHODS: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N. RESULTS: Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history. CONCLUSIONS: Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Cápside , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Mutación
15.
Artículo en Inglés | MEDLINE | ID: mdl-31988104

RESUMEN

Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are prodrugs of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). In vivo, TAF achieves >4-fold-higher intracellular levels of TFV diphosphate (TFV-DP) compared to TDF. Since thymidine analog-associated mutations (TAMs) in HIV-1 confer reduced TFV susceptibility, patients with TAM-containing HIV-1 may benefit from higher TFV-DP levels delivered by TAF. Moreover, the presence of the M184V mutation increases TFV susceptibility during TDF- or TAF-based therapy. The susceptibilities to antiviral drugs of site-directed mutants (SDMs) and patient-derived mutants containing combinations of TAMs (M41L, D67N, K70R, L210W, T215Y, and K219Q) with or without the M184V mutation (TAMs±M184V) were evaluated using either 5-day multicycle (MC; n = 110) or 2-day single-cycle (SC; n = 96) HIV assays. The presence of M184V in TAM-containing HIV-1 SDMs (n = 48) significantly increased TAF sensitivity compared to SDMs without M184V (n = 48). The comparison of TAF and TDF resistance profiles was further assessed in viral breakthrough (VB) experiments mimicking clinically relevant drug concentrations. A total of 68 mutants were assayed at physiological concentration in VB experiments, with 15/68 mutants breaking through with TDF (TFV, the in vitro equivalent of TDF, was used in these experiments), and only 3 of 68 mutants breaking through under TAF treatment. Overall, in the VB assay mimicking the 4-fold-higher intracellular levels of TFV-DP observed clinically with TAF versus TDF, TAF inhibited viral breakthrough of most TAM-containing HIV-1, whereas TDF did not. These results indicate that TAF has a higher resistance threshold than TDF and suggest that higher resistance cutoffs should be applied for TAF compared to TDF in genotypic and phenotypic resistance algorithms.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Adenina/farmacología , Alanina , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Mutagénesis Sitio-Dirigida , Profármacos/farmacología , Tenofovir/farmacología , Timidina/análogos & derivados
16.
Dig Liver Dis ; 52(2): 214-220, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31427089

RESUMEN

BACKGROUND: Indication for adjuvant chemotherapy in ypN0 rectal cancer patients after chemoradiotherapy (CRT) is debated. The clinical significance of the presence of sterilized lymph nodes (LNS) in ypN0 patients remains to be determined. AIMS: To assess the prognostic value of LNS in ypN0 rectal cancers after neoadjuvant CRT. METHODS: From 2006-2016, 235 patients underwent TME surgery for non-metastatic mid-low rectal cancer after CRT. A lymph node was considered sterilized if there were signs of treatment response (fibrosis, necrosis or mucus) without residual tumor cells. RESULTS: 180 patients (77%) were classified ypN0 and 55 (23%) ypN+. LNS was present in 20 patients (9%). In ypN0 patients, 5-year OS was similar between patients with and without LNS. In contrast, 5-year DFS was significantly lower in ypN0/LNS + patients (58% vs. 78%, p = 0.043) and was similar to those staged ypN+. In multivariate analysis, two factors were independent predictors of DFS: mesorectal grading (OR = 3.14; 95%CI: 1.10-8.34; p = 0.033) and the presence of LNS (OR = 3.93, 95% CI: 1.06-11.81, p = 0.042) CONCLUSION: The presence of LNS in ypN0 rectal cancer after neoadjuvant CRT is associated with an increased risk of recurrence and may be taken into account for the discussion of adjuvant chemotherapy.


Asunto(s)
Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasia Residual , Cuidados Preoperatorios , Estudios Retrospectivos , Tasa de Supervivencia , Adulto Joven
17.
J Med Virol ; 91(12): 2188-2194, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31389026

RESUMEN

The development of resistance to human immunodeficiency virus 1 (HIV-1) integrase strand-transfer inhibitors (INSTI) has been documented; however, knowledge of the impact of pre-existing integrase (IN) mutations on INSTI resistance (INSTI-R) is still evolving. The frequency of HIV-1 IN mutations in 2177 treatment-naïve subjects was investigated, along with the INSTI susceptibility of site-directed mutant viruses containing major and minor INSTI-R mutations. Total 6 of 39 minor INSTI-R mutations (M50I, S119P/G/T/R, and E157Q) were found in >1% of IN-treatment-naïve subjects with no impact on INSTI susceptibility. When each combined with major INSTI-R mutation, M50I, S119P, and E157Q led to decreased susceptibility to elvitegravir but remained sensitive to dolutegravir and bictegravir.


Asunto(s)
Farmacorresistencia Viral/genética , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Amidas , Infecciones por VIH/virología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Mutación , Oxazinas , Piperazinas , Polimorfismo Genético , Piridonas , Quinolonas/farmacología
18.
Dis Colon Rectum ; 62(1): 88-96, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30451748

RESUMEN

BACKGROUND: C-reactive protein is a useful negative predictive test for the development of anastomotic leakage following colorectal surgery. Evolution of procedures (laparoscopy, enhanced recovery program, early discharge, complex redo surgery) may influence C-reactive protein values; however, this is poorly studied to date. OBJECTIVE: The aim of this study is to evaluate C-reactive protein as an indicator of postoperative complication and as a predictor for discharge. DESIGN: This is retrospective study of a consecutive monocentric cohort. SETTINGS: All patients undergoing a colorectal resection with anastomosis (2014-2015) were included. MAIN OUTCOMES MEASURES: C-reactive protein, leukocytosis, type of resection, and postoperative course were the primary outcomes measured. RESULTS: A total of 522 patients were included. The majority had either a colorectal (n = 159, 31%) or coloanal anastomosis (n = 150, 29%). Overall morbidity was 29.3%. C-reactive protein was significantly higher among patient having intra-abdominal complications at an early stage (day 1-2) (164.6 vs 136.2; p = 0.0028) and late stage (day 3-4) (209.4 vs 132.1; p < 0.0001). In multivariate analysis, early C-reactive protein was associated with BMI (coefficient, 4.9; 95% CI, 3.2-6.5; p < 0.0001) and open surgical procedures (coefficient, 43.1; 95% CI, 27-59.1; p < 0.0001), while late C-reactive protein value was influenced by BMI (coefficient, 4.8; 95% CI, 2.5-7.0; p = 0.0024) and associated extracolonic procedures (coefficient, 34.2; 95% CI, 2.7-65.6; p = 0.033). Sensitivity, specificity, negative predictive values, and positive predictive values for intra-abdominal complication were 85.9%, 33.6%, 89.3%, and 27.1% for an early C-reactive protein <100 mg/L and 72.7%, 75.4%, 89.4%, and 49.2% for a late C-reactive protein <100 mg/L. Four hundred seven patients with an uneventful postoperative course were discharged at day 8 ± 6.4 with a mean discharge C-reactive protein of 83.5 ± 67.4. Thirty-eight patients (9.3%) were readmitted and had a significantly higher discharge C-reactive protein (138.6 ± 94.1 vs 77.8 ± 61.2, p = 0.0004). Readmission rate was 16.5% for patients with a discharge C-reactive protein >100 mg/L vs 6% with C-reactive protein <100 mg/L (p = 0.0008). For patients included in an enhanced recovery program (discharge at day 4 ± 2.4), the threshold should be higher because discharge is around day 3 or 4. With a C-reactive protein <140, readmission rate was 2% vs 19%, (p = 0.056). LIMITATIONS: This study includes retrospective data. CONCLUSION: C-reactive protein <100 mg/L is associated with a lower risk of intra-abdominal complication and readmission rates. See Video Abstract at http://links.lww.com/DCR/A749.


Asunto(s)
Fuga Anastomótica/diagnóstico , Proteína C-Reactiva/metabolismo , Colectomía , Proctectomía , Adulto , Anciano , Fuga Anastomótica/metabolismo , Femenino , Humanos , Recuento de Leucocitos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Alta del Paciente , Readmisión del Paciente/estadística & datos numéricos , Periodo Posoperatorio , Estudios Retrospectivos , Sensibilidad y Especificidad
19.
J Med Virol ; 91(5): 890-893, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30548936

RESUMEN

An human immunodeficiency virus (HIV)-1 integrase (IN) genotyping assay was developed to evaluate clinical samples from patients infected with HIV-1 subtype AE, a subtype highly prevalent in Asia. The HIV-1 IN gene was amplified from plasma-derived HIV-1 viral RNA via reverse transcription polymerase chain reaction followed by population sequencing. Assay sensitivity was also evaluated using serially diluted plasma samples. The genotyping assay successfully amplified the IN gene from patient plasma samples with HIV-1 RNA as low as 500 copies/mL. This assay is suitable for IN genotyping to identify IN drug resistance mutations in HIV-1 patients harboring subtype AE virus.


Asunto(s)
Técnicas de Genotipaje/métodos , Infecciones por VIH/virología , Integrasa de VIH/genética , VIH-1/clasificación , VIH-1/genética , Asia , Genotipo , Humanos , Sensibilidad y Especificidad
20.
J Clin Virol ; 103: 37-42, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29627709

RESUMEN

BACKGROUND: The single tablet regimen (STR) composed of elvitegravir (E), cobicistat (C), emtricitabine (F), and tenofovir alafenamide (TAF) (E/C/F/TAF) was compared to the STR composed of E, C, F, and tenofovir disoproxil fumarate (TDF) (E/C/F/TDF) in 2 phase 3 studies in 1733 HIV-1 infected treatment-naïve adults. Superior efficacy of E/C/F/TAF compared to E/C/F/TDF was demonstrated at Week 144 with 84% treatment success compared to 80%, respectively, along with significantly better outcomes of bone and renal safety. OBJECTIVES: Analyze the emergence of HIV-1 resistance in treatment-naïve adults receiving E/C/F/TAF for 144 weeks. STUDY DESIGN: We conducted an integrated resistance analysis of the 2 Phase 3 studies, comprising pretreatment HIV-1 sequencing for all participants (N = 1733) and post-baseline HIV-1 resistance analysis for participants with virologic failure (HIV-1 RNA ≥400 copies/mL). RESULTS: Primary resistance-associated mutations (RAMs) were observed pre-treatment in 7.4% (NRTI-RAMs), 18.1% (NNRTI-RAMs), and 3.3% (PI-RAMs) of enrolled subjects. Baseline HIV-1 subtype or pre-existing RAMs did not affect E/C/F/TAF treatment response at week 144. Virologic failure resistance analyses were conducted for 28/866 (3.2%) and 30/867 (3.5%) patients in the E/C/F/TAF and E/C/F/TDF arms, respectively. Over the 3-year study, the rate of resistance emergence remained low at 1.4% in each group (12/866 in E/C/F/TAF; 12/867 in E/C/F/TDF). Resistant virus emerged in 24 patients who developed resistance to antiretrovirals in the regimens (E/C/F/TAF: M184V/I [1.3%], INSTI-RAMs [0.9%], K65R/N [0.2%]; E/C/F/TDF: M184V/I [1.0%], INSTI-RAMs [0.9%], K65R/N [0.5%]). CONCLUSIONS: Resistance emergence was rare (1.4%) with similar patterns of emergent mutations in both groups. M184V/I was the most prevalent RAM (1.2% overall).


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Adulto , Fármacos Anti-VIH/farmacología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Tasa de Mutación , Prevalencia , Análisis de Secuencia de ADN , Resultado del Tratamiento
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