RESUMO
BACKGROUND: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per µL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING: ANRS MIE.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , HIV-2 , Ritonavir , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Adulto , Masculino , Feminino , HIV-2/efeitos dos fármacos , Tenofovir/uso terapêutico , Tenofovir/efeitos adversos , Projetos Piloto , Contagem de Linfócito CD4 , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Resultado do Tratamento , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Lopinavir/uso terapêutico , Lopinavir/efeitos adversos , Lopinavir/administração & dosagem , Raltegravir Potássico/uso terapêutico , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/administração & dosagem , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Carga Viral/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade , Pessoa de Meia-Idade , Zidovudina/uso terapêutico , Zidovudina/efeitos adversos , Zidovudina/administração & dosagem , Quimioterapia Combinada , HIV-1/efeitos dos fármacosRESUMO
Human immunodeficiency viruses induce rare attenuated diseases due either to HIV-1 in the exceptional long-term nonprogressors (LTNPs) or to HIV-2 in West Africa. To better understand characteristics of these two disease types we performed a multiplex comparative analysis of cell activation, exhaustion, and expression of coreceptors and restriction factors in CD4 T cells susceptible to harbor those viruses. We analyzed by flow cytometry the expression of HLA-DR, PD1, CCR5, CXCR6, SAMHD1, Blimp-1, and TRIM5α on CD4 T cell subsets from 10 HIV-1+ LTNPs and 14 HIV-2+ (12 nonprogressors and 2 progressors) of the ANRS CO-15 and CO-5 cohorts, respectively, and 12 HIV- healthy donors (HD). The V3 loop of the HIV-1 envelope from 6 HIV-1+ LTNPs was sequenced to determine the CXCR6-binding capacity. Proportions of HLA-DR+ and PD1+ cells were higher in memory CD4 T subsets from HIV-1 LTNPs compared with HIV-2 and HD. Similar findings were observed for CCR5+ cells although limited to central-memory CD4 T cell (TCM) and follicular helper T cell subsets, whereas all major subsets from HIV-1 LTNPs contained less CXCR6+ cells compared with HIV-2. All six V3 loop sequences from HIV-1 LTNPs contained a proline at position 326. Proportions of SAMHD1+ cells were higher in all resting CD4 T subsets from HIV-1 LTNPs compared with the other groups, whereas Blimp-1+ and Trim5α+ cells did not differ. The CD4 T cell subsets from HIV-1 LTNPs differ from those of HIV-2-infected subjects by higher levels of activation, exhaustion, and SAMHD1 expression that can reflect the distinct patterns of host/virus relationships.
Assuntos
Infecções por HIV , HIV-1 , Fatores de Restrição Antivirais , Linfócitos T CD4-Positivos , Sobreviventes de Longo Prazo ao HIV , HIV-2 , Humanos , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/µL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/µL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/µL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.
Assuntos
Células Dendríticas/imunologia , Infecções por HIV/imunologia , HIV-2/imunologia , Monócitos/imunologia , Proteínas Supressoras de Tumor/imunologia , Adulto , África Ocidental/etnologia , Idoso , Biomarcadores/sangue , População Negra , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Infecções por HIV/diagnóstico , Infecções por HIV/etnologia , Infecções por HIV/metabolismo , Sobreviventes de Longo Prazo ao HIV , Interações Hospedeiro-Patógeno , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Paris/epidemiologia , Fenótipo , Proteínas Supressoras de Tumor/sangue , Adulto JovemRESUMO
The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/metabolismo , Infecções por HIV/metabolismo , HIV-2/imunologia , Memória Imunológica/imunologia , Leucócitos Mononucleares/metabolismo , Receptores CXCR6/metabolismo , Adulto , Idoso , Fatores de Restrição Antivirais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Células Cultivadas , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-2/genética , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR6/genética , Transcriptoma , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
OBJECTIVE: HIV-1 and HIV-2 differ notably in their epidemiology, with worldwide HIV-1 spread and HIV-2 mainly confined to West Africa. Natural killer (NK) cells are critical antiviral effectors of the immune system; however, limited information is available about these innate effector cells during HIV-2 infection. METHOD: In this study, 24 untreated HIV-2-infected patients were analyzed and compared with 21 long-term nonprogressor and 10 controller HIV-1 patients, and healthy donors. Extensive phenotype and functional NK-cell characteristics, as well as ligands of activating NK receptors involved in NK lysis were determined by flow cytometry. RESULTS: We report in HIV-2 patients a very significant reduced expression of the activating NKp30 receptor (Pâ<â0.0001) on NK cells, much higher than observed in HIV-1 patients. The impaired expression of NKp30 is correlated negatively with HLA-DR (râ=â-0.5970; Pâ=â0.0002), and positively with both NKG2A (râ=â0.5324; Pâ<â0.0001) and Siglec-7 (râ=â0.5621; Pâ=â0.0004). HIV-2 patients with NKp30 NK cells displayed overproduction of IFN-γ (Pâ<â0.0001) associated with impaired cytolytic function when tested against target cells expressing surface B7-H6. This cellular ligand of NKp30 is strongly detectable as a surface molecule on CD4 T cells infected by HIV-2. CONCLUSION: Altogether, our data suggested that the defective expression of NKp30 may be induced by the chronic engagement of this receptor by B7-H6 expressed on HIV-2-infected target cells. This represents a novel mechanism by which the chronic ligand exposure by the viral environment may subvert NK-cell-mediated function to establish persistent HIV-2 infection.
Assuntos
Antígenos B7/metabolismo , Regulação para Baixo , Infecções por HIV/virologia , HIV-2/patogenicidade , Evasão da Resposta Imune , Células Matadoras Naturais/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/biossíntese , Adulto , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Background: New options for first-line treatment of human immunodeficiency virus type 2 (HIV-2) infection are needed. We evaluated an integrase inhibitor (raltegravir)-containing regimen. Methods: Antiretroviral therapy (ART)-naive adults with symptomatic infection by HIV-2 only, CD4 count <500 cells/µL or CD4 decrease >50 cells/µL/year over the past 3 years, or a confirmed plasma HIV-2 RNA (pVL) load ≥100 copies/mL were eligible for this noncomparative trial. The composite primary endpoint was survival at 48 weeks without any of the following: CD4 gain from baseline <100 cells/µL, confirmed pVL ≥40 copies/mL from week 24, raltegravir permanent discontinuation, or incident B or C event. HIV-2 ultrasensitive pVL (uspVL) and total DNA were assessed using in-house polymerase chain reaction (PCR) assays. Results: Baseline median CD4 count of 30 enrolled individuals (67% women) was 436 cells/µL (interquartile range [IQR], 314-507 cells/µL); pVL was ≥40 copies/mL in 67% of them, uspVL was ≥5 copies/mL in 92%, and total DNA was >6 copies by PCR in 32%. At week 48, the composite endpoint of success was reached in 40% [95% confidence interval, 22.7%-59.4%]. Failure was mainly (50%) due to CD4 gain <100 cells/µL; uspVL was <5 copies/mL in 87% and total DNA >6 copies by PCR in 12% of participants. Median CD4 gain was 87 cells/µL (IQR, 38-213 cells/µL; n = 28). No serious adverse reactions were reported. Conclusions: Raltegravir-containing ART is a safe option for first-line treatment of HIV-2 infection, yielding a comparable success rate to protease inhibitors. Clinical Trials Registration: NCT 01605890.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Raltegravir Potássico/uso terapêutico , Tenofovir/uso terapêutico , Adulto , Idoso , Contagem de Linfócito CD4 , Estudos de Coortes , Quimioterapia Combinada , Feminino , HIV-2 , Humanos , Inibidores de Integrase/uso terapêutico , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga ViralRESUMO
Background: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). Methods: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. Results: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients. Conclusions: A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Estudos de Coortes , Europa (Continente) , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga ViralRESUMO
Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8(+) T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8(+) T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8(+) T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag-specific CD8(+) T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowledge, we show for the first time that HIV-2 controllers possess CD8(+) T cells that show an unusually strong capacity to suppress HIV-2 infection in autologous CD4(+) T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the preservation of potent immune functions, thus preventing HIV-2 disease progression.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-2/imunologia , Linfopoese/imunologia , Adulto , Idoso , Feminino , Infecções por HIV/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study was to describe HIV-2 R5/X4-tropism distribution in antiretroviral-naive HIV-2-infected patients. Population sequencing of the gp105 region was performed on peripheral blood mononuclear cells issued from 151 antiretroviral-naive patients. Tropism was successfully determined in 46 of 151 samples (30%) with six of 46 (13%) X4-tropic viruses. X4-tropism was associated with lower CD4 cell count (337 vs. 551/mm; Pâ=â0.032) but not with plasma viral load. Thus, X4-tropism prevalence in HIV-2 antiretroviral-naive patients is similar to that observed in HIV-1.
Assuntos
Infecções por HIV/virologia , HIV-2/isolamento & purificação , HIV-2/fisiologia , Receptores de HIV/metabolismo , Tropismo Viral , Adulto , Feminino , HIV-2/genética , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Internalização do Vírus , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
BACKGROUND: Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 susceptibility to cenicriviroc, a novel, once-daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection. METHODS: Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual-tropic HIV-2 clinical primary isolates. All isolates were obtained by co-cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist-naïve patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines. RESULTS: Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively. CONCLUSIONS: In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Infecções por HIV/patologia , HIV-2/isolamento & purificação , Imidazóis/farmacologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR5/química , Fármacos Anti-HIV/uso terapêutico , Antagonistas dos Receptores CCR5/uso terapêutico , Células Cultivadas , Técnicas de Cocultura , Cicloexanos/farmacologia , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-2/efeitos dos fármacos , HIV-2/fisiologia , Humanos , Imidazóis/uso terapêutico , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Maraviroc , Fenótipo , Fito-Hemaglutininas/farmacologia , Receptores CCR2/metabolismo , Receptores CCR5/metabolismo , Sulfóxidos , Triazóis/farmacologia , Triazóis/uso terapêutico , Replicação Viral/efeitos dos fármacosRESUMO
OBJECTIVE: In HIV-1, hypermutation introduced by APOBEC3F/3G cytidine deaminase activity leads to defective viruses. In-vivo impact of APOBEC3F/3G editing on HIV-2 sequences remains unknown. The objective of this study was to assess the level of APOBEC3F/3G editing in HIV-2-infected antiretroviral-naive patients. METHODS: Direct sequencing of vif and pol regions was performed on HIV-2 proviral DNA from antiretroviral-naive patients included in the French Agence Nationale de Recherches sur le SIDA et les hépatites virales CO5 HIV-2 cohort. Hypermutated sequences were identified using Hypermut2.0 program. HIV-1 proviral sequences from Genbank were also assessed. RESULTS: Among 82 antiretroviral-naive HIV-2-infected patients assessed, 15 (28.8%) and five (16.7%) displayed Vif proviral defective sequences in HIV-2 groups A and B, respectively. A lower proportion of defective sequences was observed in protease-reverse transcriptase region. A higher median number of G-to-A mutations was observed in HIV-2 group B than in group A, both in Vif and protease-reverse transcriptase regions (Pâ=â0.02 and Pâ=â0.006, respectively). Compared with HIV-1 Vif sequences, a higher number of Vif defective sequences was observed in HIV-2 group A (Pâ=â0.00001) and group B sequences (Pâ=â0.013). CONCLUSION: We showed for the first time a high level of APOBEC3F/3G editing in HIV-2 sequences from antiretroviral-naive patients. Our study reported a group effect with a significantly higher level of APOBEC3F/3G editing in HIV-2 group B than in group A sequences.
Assuntos
Citidina Desaminase/metabolismo , Citosina Desaminase/metabolismo , HIV-2/genética , RNA Viral/metabolismo , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Adulto , Estudos de Coortes , Biologia Computacional , DNA Viral/química , DNA Viral/genética , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Provírus/genética , Análise de Sequência de DNARESUMO
OBJECTIVES: It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. METHODS: This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. RESULTS: Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (ORâ=â2.75, 95% CIâ=â1.35-5.60, Pâ=â0.005); similar associations were observed for at least one MV versus no NRTI MVs (ORâ=â2.27, 95% CIâ=â0.76-6.77, Pâ=â0.140) and at least one MV versus no NNRTI MVs (ORâ=â2.41, 95% CIâ=â1.12-5.18, Pâ=â0.024). A dose-effect relationship between virological failure and mutational load was found. CONCLUSIONS: Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Biologia Computacional , Europa (Continente) , Feminino , Genótipo , HIV-1/genética , HIV-1/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Medição de Risco , Análise de Sequência de DNA , Falha de Tratamento , Adulto JovemRESUMO
INTRODUCTION: We compared the effectiveness of tenofovir/emtricitabine (TDF/FTC) combined with either lopinavir/r (LPV/r) or another recommended third drug in the 2010 French guidelines in antiretroviral-naïve patients starting combination antiretroviral therapy in 2004-2008 in the French Hospital Database on HIV. METHODS: The outcomes were stop or switch of the third component, viral load (VL) <500 copies/ml, an increase of at least 100 CD4 cells/mm(3), AIDS-defining event and non-AIDS-defining hospitalization or death. Propensity scores were estimated by logistic regression based on the clinical centre and other confounders. In each clinical centre, each patient initiating LPV/r was matched with a patient initiating another third drug (efavirenz or atazanavir/r) and having a close propensity score. Cox's proportional hazards models were then used, with treatment as covariate. Time was right-censored at four years. RESULTS: 1269 patients started LPV/r plus TDF/FTC, and 890 could be matched to 890 patients receiving another third drug. Baseline characteristics were well balanced between these two groups. LPV/r was associated with a higher risk of third drug stop (hazard ratio (HR): 1.69; 95% confidence interval (CI), 1.42-2.00) and with less rapid viral suppression (HR: 0.83; 95% CI, 0.72-0.95). There was no difference in the time required for a CD4 cell increment of at least 100/mm(3), or to the occurrence of an AIDS-defining event. Non-AIDS-defining hospitalizations or deaths were more frequent with LPV/r (HR: 1.79; 95% CI, 1.33-2.39). CONCLUSIONS: For first-line therapy, in this observational setting, TDF/FTC plus LPV/r were less durable than TDF/FTC plus another recommended third drug, led to a less rapid viral suppression and were associated with a higher risk of non-AIDS morbidity.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Lopinavir/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Emtricitabina , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Estudos Prospectivos , Tenofovir , Falha de Tratamento , Carga ViralRESUMO
The distribution and evolution of X4/R5 viral tropism during HIV-2 infection remains unknown. HIV-2 tropism was assessed in 83 antiretroviral-experienced patients with virological failure. Tropism was predicted as X4 in 58% of patients and was associated with a CD4 cell count of less than 100 cells/µl, and with a higher number of drug resistance mutations. This high prevalence of X4 virus might compromise the use of CCR5 inhibitors, currently mostly considered in HIV-2 salvage therapy of highly pretreated patients.
Assuntos
Antagonistas dos Receptores CCR5/uso terapêutico , Cicloexanos/uso terapêutico , Infecções por HIV/imunologia , HIV-2 , Receptores CCR5/efeitos dos fármacos , Triazóis/uso terapêutico , Tropismo Viral , Contagem de Linfócito CD4 , Progressão da Doença , Farmacorresistência Viral , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , HIV-2/fisiologia , Humanos , Maraviroc , Prevalência , Estudos Retrospectivos , Carga ViralRESUMO
OBJECTIVES: To describe the virological and pharmacological outcomes of three different recommended once-daily first-line regimens in a cross-sectional analysis within an observational cohort using ultra-sensitive HIV quantification. PATIENTS AND METHODS: We enrolled all HIV-1-infected patients who initiated tenofovir/emtricitabine with efavirenz, darunavir/ritonavir or atazanavir/ritonavir as a first-line regimen between 1 November 2010 and 30 June 2012. An ultrasensitive viral load (VL) assay was performed and plasma drug concentrations at 24 h (C24) were determined at Week (W) 4, W12, W24, W36 and W48. RESULTS: Sixty patients initiated efavirenz, 81 darunavir/ritonavir and 27 atazanavir/ritonavir. A higher proportion of patients with a VL >100â000 copies/mL received darunavir/ritonavir (Pâ=â0.022). At W48, 89%, 85% and 88% of the patients had a VL <50 copies/mL, 69%, 73% and 79% had a VL <20 copies/mL and 45%, 48% and 54% had a VL <1 copy/mL using the ultrasensitive assay in the efavirenz, darunavir/ritonavir and atazanavir/ritonavir groups, respectively. Patients with a detectable VL signal at W48 had a higher baseline VL than those with no detectable VL signal (Pâ=â0.0001). A total of 92%, 93% and 91% of the efavirenz, darunavir and atazanavir C24 values were above the respective effective cut-offs. CONCLUSIONS: In this observational cohort, the choice of the regimen was related to the physicians' preferences and the patients' characteristics. The proportion of patients reaching VL <1 copy/mL at W48 was similar in the three regimens and was not associated with drug concentrations.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Adulto , Contagem de Linfócito CD4 , Estudos Transversais , Monitoramento de Medicamentos , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVE: To assess the virological response, genotypic resistance profiles, and antiretroviral plasma concentrations in HIV-2 antiretroviral-treated (antiretroviral therapy, ART) patients in Côte d'Ivoire. METHODS: A cross-sectional survey was conducted among HIV-2 patients receiving ART. Plasma HIV-2 viral load was performed using the Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) assay. Protease and reverse transcriptase sequencing was performed using in-house methods and antiretroviral plasma concentrations were assessed using ultra performance liquid chromatography combined with tandem mass spectrometry. RESULTS: One hundred and forty-five HIV-2-treated patients were enrolled with a median CD4 cell count of 360 cells/µl (interquartile range, IQRâ=â215-528). Median duration of ART was 4 years (IQRâ=â2-7) and 74% of patients displayed viral load less than 50âcopies/ml. Median plasma HIV-2 RNA among patients with viral load more than 50âcopies/ml was 3016âcopies/ml (IQRâ=â436-5156). Most patients (84%) received a lopinavir/ritonavir-based regimen. HIV-2 resistance mutations to nucleoside reverse transcriptase inhibitors and protease inhibitors were detected in 21 of 25 (84%) and 20 of 29 (69%) samples, respectively. The most prevalent nucleoside reverse transcriptase inhibitor resistance mutations were M184I/V (90%), Q151M (24%), and S215F/Y (24%). The most prevalent protease inhibitor resistance mutations were V47A (60%) and I54M (30%). Median CD4 cell counts were 434 cells/µl (292-573) and 204 cells/µl (122-281) in patients with viral load less than 50âcopies/ml and those exhibiting virological failure (Pâ<â0.0001), respectively. The proportions of patients with adequate antiretroviral plasma concentrations were 81 and 93% in patients displaying virological failure and in those with viral load less than 50âcopies/ml, respectively (Pâ=â0.046), suggesting good treatment adherence. CONCLUSION: We observed adequate drug plasma concentrations and virological suppression in a high proportion of HIV-2-infected patients. However, in cases of virological failure, the limited HIV-2 therapeutic arsenal and cross-resistance dramatically reduced treatment options.
Assuntos
Antirretrovirais/sangue , Farmacorresistência Viral/genética , Infecções por HIV/genética , HIV-2/genética , Mutação/genética , Adulto , Antirretrovirais/uso terapêutico , Cromatografia Líquida/métodos , Côte d'Ivoire , Estudos Transversais , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Análise de Sequência de RNA/métodos , Espectrometria de Massas em Tandem/métodos , Resultado do Tratamento , Carga ViralRESUMO
In this study, we assessed phenotypic susceptibility to dolutegravir and raltegravir in a large variety of HIV-1 'non-B' subtypes (nâ=â72) issued from integrase inhibitor-naive clinical isolates. All samples were susceptible to both dolutegravir and raltegravir with median IC50 values of 1.22 nmol/l and 1.53 nmol/l, respectively; similar to that observed for the B subtype. Thus, despite the high prevalence of polymorphic substitutions in integrase in 'non-B' clinical isolates, phenotypic susceptibility to dolutegravir remained unchanged.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Pirrolidinonas/farmacologia , Genótipo , Integrase de HIV/genética , HIV-1/isolamento & purificação , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Mutação de Sentido Incorreto , Oxazinas , Piperazinas , Piridonas , Raltegravir PotássicoRESUMO
Here, we summarize the discussions and conclusions from an expert workshop held in October 2012 to consider the implications of HIV drug resistance in the context of scale-up of access to antiretroviral therapy and prophylaxis in resource-limited settings. Topics considered during the workshop included the implications of drug resistance for the selection of first-line regimens and sequencing of treatments, optimal surveillance strategies and prevention of mother-to-child transmission.