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1.
Blood Cancer J ; 11(8): 142, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376633

RESUMO

This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/complicações , COVID-19/imunologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/administração & dosagem , Comorbidade , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
2.
J Antimicrob Chemother ; 76(9): 2400-2406, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34100068

RESUMO

BACKGROUND: Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance. MATERIALS AND METHODS: A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm. RESULTS: Overall, 1104 patients failing any INSTI-containing regimen (2DRs, n = 207; 3DRs, n = 897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (OR = 1.24 per 1 log10 copies/mL increase); non-B versus B subtype (OR = 1.75); low genotypic sensitivity score (GSS) (OR = 0.10 for GSS = 2 versus GSS = 0-0.5); and dolutegravir versus raltegravir (OR = 0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (OR = 0.59, P = 0.007), the variable is not retained in the final model. CONCLUSIONS: This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.

3.
Diagn Microbiol Infect Dis ; 100(3): 115366, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33756311

RESUMO

RT-PCR is the reference method for diagnosis of a Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection. During the setting up of 6 SARS-CoV-2 RT-PCR assays in our laboratory, comparative evaluations were systematically undertaken and allowed to evidence major discrepancies on cycle threshold RT-PCR results between techniques. These tendencies were confirmed in routine application when analyzing sequential samples from the same patients. Our aim was to examine the impact of the technique among factors influencing RT-PCR result, a far surrogate of 'viral load' in the heterogeneous environment of respiratory specimens.


Assuntos
Teste de Ácido Nucleico para COVID-19/estatística & dados numéricos , COVID-19/virologia , SARS-CoV-2/isolamento & purificação , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19/métodos , Conjuntos de Dados como Assunto , Testes Diagnósticos de Rotina , Genoma Viral , Humanos , Nasofaringe/virologia , RNA Viral/genética , SARS-CoV-2/genética , Carga Viral
4.
J Antimicrob Chemother ; 75(5): 1272-1279, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32073629

RESUMO

BACKGROUND: In the perspective of ART-free HIV remission, vertically infected children treated with suppressive ART from early infancy represent an optimal population model to better understand the genetic complexity of the reservoir. OBJECTIVES: To evaluate the proportion of defective viral population and the genotypic resistance patterns in cell-associated HIV DNA. METHODS: In a cohort including 93 ART-treated vertically HIV-infected (VHIV) children in Mali with plasma HIV-1 RNA ≤50 copies/mL for at least 6 months, we studied total HIV DNA, percentage of defective genomes and resistance by reverse transcriptase and protease bulk sequencing from whole blood in dried blood spots. RESULTS: Children had a median age of 9.9 years at the time of inclusion (IQR = 7.6-13.4) and 3.3 years (IQR = 2-7) at ART initiation; median ART duration was 5.5 years (IQR = 3.7-7.3). The median level of total HIV DNA was 470 copies/106 cells with one patient presenting undetectable HIV DNA (<66 copies/106 cells). We observed the presence of at least one stop codon in viruses from 34 patients (37%). The presence of stop codons was not correlated with the level of HIV DNA or duration of ART. We showed a high prevalence of HIV-1 resistance in DNA with 26% of children harbouring virus resistant to at least one NRTI and 40% to at least one NNRTI. CONCLUSIONS: While these VHIV children were successfully treated for a long time, they showed high prevalence of resistance in HIV DNA and a moderate defective HIV reservoir.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Criança , Resistência a Medicamentos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Mali/epidemiologia , Carga Viral
5.
Artigo em Inglês | MEDLINE | ID: mdl-34532653

RESUMO

The 2014-2016 Ebola epidemic in Guinea highlighted the need for more extensive evaluation of laboratories diagnostic capacities and preparedness in anticipation of future emerging viral disease outbreaks. We developed a questionnaire to assess the diagnostic capacities and preparedness of the four major medical laboratories in Guinea and Mali that are responsible for the provision of Ebola, Lassa, and Dengue diagnostics. The questionnaire inquired about the current state and need for equipment and reagents and adequacy of equipment and training received. In Guinea, all three diagnostic laboratories have the capacity and are well-prepared to perform Ebola diagnostics, however, only two have the capacity and trained staff to diagnose Lassa and none are currently prepared to diagnose Dengue infection. In Mali, the University Clinical Research Center (UCRC) laboratory, which was in charge of Ebola diagnostics during the last epidemic, currently has the capacity and is prepared to diagnose Ebola, Lassa, and Dengue infections. Combined, Guinea and Mali appear to have complementary capacity and preparedness to diagnose these Category A Priority Pathogens. While, the equipment, reagents and training efforts should be maintained, the gap in Dengue diagnostic capability in Guinea should be addressed with further equipping and training of additional district laboratories to strengthen the public health response for all viral diseases in these high-risk, yet, low-resource settings.

6.
BMC Infect Dis ; 19(1): 1064, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856758

RESUMO

BACKGROUND: HIV, HBV and HCV remain a global public health concern especially in Africa. Prevalence of these infections is changing and identification of risk factors associated with each infection in Mali is needed to improve medical care. METHODS: We conducted a cross-sectional study of all individuals donating blood (n = 8207) in 2018 to the blood bank at university hospital in Bamako, Mali, to assess prevalence and risks factors associated with HIV, HBV, HCV and syphilis infections. RESULTS: HIV-seroprevalence was 2.16% and significantly increased with age, being married and decreasing education level. In multivariate analysis, after adjustements with age, marital status and geographical setting, only education level was associated with HIV-infection (OR, 1.54 [95% CI, 1.15-2.07], p = 0.016). HBsAg prevalence was 14.78% and significantly increased with to be male gender. In multivariate analysis, adjusting for age, marital status and type of blood donation, education level (OR, 1.17 [95%CI, 1.05-1.31], p = 0.02) and male gender (OR, 1.37 [95%CI, 1.14-1.65], p = 0.005) were associated with HBV-infection. HCV-prevalence was 2.32% and significantly increased with living outside Bamako. In multivariate analysis, adjusting for gender, age and education level, living outside Bamako was associated with HCV-infection (OR, 1.83 [95% CI, 1.41-2.35], p < 0.001). Syphilis seroprevalence was very low (0.04%) with only 3 individuals infected. Contrary to a prior study, blood donation type was not, after adjustments, an independent risk factor for each infection. CONCLUSIONS: Overall, HIV and HBV infection was higher in individuals with a lower level of education, HBV infection was higher in men, and HCV infection was higher in people living outside of Bamako. Compared to studies performed in 1999, 2002 and 2007 in the same population, we found that HIV and HCV prevalence have decreased in the last two decades whereas HBV prevalence has remained stable. Our finding will help guide infection prevention and treatment programs in Mali.


Assuntos
Doadores de Sangue , Infecções por HIV/epidemiologia , Soroprevalência de HIV/tendências , HIV/imunologia , Hepacivirus/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Sífilis/epidemiologia , Treponema pallidum/imunologia , Adolescente , Adulto , Coinfecção , Estudos Transversais , Feminino , Hospitais Universitários , Humanos , Masculino , Mali , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto Jovem
7.
Open Forum Infect Dis ; 6(5): ofz177, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31123690

RESUMO

Background: During antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear. Methods: HIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements. Results: Between 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3-4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed. Conclusions: VL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

8.
J Antimicrob Chemother ; 74(5): 1368-1375, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789205

RESUMO

OBJECTIVES: To describe integrase strand transfer inhibitor (INSTI) resistance profiles and factors associated with resistance in antiretroviral-naive and -experienced patients failing an INSTI-based regimen in clinical practice. METHODS: Data were collected from patients failing an INSTI-containing regimen in a multicentre French study between 2014 and 2017. Failure was defined as two consecutive plasma viral loads (VL) >50 copies/mL. Reverse transcriptase, protease and integrase coding regions were sequenced at baseline and failure. INSTI resistance-associated mutations (RAMs) included in the Agence Nationale de Recherches sur le SIDA genotypic algorithm were investigated. RESULTS: Among the 674 patients, 359 were failing on raltegravir, 154 on elvitegravir and 161 on dolutegravir therapy. Overall, 90% were experienced patients and 389 (58%) patients showed no INSTI RAMs at failure. The strongest factors associated with emergence of at least one INSTI mutation were high VL at failure (OR = 1.2 per 1 log10 copies/mL increase) and low genotypic sensitivity score (GSS) (OR = 0.08 for GSS ≥3 versus GSS = 0-0.5). Patients failing dolutegravir also had significantly fewer INSTI RAMs at failure than patients failing raltegravir (OR = 0.57, P = 0.02) or elvitegravir (OR = 0.45, P = 0.005). Among the 68 patients failing a first-line regimen, 11/41 (27%) patients on raltegravir, 7/18 (39%) on elvitegravir and 0/9 on dolutegravir had viruses with emergent INSTI RAMs at failure. CONCLUSIONS: These results confirmed the robustness of dolutegravir regarding resistance selection in integrase in the case of virological failure in routine clinical care.


Assuntos
Farmacorresistência Viral Múltipla/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Adulto , Feminino , Genótipo , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fatores de Risco , Análise de Sequência de DNA , Falha de Tratamento
9.
Open Forum Infect Dis ; 5(10): ofy227, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30324127

RESUMO

Background: Occult hepatitis B infection (OBI) is recognized as a risk factor for cirrhosis and hepato-cellular carcinoma. However, OBI brings together a large spectrum of patients who might harbor different characteristics and prognosis. Methods: We analyzed the databases of a university hospital in Paris to identify OBI among patients (n = 3966) concomitantly tested for hepatitis B virus (HBV) DNA and serology during a 7-year period. OBI patients were gathered into clinical entities according to their clinical records. Results: Forty-seven OBIs were identified (1.2%). All patients had detectable anti-HBc, isolated (n = 26) or associated with anti-HBs (n = 21). The proportion of OBIs was 3.4% for patients with isolated anti-HBc and 4.2% for patients with both anti-HBc and anti-HBs. Four clinical categories of OBI patients were identified: patients with a passed HBV infection with HBs Ag clearance (group A, 23.4%); HBV-exposed patients receiving immunosuppressive therapy (group B, 29.8%); HIV/HBV-coinfected patients with therapy discontinuation (group C, 17%); HBV-exposed patients with severe liver conditions (group D, 29.8%). Significant follow-up was available for 32 patients, showing a more deleterious prognosis in group D patients, associated more with their underlying condition than the OBI status. Conclusions: OBI is a heterogeneous condition with various clinical implications.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30613797

RESUMO

Tuberculosis (TB) is the deadliest infectious disease in the world which disproportionately affects low-and-middle-income countries (LMICs) where diagnostic resources and treatment options are limited. The incidence of pulmonary non-tuberculous mycobacteria (NTM) disease is also rapidly increasing in these regions traditionally dominated by TB infections. This poses significant diagnostic and treatment challenges, since these two diseases are often indistinguishable clinically or by sputum smear microscopy (SSM), the most commonly used TB diagnostic tool in LMICs. Consequently, NTM-infected patients usually receive unnecessary TB treatment for months. TB patients with NTM co-infections may also be treated incorrectly due to inaccurate SSM and Xpert™ MTB/RIF (M. tuberculosis./rifampin) results. These issues complicate the management of patients and contribute to the worsening of the current TB and NTM epidemiological features including development of drug resistant strains. It is therefore critical to develop improved diagnostic tools to accurately distinguish these two different pathogens that have many similar clinical and epidemiological features but have different treatment regimens. In this review, we will discuss limitations with current diagnostic tools and the need to develop novel techniques that can accurately and simultaneously diagnose TB and NTM disease._.

11.
Pediatr Infect Dis J ; 36(11): e258-e263, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28198788

RESUMO

BACKGROUND: Limited data exist on drug resistance and antiretroviral treatment (ART) outcomes in HIV-1-infected children in West Africa. We determined the prevalence of baseline resistance and correlates of virologic failure (VF) in a cohort of ART-naive HIV-1-infected children <10 years of age initiating ART in Mali. METHODS: Reverse transcriptase and protease genes were sequenced at baseline (before ART) and at 6 months. Resistance was defined according to the Stanford HIV Genotypic Resistance database. VF was defined as viral load ≥1000 copies/mL after 6 months of ART. Logistic regression was used to evaluate factors associated with VF or death >1 month after enrollment. Post hoc, antiretroviral concentrations were assayed on baseline samples of participants with baseline resistance. RESULTS: One-hundred twenty children with a median age 2.6 years (interquartile range: 1.6-5.0) were included. Eighty-eight percent reported no prevention of mother-to-child transmission exposure. At baseline, 27 (23%), 4 (3%) and none had non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor or protease inhibitor resistance, respectively. Thirty-nine (33%) developed VF and 4 died >1 month post-ART initiation. In multivariable analyses, poor adherence [odds ratio (OR): 6.1, P = 0.001], baseline NNRTI resistance among children receiving NNRTI-based ART (OR: 22.9, P < 0.001) and protease inhibitor-based ART initiation among children without baseline NNRTI resistance (OR: 5.8, P = 0.018) were significantly associated with VF/death. Ten (38%) with baseline resistance had detectable levels of nevirapine or efavirenz at baseline; 7 were currently breastfeeding, but only 2 reported maternal antiretroviral use. CONCLUSIONS: Baseline NNRTI resistance was common in children without reported NNRTI exposure and was associated with increased risk of treatment failure. Detectable NNRTI concentrations were present despite few reports of maternal/infant antiretroviral use.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Lactente , Masculino , Mali , Estudos Prospectivos , Falha de Tratamento
12.
J Antimicrob Chemother ; 72(4): 1147-1151, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28039275

RESUMO

Background: Absence of detectable viraemia after treatment cessation in some vertically HIV-infected (VHIV) children suggests that early initiation of HAART could lead to functional cure. Objectives: We described the factors associated with HIV antibody levels and the viral reservoir size in HAART-treated VHIV children. Methods: Study included 97 VHIV children with virological suppression, in Bamako, Mali. The anti-gp41 antibody activities and HIV serostatus were assessed. The viral reservoir size was measured by quantifying total cell-associated HIV DNA. Results: Among the children studied, the median total HIV DNA level was 445 copies/10 6 cells (IQR = 187-914) and the median anti-gp41 antibody activity was 0.29 OD (IQR = 0.18-0.75). Low activity of anti-gp41 antibodies was associated with a younger age of HAART initiation ( P = 0.01). Overall, eight HIV-1 seroreversions were identified. Conclusions: Study identified potential candidates with low viral reservoir and low antibody levels or activities for future trials aiming to reduce HIV-1 reservoir to limit HAART duration.


Assuntos
Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Transmissão Vertical de Doenças Infecciosas , Carga Viral , Adolescente , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Criança , Pré-Escolar , Estudos Transversais , Feminino , Infecções por HIV/transmissão , HIV-1/imunologia , Humanos , Masculino , Estudos Prospectivos , Viremia/imunologia , Adulto Jovem
13.
J Antimicrob Chemother ; 71(3): 751-61, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26676973

RESUMO

OBJECTIVES: The objective of this study was to address the dynamics of archived resistant quasispecies in cell-associated HIV-1 DNA over time in heavily ART-experienced patients with currently suppressed plasma HIV-1 RNA. METHODS: Longitudinal ultra-deep sequencing (UDS) analysis of reverse transcriptase, protease and V3 Env regions was performed on blood-cell-associated HIV-1 DNA samples. Drug-resistance-associated mutations (DRAMs) and tropism were interpreted using the ANRS and Geno2Pheno algorithms. We analysed frozen blood cells from patients enrolled in the INNOVE and ANRS 123 ETOILE studies who achieved sustained viral suppression after salvage optimized ART (SOT). RESULTS: Samples were available at baseline and 6 and ≥12 months after SOT initiation in 10 patients. V3 loop sequences displayed wide intra-individual dynamics over time. Viral variants harbouring DRAMs exhibited three non-exclusive scenarios. First, when SOT exerted the same selective pressure as previous failing regimens, some viral quasispecies still harboured the same DRAMs at the same level as at the time of virological failure. Thus, as DRAMs were mostly associated with the same viral variant, variants with a complete resistance pattern remained archived. Second, some viral variants harbouring DRAMs were no longer detected over time when SOT consisted of new antiretroviral classes or had resistance profiles distinct from those of previous failing regimens. Third, variants with new DRAMs associated with SOT emerged in blood cells during follow-up despite sustained virological control. CONCLUSIONS: Using longitudinal UDS analysis and focusing on DRAMs and tropism as markers, we demonstrated that, despite sustained virological control, archived HIV-1 DNA quasispecies continued to evolve.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Tropismo Viral , Células Sanguíneas/virologia , DNA Viral/química , DNA Viral/genética , DNA Viral/isolamento & purificação , Genótipo , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/genética , HIV-1/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estudos Longitudinais , Mutação , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
14.
J Antimicrob Chemother ; 70(1): 130-5, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25270328

RESUMO

OBJECTIVES: The genetic barrier (defined as the number of genetic transitions/transversions needed to produce a resistance mutation) can differ between HIV-1 subtypes. The genetic barrier for the new attachment inhibitor BMS-626529 was evaluated in five HIV-1 subtypes. METHODS: Nine substitutions associated with BMS-626529 resistance at seven amino acid positions (116, 204, 375, 426, 434, 475 and 506) were analysed in 300 nucleotide sequences of the env gene encoding the gp120 protein from antiretroviral-naive patients (60 for each subtype and recombinant: B, C, D, CRF01_AE and CRF02_AG). RESULTS: Differently from the B subtype, some resistance mutations were found as natural polymorphisms in the C and D subtypes and the CRF02_AG and CRF01_AE recombinants for four positions of the env gene encoding the gp120 protein (375, 426, 434 and 475). The majority (five out of seven) of amino acid positions studied (116, 426, 434, 475 and 506) were relatively conserved (>63%) between the five HIV-1 subtypes, leading to a similar genetic barrier to mutations associated with resistance to BMS-626529. However, at positions 116 and 506 a minority of C and CRF02_AG subtypes had codons leading to a higher genetic barrier. Different predominant codons were observed at two out of seven positions (204 and 375) between the subtypes, with no effect on the calculated genetic barrier. However, for position 375, a minority of CRF02_AG sequences showed a lower genetic barrier to S375M/T resistance mutations. CONCLUSIONS: In non-B HIV-1 subtypes, four out of seven studied positions presented mutations implicated in BMS-626529 resistance. Despite great variability of the HIV-1 envelope, there was no major impact of polymorphisms on the genetic barrier to acquisition of BMS-626529 resistance.


Assuntos
Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/genética , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Piperazinas/farmacologia , Triazóis/farmacologia , Substituição de Aminoácidos , Genótipo , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Mutação de Sentido Incorreto , Polimorfismo Genético
15.
AIDS Res Hum Retroviruses ; 29(1): 182-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22823755

RESUMO

The WHO recommends regular surveillance for transmitted antiretroviral drug-resistant viruses in HIV antiretroviral treatment (ART)-naive patients in resource-limited settings. This study aimed to assess the prevalence of mutations associated with resistance in ART-naive patients newly diagnosed with HIV in Bamako and Ségou in Mali. HIV-positive patients who never received ART were recruited in Bamako and Ségou, Mali. The reverse transcriptase (RT) and protease (PR) genes of these patients were sequenced by the "ViroSeq" method. Analysis and interpretation of the resistance were made according to the WHO 2009 list of drug resistance mutations. In all, 51/54 (94.4%) sample patients were sequenced. The median age (IQR) of our patients was 24 (22-27) years and the median CD4 count was 380 (340-456) cells/mm(3). The predominant subtype was recombinant HIV-1 CRF02_AG (66.7%) followed by CRF06_cpx (12%) and CRF09_cpx (4%). Four patients had mutations associated with resistance, giving an overall prevalence of resistance estimated at 7.9%. There were two (4%) patients with nucleoside reverse transcriptase inhibitor (NRTI) mutations (one M184V and one T215Y), two (4%) with non-NRTI mutations (two K103N), and one (2%) with a protease inhibitor mutation (one I54V). The prevalence of primary resistance in newly infected patients in Mali is moderate (7.9%). This indicates that the standard NNRTI-based first-line regimen used in Mali is suboptimal for some patients. This study should be done regularly to inform clinical practice.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/transmissão , HIV-1/genética , Adulto , Contagem de Linfócito CD4 , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Mali/epidemiologia , Mutação , Prevalência , Análise de Sequência , Adulto Jovem
16.
J Antimicrob Chemother ; 67(12): 2943-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22888273

RESUMO

OBJECTIVES: We describe the outcomes of second-line drug resistance profiles and predict the efficacy of drugs for third-line therapy in patients monitored without the benefit of plasma HIV-1 RNA viral load (VL) or resistance testing. METHODS: We recruited 106 HIV-1-infected patients after second-line treatment failure in Mali. VL was determined by the Abbott RealTime system and the resistance by the ViroSeq HIV-1 genotyping system. The resistance testing was interpreted using the latest version of the Stanford algorithm. RESULTS: Among the 106 patients, 93 had isolates successfully sequenced. The median age, VL and CD4 cells were respectively 35 years, 72 000 copies/mL and 146 cells/mm(3). Patients were exposed to a median of 4 years of treatment and to six antiretrovirals. We found 20% of wild-type viruses. Resistance to etravirine was noted in 38%, to lopinavir in 25% and to darunavir in 12%. The duration of prior nucleos(t)ide reverse transcriptase inhibitor exposure was associated with resistance to abacavir (P < 0.0001) and tenofovir (P = 0.0001), and duration of prior protease inhibitor treatment with resistance to lopinavir (P < 0.0001) and darunavir (P = 0.06). CONCLUSION: Long duration of therapy prior to failure was associated with high levels of resistance and is directly related to limited access to VL monitoring and delayed switches to second-line treatment, precluding efficacy of drugs for third-line therapy. This study underlines the need for governments and public health organizations to recommend the use of VL monitoring and also the availability of darunavir and raltegravir for third-line therapies in the context of limited-resource settings.


Assuntos
Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adulto , Monitoramento de Medicamentos , Feminino , HIV-1/isolamento & purificação , Humanos , Masculino , Mali , Pessoa de Meia-Idade , Falha de Tratamento , Carga Viral , Adulto Jovem
17.
J Acquir Immune Defic Syndr ; 61(3): 293-6, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22828721

RESUMO

Mutations in the connection domain (CD) of reverse transcriptase have been implicated in reverse transcriptase inhibitor (RTI) resistance, but this is controversial and little is known in non-B subtype HIV-1. We determined CD mutations prevalence in a population infected predominantly with CRF02_AG and investigated associations with phenotypic RTI resistance. Detected CD mutations were G335D (82.3%), A371V (69.8%), E399D (9.4%), N348I (5.2%), V365I (4.2), Y318F (2.1%), G333E (2.1%), and A360V (2.1%). Mutations were largely polymorphic and did not confer RTI resistance. The observed trend toward reduced likelihood of etravirine or nevirapine resistance in the presence of G335D should be investigated further.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , Alcinos , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Ciclopropanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Farmacorresistência Viral/genética , Emtricitabina , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Mali , Mutação/genética , Nevirapina/farmacologia , Nevirapina/uso terapêutico , Fenótipo , Falha de Tratamento
18.
AIDS ; 26(13): 1619-24, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22695298

RESUMO

BACKGROUND: Recent clinical trials with rilpivirine combined with emtricitabine and tenofovir revealed that patients failing treatment, frequently, harbored viruses encoding resistance-associated mutations in the HIV-1 reverse transcriptase at position E138K and M184I. We show here that APOBEC3 proteins play a role in the emergence of these drug resistance mutations. METHODS: We used a Vif mutant that has suboptimal activity against APOBEC3 to assess the in-vitro frequency of APOBEC3-induced resistance mutations in reverse transcriptase. To assess the degree of in-vivo G-to-A viral hypermutation, a large amount of data of HIV-1 RT proviral sequences from peripheral blood mononuclear cells (PBMCs) recovered from infected patients under HAART was analyzed. RESULTS: In-vitro replication experiments in cell lines with and without APOBEC3 expression suggest that APOBEC3-driven mutagenesis contributes to the generation of both M184I and E138K within HIV proviral repository in the absence of drug exposure. Additionally, analysis of 601 patients PBMCs sequences revealed that the copresence of mutations E138K and M184I were never detected in nonhypermutated sequences, whereas these mutations were found at a high frequency (24%) in the context of APOBEC3 editing and in the absence of exposure to etravirine-rilpivirine. CONCLUSION: We demonstrate using in-vitro experiments and analyzing patients PBMCs sequences that M184I and E138K resistance-associated mutations may pre-exist in proviral reservoir at a high frequency prior to drug exposure, as a result of APOBEC3 editing. Thus, incomplete neutralization of one or more APOBEC3 proteins may favor viral escape to rilpivirine-emtricitabine.


Assuntos
Fármacos Anti-HIV/farmacologia , Citosina Desaminase/genética , Transcriptase Reversa do HIV/genética , HIV-1/genética , Mutação , Adenina/análogos & derivados , Adenina/farmacologia , Citidina Desaminase , Citosina Desaminase/efeitos dos fármacos , Citosina Desaminase/imunologia , Análise Mutacional de DNA , Farmacorresistência Viral , Feminino , Ácido Glutâmico , Transcriptase Reversa do HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Isoleucina , Lisina , Masculino , Metionina , Nitrilas/farmacologia , Organofosfonatos/farmacologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Rilpivirina , Tenofovir , Falha de Tratamento , Replicação Viral
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