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2.
AIDS ; 35(9): 1333-1342, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33730748

RESUMO

OBJECTIVE: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc. DESIGN AND METHODS: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination. RESULTS: Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35). CONCLUSION: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Piridonas , Rilpivirina
3.
J Med Virol ; 93(3): 1780-1785, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32926453

RESUMO

In early 2020 the new respiratory syndrome COVID-19 (caused by the zoonotic SARS-CoV-2 virus) spread like a pandemic, starting from Wuhan, China, causing severe economic depression. Despite some advances in drug treatments of medical complications in the later stages of the disease, the pandemic's death toll is tragic, as no vaccine or specific antiviral treatment is currently available. By using a systems approach, we identify the host-encoded pathway, which provides ribonucleotides to viral RNA synthesis, as a possible target. We show that methotrexate, an FDA-approved inhibitor of purine biosynthesis, potently inhibits viral RNA replication, viral protein synthesis, and virus release. The effective antiviral methotrexate concentrations are similar to those used for established human therapies using the same drug. Methotrexate should be most effective in patients at the earliest appearance of symptoms to effectively prevent viral replication, diffusion of the infection, and possibly fatal complications.


Assuntos
Antivirais/farmacologia , COVID-19/etiologia , Metotrexato/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Pandemias/prevenção & controle , RNA Viral/genética , Células Vero
4.
Liver Int ; 39(10): 1986-1998, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31172639

RESUMO

BACKGROUND & AIMS: We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. METHODS: Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. RESULTS: At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. CONCLUSIONS: Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Transplante de Fígado , Proteínas não Estruturais Virais/genética , Idoso , Carcinoma Hepatocelular/cirurgia , Coinfecção/tratamento farmacológico , Quimioterapia Combinada , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Filogenia , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento
5.
Antivir Ther ; 24(5): 321-331, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977466

RESUMO

BACKGROUND: Pre-cART (combined antiretroviral therapy) plasma viral load >500,000 copies/ml has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance of virological suppression are available. In this study we aimed to clarify whether high levels of pre-cART viraemia are associated with virological rebound (VR) after virological suppression. METHODS: HIV-infected individuals who achieved virological suppression after first-line cART were included. VR was defined as the first of two consecutive viraemia >50 copies/ml (VR50) or, in an alternative analysis, >200 copies/ml (VR200). The impact of pre-cART viraemia on the risk of VR was evaluated by survival analyses. RESULTS: Among 5,766 patients included, 59.2%, 31.4%, 5.2% and 4.2% had pre-cART viraemia ≤100,000, 100,001-500,000, 500,001-1,000,000 and >1,000,000 copies/ml, respectively. Patients with pre-cART viraemia levels >1,000,000 copies/ml had the highest probability of VR (>1,000,000; 500,000-1,000,000; 100,000-500,000; <100,000 copies/ml; VR50: 28.4%; 24.3%; 17.6%; 13.8%, P<0.0001; VR200: 14.4%; 11.1%; 7.2%; 7.6%; P=0.009). By Cox multivariable analyses, patients with pre-cART viraemia >500,000 and >1,000,000 copies/ml showed a significantly higher risk of VR regardless of the VR end point used. No difference in the risk of VR was found between patients with pre-cART viraemia ranging 500,000-1,000,000 copies/ml and those with pre-cART viraemia >1,000,000 copies/ml, regardless of the VR end point used. CONCLUSIONS: Pre-cART plasma viral load levels >500,000 copies/ml can identify fragile patients with poorer chance of maintaining virological control after an initial response. An effort in defining effective treatment strategies is mandatory for these patients that remain difficult to treat.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/fisiologia , Carga Viral , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , HIV-1/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Fatores de Risco , Resultado do Tratamento
6.
Drug Metab Pers Ther ; 34(1)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840585

RESUMO

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Genótipo , Metiltransferases/genética , Fenótipo , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Cromatografia Líquida de Alta Pressão , Doença Crônica , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Itália , Masculino , Metiltransferases/metabolismo
7.
BMC Infect Dis ; 18(1): 251, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859062

RESUMO

BACKGROUND: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. METHODS: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. RESULTS: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32-3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. CONCLUSIONS: Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.


Assuntos
Antivirais/uso terapêutico , Códon de Terminação , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/imunologia , Mutação , Adulto , Substituição de Aminoácidos , Europa (Continente) , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade
9.
Drug Resist Updat ; 37: 17-39, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29525636

RESUMO

Nowadays, due to the development of potent Direct-Acting Antiviral Agents (DAAs) that specifically target NS3, NS5A and NS5B viral proteins, several new and highly efficacious options to treat chronic Hepatitis C virus (HCV) infection are available. The natural presence of resistance associated substitutions (RASs), as well as their rapid emergence during incomplete drug-pressure, are intrinsic characteristics of HCV that greatly affect treatment outcome and the chances to achieve a virolgical cure. To date, a high number of RASs in NS3, NS5A, and NS5B have been associated in vivo and/or in vitro with reduced susceptibility to DAAs, but no comprehensive RASs list is available. This review thus provides an updated, systematic overview of the role of RASs to currently approved DAAs or in phase II/III of clinical development against HCV-infection, discriminating their impact in different HCV-genotypes and DAAs, providing assistance for a fruitful use of HCV resistance testing in clinical practice.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Desenho de Fármacos , Farmacorresistência Viral/genética , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Terapia de Alvo Molecular , Mutação , Falha de Tratamento , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
10.
Infection ; 46(2): 147-163, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29098647

RESUMO

BACKGROUND: The recent availability of direct acting antiviral drugs (DAAs) has drastically changed hepatitis C virus (HCV) treatment scenarios, due to the exceedingly high rates of sustained virological response (SVR) and excellent tolerability allowing for treatment at all disease stages. METHODS: A panel of Italian experts was convened twice, in November 2016 and January 2017, to provide further support on some open issues and provide guidance for personalized HCV care, also in light of forthcoming regimens. RESULTS AND CONCLUSIONS: Treatment recommendations issued by international and national liver societies to guide clinicians in the management of HCV infection are constantly updated due to accumulating new data. Such recommendations may not be applicable to all healthcare settings for a variety of reasons. Moreover, some gaps still remain and the spectrum of patients to be treated is also evolving.


Assuntos
Antivirais , Hepatite C/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/uso terapêutico , Comorbidade , Humanos , Itália
11.
Liver Int ; 37(4): 514-528, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28105744

RESUMO

BACKGROUND & AIMS: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. METHODS: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70). RESULTS: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. CONCLUSIONS: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Proteínas não Estruturais Virais/genética , Idoso , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Interferons/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva , Ribavirina/uso terapêutico , Análise de Sequência de DNA , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento
12.
Liver Int ; 37(5): 653-661, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27782373

RESUMO

BACKGROUND & AIMS: The proportion of HCV-infected patients over age 65 years in Western countries is increasing. This growth and the advent of new antiviral therapy bring into the question the real-world efficacy and safety of the combination of sofosbuvir (SOF) and simeprevir (SMV) plus a flat dose of 800 mg/d ribavirin (RBV) in elderly patients with cirrhosis compared to younger patients. METHODS: Retrospective observational multicentre real-life investigation study of SOF/SMV/RBV for a duration of 12 weeks in HCV genotype 1-infected patients with cirrhosis. RESULTS: Of the 270 patients enrolled in this study, with compensated cirrhosis, 133 (49.2%) were ≥65 years of age. Sustained virological response at 12 weeks (SVR12) was achieved by 94.2% (129/137) of those aged <65 years and 97.7% (130/133) of those ≥65 years. Diabetes was the most common comorbidity in patients ≥65 years compared to younger patients (26.3% vs 12.4% P<.003). The most common adverse event (AE) in elderly patients was a grade 2 anaemia (35.3% vs 19.9% P<.004). CONCLUSIONS: Sofosbuvir/simeprevir plus a daily flat dose of RBV 800 mg for 12 weeks was highly effective and safe in genotype 1 elderly patients with compensated cirrhosis.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Ribavirina/administração & dosagem , Simeprevir/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Antivirais/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Humanos , Itália , Cirrose Hepática/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Ribavirina/efeitos adversos , Simeprevir/efeitos adversos , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada
13.
AIDS ; 30(5): 731-41, 2016 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-26595543

RESUMO

OBJECTIVE: The impact of HIV-1 tropism on the emergence of non-AIDS events was evaluated in a cohort of 116 antiretroviral therapy (ART) responder patients. METHODS: The patients were followed for the emergence of hypertension, renal impairment, metabolic and bone disorders (defined as non-AIDS events) each 8 weeks at standard visits. A V3 plasma sequence genotype analysis was performed at the time of ART initiation and the geno2pheno algorithm with the results that defines the false-positive rate (FPR) was used to infer HIV tropism. The associations between the non-AIDS events and the FPR at baseline were evaluated using the χ test for trend. A Cox-regression analysis using the counting process formulation of Andersen and Gill was performed to define whether the emergence of non-AIDS events was correlated to FPR. RESULTS: The prevalence of at least one non-AIDS event resulted higher in patients with a FPR below 10% than in patients with a R5 virus (P = 0.033). Patients with a FPR below 5.0% most frequently developed non-AIDS events during ART (P = 0.01). A higher prevalence of patients with at least two AIDS events was found in the group of patients with a FPR below 5.0% with respect to the others (P < 0.001). At multivariate Cox-regression analysis, having an X4 virus and age were independently associated with a higher probability of non-AIDS event development. CONCLUSION: This study shows that an X4 virus, particularly a FPR less than 5%, is related to non-AIDS events development. Further studies are warranted to understand the mechanisms underlying this phenomenon.


Assuntos
Antirretrovirais/uso terapêutico , Doenças Ósseas/epidemiologia , Infecções por HIV/complicações , HIV-1/fisiologia , Hipertensão/epidemiologia , Insuficiência Renal/epidemiologia , Tropismo Viral , Adulto , Feminino , Técnicas de Genotipagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
New Microbiol ; 37(4): 423-38, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25387281

RESUMO

The efficacy data obtained with boceprevir and telaprevir for persons with hepatitis C virus (HCV) genotype 1 infection raise the question of whether HCV protease inhibitors should be used in human immunodeficiency virus (HIV)/HCV co-infected persons. The Italian Association for the Study of Infectious and Tropical Diseases has made these recommendations to provide the rationale and practical indications for the use of triple anti-HCV therapy in persons living with HIV (PLWHIV). A Writing Committee of experts indicated by the President of the Association and a Consulting Committee con- tributed to the document. The final draft was submitted to the evaluation of external experts and the text modified according to their suggestions and comments. Treatment of HCV co-infection should be considered for all HCV RNA positive PLWHIV. Response-guided therapy with pegylated interferon and ribavirin is the standard treatment of PLWHIV with infection by HCV genotype 2, 3, 4, 5 and 6. Boceprevir and telaprevir should be used to treat HCV genotype 1 infection in HIV/HCV co-infected patients for 48 weeks on an individual basis, with close monitoring of their efficacy and tolerability with concur- rent antiretroviral therapy, taking into account potential drug-drug interactions. The decision to treat a patient or to wait for better treatment options, or to discontinue treatment should be made on an individual basis taking into account pre-treatment variables and the on-treatment HCV RNA kinetics.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Coinfecção/virologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Hepacivirus/fisiologia , Hepatite C Crônica/virologia , Humanos , Itália , Reconciliação de Medicamentos , Guias de Prática Clínica como Assunto , Resultado do Tratamento
15.
AIDS ; 28(17): 2531-9, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25574957

RESUMO

BACKGROUND: Fixed-dose combination antiretroviral therapy administered as a single-tablet regimen (STR) may improve virologic suppression rates. The effect of STRs on development of resistance when virologic failure occurs on STRs is not known. OBJECTIVES: To compare the rate of emergent drug resistance mutations (DRMs) on first-line therapy with coformulated tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) as an STR versus TDF, lamivudine (3TC) or FTC, and EFV given as non-STR. METHODS: Patients from eight cohorts and four randomized clinical trials who received first-line antiretroviral therapy with Atripla (STR group) or with TDF + FTC/3TC + EFV (non-STR group) were eligible if a genotypic resistance test was available immediately after the first episode of viral failure. The DRM list from the 2013 version of IAS-USA was used. RESULTS: One hundred and eighty-six patients were included in the final analysis, 122 (65.6%) from eight cohorts and 64 (34.1%) from four randomized clinical trials. The overall proportion of patients with at least one DRM at viral failure was 67.7%, including 53.4% (31 of 58) in the STR group vs. 74.2% (95 of 128) in the non-STR group (P = 0.005). Among patients exclusively from cohorts, at least one DRM was detected in 53.4% (31 of 58) in the STR group vs. 78.1% (50 of 64) in the non-STR group (P = 0.004). DRMs for individual drugs were: TDF, 15.5 vs. 16.4% (P = 0.87); 3TC/FTC, 31 vs. 35.2% (P = 0.58); and NNRTI, 51.7 vs. 65.6% (P = 0.07). The proportion of patients with an M184V/I among the 128 patients who received FTC was 32.8 vs. 36.2% among the 58 treated with 3TC (P = 0.65). CONCLUSIONS: Compared to patients receiving the STR-Atripla, those receiving the same components individually in a non-STR regimen have a statistically significantly increased risk of selecting for DRMs associated with their drugs on failure.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV/genética , Mutação , Adolescente , Adulto , Idoso , Antirretrovirais/farmacologia , Estudos de Coortes , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Falha de Tratamento , Estados Unidos , Adulto Jovem
16.
Biomed Res Int ; 2013: 810617, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24369538

RESUMO

INTRODUCTION: The evolutionary and demographic history of the circular recombinant form CRF02_AG in a selected retrospective group of HIV-1 infected men who have sex with men (MSM) resident in Central Italy was investigated. METHODS: A total of 55 HIV-1 subtype CRF02_AG pol sequences were analyzed using Bayesian methods and a relaxed molecular clock to reconstruct their dated phylogeny and estimate population dynamics. RESULTS: Dated phylogeny indicated that the HIV-1 CRF02_AG strains currently circulating in Central Italy originated in the early 90's. Bayesian phylogenetic analysis revealed the existence of a main HIV-1 CRF02_AG clade, introduced in the area of Rome before 2000 and subsequently differentiated in two different subclades with a different date of introduction (2000 versus 2005). All the sequences within clusters were interspersed, indicating that the MSM analyzed form a close and restricted network where the individuals, also moving within different clinical centers, attend the same places to meet and exchange sex. CONCLUSIONS: It was suggested that the HIV-1 CRF02_AG epidemic entered central Italy in the early 1990s, with a similar trend observed in western Europe.


Assuntos
Infecções por HIV/genética , HIV-1/genética , Epidemiologia Molecular , Filogenia , Teorema de Bayes , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Homossexualidade Masculina , Humanos , Itália/epidemiologia , Masculino , Estudos Retrospectivos , Sexo
17.
Semin Thromb Hemost ; 39(7): 779-93, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24030344

RESUMO

Substantial improvements in the safety of blood and plasma products for the management of bleeding disorders have been achieved in recent decades. This has led some clinicians to believe that the infectious threat is over and that inhibitor formation is the foremost complication of hemophilia therapy. On the contrary, elimination of all microbes from blood is difficult, potentially impossible, and there are always threats from emerging pathogens. The risk of infection transmission is also increasing due to greater exposure to products, increasing prophylaxis and high-dose regimens for immune tolerance, and longevity of hemophilia patients. Current products can be considered "reasonably safe," but pathogen testing is not all-inclusive, and manufacturing and purification techniques are often not standardized. Although safer nonplasma-derived products are widely used, they are not available for all bleeding disorders, and so there is an ongoing need for plasma-derived products. This review will discuss the evolving risk from emerging pathogens in the context of the issues described. Reducing the risk from emerging infections requires global collaboration to devise ways to monitor and continue to improve blood safety.


Assuntos
Transtornos da Coagulação Sanguínea/microbiologia , Transtornos da Coagulação Sanguínea/terapia , Transfusão de Sangue/métodos , Infecções/sangue , Infecções/transmissão , Reação Transfusional , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Hemofilia A/microbiologia , Hemofilia A/terapia , Humanos
18.
Antivir Ther ; 18(6): 831-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23740717

RESUMO

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.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Recursos em Saúde , Países em Desenvolvimento , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos
19.
Antivir Ther ; 18(4): 645-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23411358

RESUMO

A patient classified as HCV-1a-positive by both LiPA Siemens 2.0 and Abbott RealTime HCV Genotype II was instead found to be infected with HCV-1g, as determined by phylogenetic analysis of NS3 sequences. HCV-1g NS3 sequences available to date naturally harbour the resistance substitution T54S, plus P131S and L135F changes, located in the highly conserved NS3 positions within the boceprevir-binding site, as determined by structural modelling. HCV-1g NS3 sequences show some similarities to HCV-4 and are poorly responsive to interferon/ribavirin and to boceprevir/telaprevir; this patient was also a null-responder to boceprevir treatment. Baseline genotypic resistance testing may provide crucial information for the management of first-generation protease-inhibitor-based regimens, including both HCV genotype/subtype and natural resistance.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Prolina/análogos & derivados , Inibidores de Proteases/uso terapêutico , Proteínas não Estruturais Virais/genética , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Farmacorresistência Viral/efeitos dos fármacos , Técnicas de Genotipagem , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Filogenia , Prolina/uso terapêutico , Falha de Tratamento , Proteínas não Estruturais Virais/classificação
20.
J Med Virol ; 84(5): 721-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22431019

RESUMO

Currently the prevalence of HIV-1 infection in Cameroon is 5.1%, CRF02_AG subtype is responsible for about 50% of infections. Since an HIV-1 drug resistance test is not yet available widely, accurate data on the prevalence of resistant viral strains are missing. The objective of this study was to determine HIV-1 genetic diversity and to characterize HIV-1 mutations conferring drug resistance among antiretroviral therapy (ART)-naïve and ART-treated patients. A cohort of 239 patients infected with HIV were followed-up between January 2007 and July 2010 in Cameroon. Two hundred and sixteen plasma samples were sequenced for phylogenetic analysis and identification of drug resistance mutations in the HIV-1 pol region. A significant genetic diversity was found: Seven pure subtypes (A1, A3, D, F1, F2, G, H), nine circulating recombinant forms (CRFs: 01_AE, 02_AG, 06cpx, 09cpx, 11cpx, 13cpx, 16cpx, 18cpx, 37cpx) and one new unique recombinant form (URF) (G/F2). The rate of transmitted drug resistance (TDR) in naïve patients was 8.2% (4/49). Around 80% of patients failing a first-line ART harbored a virus with at least one resistance mutation to two antiretroviral (ARV) classes, and 36% of those failing a second-line regimen carried a virus with at least one resistant mutation to three ARV classes. The high level of drug resistance observed in the cohort is alarming because this occurred as a result of only few years of treatment. Adherence to therapy, adequate education of physicians, and the appropriate use of genotypic resistance assay are critical points of intervention for the improvement of patient care.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Variação Genética , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/farmacologia , Camarões/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Filogenia , Prevalência , Recombinação Genética , Inibidores da Transcriptase Reversa/farmacologia , Análise de Sequência de DNA , Falha de Tratamento , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
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