Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
1.
J Infect Dis ; 218(5): 688-697, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29617822

RESUMO

Background: A high genetic barrier to resistance to the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and in vivo. We describe the dynamics of INSTI resistance-associated mutations (INSTI-RAMs) and mutations in the 3'-polypurine tract (3'-PPT) in relation to virologic failure (VF) observed in the randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828). Methods: From 10 patients with VF, plasma samples were collected before the start of cART and during VF, and were used to generate Sanger sequences of integrase, the 5' terminal bases of the 3' long terminal repeat (LTR), and the 3'-PPT. Results: Median human immunodeficiency virus RNA load at VF was 3490 copies/mL (interquartile range 1440-4990 copies/mL). INSTI-RAMs (S230R, R263K, N155H, and E92Q+N155H) were detected in 4 patients, no INSTI-RAMs were detected in 4 patients, and sequencing of the integrase gene was unsuccessful in 2 patients. The time to VF ranged from 4 weeks to 72 weeks. In 1 patient, mutations developed in the highly conserved 3'-PPT. No changes in the terminal bases of the 3'-LTR were observed. Conclusions: The genetic barrier to resistance is too low to justify dolutegravir maintenance monotherapy because single INSTI-RAMs are sufficient to cause VF. The large variation in time to VF suggests that stochastic reactivation of a preexisting provirus containing a single INSTI-RAM is the mechanism for failure. Changes in the 3'-PPT point to a new dolutegravir resistance mechanism in vivo. Clinical Trials Registration: NCT02401828.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Mutação , Adulto , Feminino , HIV-1/isolamento & purificação , Humanos , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sequência de DNA , Falha de Tratamento , Carga Viral
2.
J Infect Dis ; 218(5): 698-706, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29617824

RESUMO

Background: Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of human immunodeficiency virus (HIV)-infected individuals. Owing to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virologic failure while using DTG monotherapy. Methods: We evaluated the effect of the S230R substitution in regard to integrase enzyme activity, viral infectivity, replicative capacity, and susceptibility to different INSTIs by biochemical and cell-based assays. Results: The S230R substitution conferred a 63% reduction in enzyme efficiency. S230R virus was 1.29-fold less infectious than wild-type virus but could replicate in PM1 cells without significant delay. Resistance levels against DTG, cabotegravir, raltegravir, and elvitegravir in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively, in virus with the S230R substitution. Conclusions: Our data indicate that the S230R substitution is comparable to the previously reported R263K substitution in some respects. Virologic failure during DTG monotherapy can occur through the development of the S230R or R263K mutation, without the need for high-level DTG resistance.


Assuntos
Substituição de Aminoácidos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Carga Viral , HIV/genética , HIV/crescimento & desenvolvimento , HIV/isolamento & purificação , Integrase de HIV/genética , Integrase de HIV/metabolismo , Humanos , Quimioterapia de Manutenção/métodos , Testes de Sensibilidade Microbiana , Mutação de Sentido Incorreto , Oxazinas , Piperazinas , Piridonas , Falha de Tratamento , Replicação Viral
3.
Liver Int ; 38(5): 792-796, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29285885

RESUMO

BACKGROUND AND AIMS: Infection with Hepatitis E virus (HEV) can cause chronic liver disease in immunocompromised hosts. In transplant recipients, the use of certain immunosuppressants and food habits has been proposed as risk factors for HEV. In individuals infected with the human immunodeficiency virus (HIV), risk factors for HEV infection are less clear. We aimed to study the association between a mutation in the progesterone receptor (PR) named PROGINS and HEV-infected in HIV-positive individuals. METHODS: We evaluated the presence of the SNP PROGINS via KASP in serum samples of 64 HIV-positive individuals and 187 healthy controls. We performed ELISA tests to address the serum levels of IL-10 and IL-12, as well as T-cell stimulation assays in peripheral blood to address immune response in individuals with PROGINS. RESULTS: We found a significant association between the presence of PROGINS mutation and HEV seroprevalence in individuals infected with HIV (30% in HIV+/HEV+ versus 2% in HIV+/HEV, respectively, P = .009). Moreover, we found that HIV+/HEV+ individuals expressing the PROGINS mutation had lower serum levels of IL-10 and higher levels of IL-12. The presence of the mutation led to a reduced response upon stimulation of CD4+ and CD8+ T cells compared to those without the mutation, suggesting an immune modulation associated with PROGINS. CONCLUSIONS: Our study identified a mutation in the PR that provides significant insights into mechanisms of HEV infection in immunosuppressed individuals.


Assuntos
Predisposição Genética para Doença , Soropositividade para HIV/complicações , Hepatite E/genética , Receptores de Progesterona/genética , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Vírus da Hepatite E , Humanos , Hospedeiro Imunocomprometido , Interleucina-10/sangue , Interleucina-12/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estudos Soroepidemiológicos , Transplantados
4.
Clin Infect Dis ; 65(8): 1335-1341, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28595298

RESUMO

BACKGROUND: The use of antiretroviral therapy during pregnancy is important for control of maternal human immunodeficiency virus (HIV) disease and the prevention of perinatal HIV transmission. Physiological changes during pregnancy can reduce antiretroviral exposure. We studied the pharmacokinetics of rilpivirine 25 mg once daily in HIV-1-infected women during late pregnancy. METHODS: We conducted a nonrandomized, open-label, multicenter, phase 4 study. HIV-infected pregnant women receiving rilpivirine 25 mg once daily were included. Intensive 24-hour pharmacokinetic sampling was performed in the third trimester and at least 2 weeks postpartum. Pharmacokinetic parameters were calculated by noncompartmental analysis. RESULTS: Sixteen subjects were included. Geometric mean ratios of third trimester vs postpartum were 0.55 (90% confidence interval [CI], .46-.66) for the 24-hour area under the concentration-time curve (AUC0-24h); 0.65 (90% CI, .55-.76) for the maximum concentration; and 0.51 (90% CI, .41-.63) for the minimum observed concentration (Cmin). Four of 16 (25%) subjects had Cmin below the target concentration (0.04 mg/L) in the third trimester of pregnancy. No subtherapeutic levels were observed postpartum. No detectable viral loads were observed in this study. All newborns tested negative for HIV. No birth defects were reported. The median (range, n = 5) rilpivirine cord-to-maternal plasma concentration ratio was 0.50 (range, .35-.81). CONCLUSIONS: Rilpivirine exposure is substantially lowered during late pregnancy. Despite lower exposure, virologic suppression was maintained and no perinatal transmission was observed. Overall, these results suggest that rilpivirine 25 mg once daily may be an alternative treatment option for HIV-1-infected pregnant women who are virologically suppressed, in settings where therapeutic drug monitoring and/or close viral load monitoring are feasible to detect suboptimal antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT00825929.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Gravidez , Terceiro Trimestre da Gravidez , Rilpivirina/administração & dosagem , Rilpivirina/sangue , Adulto Jovem
5.
Clin Infect Dis ; 61(5): 809-16, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25944344

RESUMO

BACKGROUND: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION: NCT00825929.


Assuntos
Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Raltegravir Potássico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Raltegravir Potássico/administração & dosagem , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/farmacocinética , Raltegravir Potássico/uso terapêutico
6.
J Antimicrob Chemother ; 70(2): 534-42, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25326090

RESUMO

OBJECTIVES: To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum. PATIENTS AND METHODS: This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929. RESULTS: Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported. CONCLUSIONS: Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Sulfonamidas/farmacocinética , Adulto , Darunavir , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Carga Viral , Adulto Jovem
7.
Sex Transm Infect ; 91(4): 245-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25596191

RESUMO

OBJECTIVES: The incidence of anal cancer is increasing especially in HIV-positive men having sex with men. Screening for the cancer precursor, high-grade squamous intraepithelial lesions (HSIL), is challenging, as current treatment is suboptimal. The aim of this prospective study was to establish the efficacy of five consecutive days a week self-administered treatment with imiquimod 5% cream for both perianal and intra-anal HSIL and to assess the adverse effects and burden of this regimen. METHODS: 44 patients with histologically proved perianal or intra-anal HSIL were treated with a five consecutive days a week imiquimod 5% cream regimen. When no response could be confirmed after the first 16 weeks of therapy, patients were encouraged to continue the use of the cream for a further 16 weeks. Side effects were routinely assessed. RESULTS: Complete or partial response was observed in 20 (45%) of 44 patients with HSIL after 16 weeks of treatment; another nine patients showed complete or partial response after an additional 16 weeks of treatment, resulting in a response rate of 29 (66%) out of 44 patients. CONCLUSIONS: Topical imiquimod 5% cream is useful in HSIL. A five consecutive days treatment regimen with imiquimod 5% cream for HSIL does not seem to be more effective compared with the customary prescription for 3 days a week. A prolonged course of imiquimod 5% cream is warranted for intra-anal HSIL. Adverse effects are comparable between 3 and 5 days treatment regimen.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Aminoquinolinas/administração & dosagem , Canal Anal/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Neoplasias do Ânus/prevenção & controle , Soropositividade para HIV/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Lesões Intraepiteliais Escamosas Cervicais/tratamento farmacológico , Administração Tópica , Canal Anal/patologia , Canal Anal/virologia , Neoplasias do Ânus/patologia , Neoplasias do Ânus/virologia , Progressão da Doença , Eletrocoagulação , Feminino , Soropositividade para HIV/complicações , Humanos , Imiquimode , Masculino , Pomadas , Papillomaviridae/patogenicidade , Estudos Prospectivos , Lesões Intraepiteliais Escamosas Cervicais/patologia , Lesões Intraepiteliais Escamosas Cervicais/virologia
9.
Clin Infect Dis ; 57(10): 1497-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23912848

RESUMO

In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/fisiopatologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Sarcoma de Kaposi/fisiopatologia , Sarcoma de Kaposi/virologia , Resultado do Tratamento , Carga Viral
10.
Retrovirology ; 10: 27, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23497283

RESUMO

BACKGROUND: The presence of a vpx gene distinguishes HIV-2 from HIV-1, the main causative agent of AIDS. Vpx degrades the restriction factor SAMHD1 to boost HIV-2 infection of macrophages and dendritic cells and it has been suggested that the activation of antiviral innate immune responses after Vpx-dependent infection of myeloid cells may explain why most HIV-2-infected individuals efficiently control viral replication and become long-term survivors. However, the role of Vpx-mediated SAMHD1 antagonism in the virological and clinical outcome of HIV-2 infection remained to be investigated. RESULTS: Here, we analyzed the anti-SAMHD1 activity of vpx alleles derived from seven viremic and four long-term aviremic HIV-2-infected individuals. We found that effective Vpx-mediated SAMHD1 degradation and enhancement of myeloid cell infection was preserved in most HIV-2-infected individuals including all seven that failed to control the virus and developed AIDS. The only exception were vpx alleles from an aviremic individual that predicted a M68K change in a highly conserved nuclear localization signal which disrupted the ability of Vpx to counteract SAMHD1. We also found that HIV-2 is less effective than HIV-1 in inducing innate immune activation in dendritic cells. CONCLUSIONS: Effective immune control of viral replication in HIV-2-infected individuals is not associated with increased Vpx-mediated degradation of SAMHD1.


Assuntos
HIV-2/imunologia , HIV-2/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores , Proteínas Monoméricas de Ligação ao GTP/imunologia , Proteínas Virais Reguladoras e Acessórias/metabolismo , Replicação Viral , Sequência de Aminoácidos , Linhagem Celular , Análise por Conglomerados , Células Dendríticas/imunologia , Células Dendríticas/virologia , Infecções por HIV/virologia , HIV-2/isolamento & purificação , Humanos , Dados de Sequência Molecular , Filogenia , Proteólise , Proteína 1 com Domínio SAM e Domínio HD , Análise de Sequência de DNA
11.
J Virol ; 86(9): 4906-20, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22345473

RESUMO

The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4(+) T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4(+) T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4(+) T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.


Assuntos
Antígenos CD28/metabolismo , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , HIV-2/metabolismo , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Substituição de Aminoácidos , Apoptose/genética , Linhagem Celular , Regulação para Baixo/imunologia , Expressão Gênica , Ordem dos Genes , Infecções por HIV/metabolismo , HIV-2/genética , HIV-2/imunologia , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Ativação Linfocitária/genética , Modelos Moleculares , Dados de Sequência Molecular , Filogenia , Ligação Proteica/imunologia , Conformação Proteica , Provírus/genética , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Receptores de Superfície Celular/metabolismo , Receptores de Morte Celular/metabolismo , Linfócitos T/imunologia , Viremia/imunologia , Viremia/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
12.
J Infect Dis ; 206(6): 974-80, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22782950

RESUMO

BACKGROUND: The kinetics of hepatitis B surface antigen (HBsAg) are predictive in HBV-infected patients treated with pegylated interferon. Knowledge about the value of HBsAg levels in patients coinfected with HBV and human immunodeficiency virus (HIV) is lacking. METHODS: We quantified serum HBsAg in a Dutch multicenter cohort of 104 patients coinfected with HIV and HBV who were treated with tenofovir disoproxil fumarate (TDF) as part of highly active antiretroviral therapy. The median duration of therapy was 57 months (interquartile range, 34-72 months). RESULTS: Hepatitis B e antigen (HBeAg)-positive patients achieved a decline of 2.2 log IU/mL in HBsAg, whereas HBeAg-negative patients only achieved a decline of 0.6 log IU/mL during 6 years of TDF therapy. Declines in HBsAg at months 6 and 12 correlated with CD4 cell count for HBeAg-positive patients. Five HBeAg-positive patients (8%) and 3 HBeAg-negative patients (8%) cleared HBsAg. HBeAg-negative patients who cleared HBsAg had lower baseline HBsAg as compared to patients who remained HBsAg positive. The majority of patients who cleared HBsAg achieved this end point within the first year. In HBeAg-positive patients, decline in HBsAg at month 6 was predictive of achieving HBsAg seroclearance. CONCLUSIONS: Receipt of TDF therapy by HIV/HBV-coinfected patients for up to 6 years led to a significant decrease in HBsAg in the HBeAg-positive population. HBsAg kinetics early during treatment were predictive of HBsAg seroclearance and correlated with an increased CD4 cell count, underlining the importance of immune restoration in HBV clearance.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/tratamento farmacológico , Ácidos Fosforosos/uso terapêutico , Adenina/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção , Esquema de Medicação , Feminino , Infecções por HIV/complicações , Hepatite B/sangue , Hepatite B/complicações , Humanos , Masculino , Pessoa de Meia-Idade
13.
Viruses ; 15(11)2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-38005913

RESUMO

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.


Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , HIV-2/genética , Sequência de Bases , Progressão da Doença
14.
PLoS Med ; 9(3): e1001196, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22479156

RESUMO

BACKGROUND: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). METHODS AND FINDINGS: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count < 350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p < 0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p < 0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. CONCLUSIONS: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adulto , Esquema de Medicação , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
15.
Clin Immunol ; 142(3): 252-68, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22177848

RESUMO

In a phase I/IIa clinical trial, 17 HIV-1 infected patients, stable on cART, received 4 vaccinations with autologous dendritic cells electroporated with mRNA encoding Tat, Rev and Nef, after which cART was interrupted. Vaccination was safe and feasible. During the analytical treatment interruption (ATI), no serious adverse events were observed. Ninety-six weeks following ATI, 6/17 patients remained off therapy. Although induced and/or enhanced CD4(+) and CD8(+) T-cell responses specific for the immunogens were observed in most of the patients, we found no correlation with the number of weeks off cART. Moreover, CD4(+) T-cell counts, plasma viral load and the time remaining off cART following ATI did not differ from historical control data. To conclude, the vaccine was safe, well tolerated and resulted in vaccine-specific immune responses. Since no correlation with clinical parameters could be found, these results warrant further research in order to optimize the efficacy of vaccine-induced T-cell responses.


Assuntos
Vacinas contra a AIDS/imunologia , Células Dendríticas/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Imunização , Adulto , Idoso , Células Cultivadas , Produtos do Gene rev/imunologia , Produtos do Gene tat/imunologia , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia
16.
Ther Drug Monit ; 34(2): 153-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22354160

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals show large interindividual variation in response to antiretroviral therapy. Efavirenz (EFV) and nevirapine (NVP) are nonnucleoside reverse transcriptase inhibitors, which are prescribed in combination with other antiretroviral therapy in so-called highly active antiretroviral therapy. Recent studies provide evidence for the role of cytochrome P450 (CYP) genes, in particular CYP2B6, in relation to EFV and NVP pharmacokinetics. In this study, the authors investigated whether common ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles are associated with plasma concentrations of EFV and NVP in HIV-infected individuals. METHODS: Plasma drug concentrations were quantified by high-performance liquid chromatography in 143 HIV-infected individuals receiving either EFV or NVP. Genotyping for common alleles was performed by restriction fragment length polymorphism and Taqman assays. Individuals were genotyped for 11 single-nucleotide polymorphisms in 5 genes. CYP2B6 haplotypes were reconstructed by PHASE. RESULTS: Plasma EFV concentrations were positively associated with CYP2B6 c.516G>T, c.785A>G, and c.983A>G single-nucleotide polymorphisms in HIV-infected individuals. Increased plasma concentrations of EFV and NVP were present in individuals with the CYP2B6*6/*6 or *6/*18 haplotype compared with CYP2B6*1/*1 [increase of 62% (95% confidence interval, 44.0-80.1) and 24% (95% confidence interval, 7.0-40.0), respectively, P < 0.01]. No significant association with other genes in relation to EFV or NVP concentrations was found. CONCLUSIONS: In this study, a strong association of CYP2B6*6 and CYP2B6*18 alleles in relation to EFV and NVP plasma concentrations was found, which confirmed previous studies.


Assuntos
Fármacos Anti-HIV/farmacocinética , Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Nevirapina/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Alcinos , Alelos , Terapia Antirretroviral de Alta Atividade/métodos , Hidrocarboneto de Aril Hidroxilases/genética , Cromatografia Líquida de Alta Pressão , Ciclopropanos , Monitoramento de Medicamentos/métodos , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único
17.
Lasers Surg Med ; 44(8): 637-44, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22899359

RESUMO

BACKGROUND AND OBJECTIVE: Anal cancer and preneoplastic anal lesions (anal intraepithelial neoplasia, AIN) rising especially in men having sex with men (MSM). There are no widely accepted treatment standards for AIN. Photodynamic therapy (PDT) using the systemic sensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the potential to treat the anal area even when the exact borders of the preneoplastic anal lesion cannot easily be visualized. STUDY DESIGN/MATERIALS AND METHODS: In this prospective intervention study, 15 HIV-positive MSM with AIN 3 were treated in 25 PDT-sessions using mTHPC intravenously administered at drug doses of 0.075-0.15 mg ml(-1) and illumination at 48 hours. The illumination was performed using a custom made applicator using either red light (652 nm) to a measured intended fluence of 10 and 20 J cm(-2) and green light (532 nm) to a measured intended fluence of 105, 210, and 340 J cm(-2) . Red and green illuminations were performed at a (green) equivalent fluence rate of 105 mW cm(-2) . RESULTS: Initial complete response was seen in 7/25 (28%) of treatments and another 4/25 (16%) initial partial responses. After an average 8 months, recurrences were detected in 7/11 (64%) of sessions that initially showed response. A total 4/25 (16%) showed persistent complete response 6-15 months after green light illumination. Red light illuminations caused more significant side effects combined with no persistent complete response. Reported side effects were intense pain, bloody and purulent rectal discharge, and anal stricture formation, in one patient. CONCLUSION: The results show that the use of systemic mTHPC is partially effective for the treatment of AIN 3.


Assuntos
Neoplasias do Ânus/tratamento farmacológico , Carcinoma in Situ/tratamento farmacológico , Mesoporfirinas/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Adulto , Neoplasias do Ânus/patologia , Carcinoma in Situ/patologia , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Medição da Dor , Fotoquimioterapia/efeitos adversos , Estudos Prospectivos
18.
J Infect Dis ; 203(7): 984-91, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21266513

RESUMO

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. METHODS: A noninferiority trial with a 10% response margin was designed. Included were patients ≥ 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: <200, 200-500, >500. Participants received 10 µg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥ 10 IU/L. RESULTS: Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3,) the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+)cell count group >500 cells/mm(3) was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001). CONCLUSION: In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4(+) cell count group >500 cells/mm(3). CLINICAL TRIALS REGISTRATION: CT00230061.


Assuntos
Infecções por HIV/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Vacinação/métodos , Adulto , Idoso , Contagem de Linfócito CD4 , Feminino , Humanos , Injeções Intramusculares , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade
19.
Gastroenterology ; 139(6): 1934-41, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20801123

RESUMO

BACKGROUND & AIMS: We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. METHODS: We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. RESULTS: At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m(2), which was most pronounced shortly after TDF therapy was initiated. CONCLUSIONS: TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Fármacos Anti-HIV/efeitos adversos , Antivirais/administração & dosagem , Contagem de Linfócito CD4 , DNA Viral/sangue , Farmacorresistência Viral , Feminino , Seguimentos , Guanina/administração & dosagem , Guanina/análogos & derivados , Infecções por HIV/complicações , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/complicações , Humanos , Estimativa de Kaplan-Meier , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Estudos Prospectivos , Tenofovir , Fatores de Tempo , Replicação Viral/efeitos dos fármacos
20.
Antivir Ther ; 14(3): 443-50, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19474478

RESUMO

BACKGROUND: Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting. METHODS: A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 +/-2), the third trimester (week 33 +/-2) and post-partum (weeks 4-6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1. RESULTS: A total of 37 women were included in the analysis. Mean (+/-sd) values for saquinavir area under the curve (AUC(0-12h)) were 23.47 h*mg/l (11.92) at week 20 (n=16), 23.65 h*mg/l (9.07) at week 33 (n=31) and 25.00 h*mg/l (11.81) post-partum (n=9). There was no significant difference in the saquinavir AUC(0-12h) when comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as <0.10 mg/l) were not observed throughout the study. No major safety concerns were noted. CONCLUSIONS: Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , HIV-1 , Complicações Infecciosas na Gravidez/tratamento farmacológico , Saquinavir/farmacocinética , Adulto , Esquema de Medicação , Quimioterapia Combinada , Europa (Continente) , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Humanos , Gravidez , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Saquinavir/administração & dosagem , Saquinavir/efeitos adversos , Comprimidos , Tailândia , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA