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1.
PLoS One ; 14(1): e0211354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695060

RESUMO

BACKGROUND: Antiretroviral therapy has surely increased the life expectancy of people living with HIV. However, long term complications like HIV associated sensory neuropathy has a negative impact on quality of life among people living with HIV (PLHIV). In Ethiopia, lack of data on magnitude of the burden and predictors of HIV associated sensory neuropathy in many resource limited setting has led to under diagnosis and eventually under management of HIV-SN. Hence, this study was set out to establish the burden of HIV-associated sensory neuropathy and, its association with demographic, health and clinical characteristics among people living with HIV in Ethiopia. METHODS: Cross-sectional study was conducted to assess the prevalence of HIV-associated sensory neuropathy and the associated factors among adult HIV patients at University of Gondar Teaching Hospital, Gondar, Ethiopia. Brief Peripheral Neuropathy Screening tool validated by AIDs Clinical trial group was used for screening HIV-associated sensory neuropathy. Data were analyzed descriptively and through uni- and multivariate logistic regression. RESULTS: In total 359 adult PLHIV with a mean age of 36.5± 9.07 years participated, their median duration of HIV infection was 60 months (IQR 36-84) and their median CD4 count 143cells/µL (IQR 69.5-201.5). Age above 40 years, anti-tuberculosis regimen, tallness, and exposure to didanosine contained antiretroviral therapy were found to be associated with HIV-associated sensory neuropathy (AOR 1.82, 1.84, 1.98 and 4.33 respectively). CONCLUSIONS: More than half of the HIV patients who attended HIV care clinic at University of Gondar hospital during the study period were found to present with peripheral sensory neuropathy. Higher age, tallness, TB medication, and didanosine in ART were significantly associated with HIV-SN as screened by effective diagnostic (BPNS) tool.


Assuntos
Infecções por HIV/complicações , Doenças do Sistema Nervoso Periférico/epidemiologia , Adulto , Estudos Transversais , Didanosina/efeitos adversos , Didanosina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doenças do Sistema Nervoso Periférico/etiologia , Qualidade de Vida
2.
J Antimicrob Chemother ; 74(1): 157-164, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304447

RESUMO

Objectives: Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients. Methods: ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs. Results: In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype. Conclusions: This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism.


Assuntos
Didesoxinucleosídeos/efeitos adversos , Eritrócitos/enzimologia , Infecções por HIV/tratamento farmacológico , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Pirofosfatases/metabolismo , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Idoso , Diabetes Mellitus/epidemiologia , Didanosina/efeitos adversos , Didanosina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Pirofosfatases/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico
3.
Environ Mol Mutagen ; 60(5): 404-409, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29206312

RESUMO

All nucleoside analogues for treating HIV infection, due to their capacity to integrate into and alter human DNA, are experimentally genotoxic to some extent. The long-term oncogenic risk after in utero exposure remains to be determined. Cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) was evaluated, by cross-checking against the National Cancer Registry, in the French perinatal study of children born to HIV+ mothers. Twenty-one cancers were identified in 15,163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero between 1990 and 2014. Five of these children were exposed to zidovudine monotherapy, and 15 to various combinations, seven of which included didanosine. Overall, the total number of cases was not significantly different from that expected for the general population (SIR = 0.8[0.47-1.24]), but the number of cases after didanosine exposure was twice that expected (SIR = 2.5 [1.01-5.19]). Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In multivariate analysis, didanosine exposure was significantly associated with higher risk (HR = 3.0 [0.9-9.8]). This risk was specifically linked to first-trimester exposure (HR = 5.5 [2.1-14.4]). Three cases of pineoblastoma, a very rare cancer, were observed, whereas 0.03 were expected. Two were associated with didanosine exposure. Despite reassuring data overall, there is strong evidence to suggest that didanosine displays transplacental oncogenicity. These findings cannot be extrapolated to other NRTIs, but they highlight the need for comprehensive evaluations of the transplacental genotoxicity of this antiretroviral class. Environ. Mol. Mutagen., 60:404-409, 2019. © 2017 Wiley Periodicals, Inc.


Assuntos
Fármacos Anti-HIV/toxicidade , Exposição Materna , Troca Materno-Fetal/fisiologia , Neoplasias/epidemiologia , Nucleosídeos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Adolescente , Fármacos Anti-HIV/uso terapêutico , Criança , Pré-Escolar , Didanosina/uso terapêutico , Didanosina/toxicidade , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Neoplasias/genética , Nucleosídeos/uso terapêutico , Gravidez , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/toxicidade , Risco , Inquéritos e Questionários , Zidovudina/uso terapêutico , Zidovudina/toxicidade
4.
AIDS Res Hum Retroviruses ; 33(12): 1185-1191, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28899102

RESUMO

Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Centros Comunitários de Saúde , Síndrome de Imunodeficiência Adquirida/mortalidade , Síndrome de Imunodeficiência Adquirida/virologia , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Estudos Transversais , Didanosina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Farmacorresistência Viral/fisiologia , Feminino , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , Ritonavir/uso terapêutico , População Rural , Falha de Tratamento , Carga Viral , Adulto Jovem , Zimbábue
5.
Artigo em Inglês | MEDLINE | ID: mdl-28559274

RESUMO

We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Relação CD4-CD8 , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Didanosina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/imunologia , Estavudina/uso terapêutico , Carga Viral , Zalcitabina/uso terapêutico , Zidovudina/uso terapêutico
6.
Rev Gastroenterol Peru ; 37(1): 87-90, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-28489843

RESUMO

Liver involvement is usually seen in patients infected with the human immunodeficiency virus (HIV), especially in patients coinfected with hepatitis B or C, in alcohol abuse, etc. However, there is a group of patients who develop liver involvement and portal hypertension of unspecified cause. Non-cirrhotic portal hypertension (NCPH) is a liver disorder recently described, but potentially serious. It has been reported in HIV-infected patients with highly active antiretroviral therapy (HAART), specifically didanosine (DDI). The pathophysiology involves the infectious agent (HIV) and its treatment (HAART), since both generate a pre-hepatic portal venulopathy. Similarly, HIV infection produces a prothrombotic state by protein S deficiency leading to the obliteration of small hepatic venules. It has been postulated that DDI as a cofactor in the pathogenesis of NCPH. All this leads that many of the liver biopsies show nodular regenerative hyperplasia. We present the case of a HIV-infected patient who was treated with a longstanding DDI. She developed upper gastrointestinal bleeding (UGB) and ascites due to NCPH, whose diagnosis was confirmed by biopsy. However, there is no similar study in our country.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didanosina/efeitos adversos , Infecções por HIV/tratamento farmacológico , Hipertensão Portal/induzido quimicamente , Adulto , Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Feminino , Infecções por HIV/complicações , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/virologia
7.
J Clin Endocrinol Metab ; 102(8): 2896-2904, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28531309

RESUMO

Context: HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth. Objective: To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure. Design: Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.4 years) within a subset of the HIV cohort (n = 33). Setting: Government outpatient research clinic. Results: Albumin/creatinine ratio, protein/creatinine ratio, anion gap, N-terminal telopeptides, and osteocalcin were significantly increased in persons with HIV compared with controls, whereas whole-body BMD and BMD z scores were lower. Within the HIV group, duration of tenofovir disoproxil fumarate (TDF) correlated with higher anion gap but did not correlate with bone parameters. Longer duration of didanosine and stavudine use correlated with lower BMD and BMD z scores. Longitudinal analyses revealed that BMD and bone metabolism significantly improved over time. No subject had an estimated glomerular filtration rate (eGFR) <60, but decline in eGFR correlated with increasing years of TDF exposure. Conclusions: Subclinical markers of renal dysfunction were increased in HIV-infected young adults and associated with TDF exposure, whereas lower bone density was associated with didanosine and stavudine exposure. The tendency for improvement in markers of bone health over time and the availability of less toxic ARV alternatives may herald improvements in renal and bone health for perinatally infected patients in adulthood.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico por imagem , Remodelação Óssea , Infecções por HIV/tratamento farmacológico , Insuficiência Renal/urina , Absorciometria de Fóton , Equilíbrio Ácido-Base , Adulto , Idade de Início , Albuminúria , Terapia Antirretroviral de Alta Atividade , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/metabolismo , Estudos de Casos e Controles , Creatinina/urina , Estudos Transversais , Didanosina/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Humanos , Testes de Função Renal , Estudos Longitudinais , Masculino , Osteocalcina/metabolismo , Estudos Prospectivos , Proteinúria , Insuficiência Renal/complicações , Fatores de Risco , Estavudina/uso terapêutico , Tenofovir/uso terapêutico , Fatores de Tempo , Adulto Jovem
8.
J Antimicrob Chemother ; 72(7): 2075-2082, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379449

RESUMO

Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: Subtype B patients ( n = 3410) were mostly MSM (78%) and those with subtype C ( n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P < 0.001). Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade , Didanosina/administração & dosagem , Didanosina/uso terapêutico , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/uso terapêutico , Farmacorresistência Viral/genética , Feminino , Estudos de Associação Genética , Genótipo , Infecções por HIV/virologia , HIV-1/classificação , Humanos , Masculino , Análise Multivariada , Análise de Sequência de DNA , Estavudina/administração & dosagem , Estavudina/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico
9.
Artigo em Inglês | MEDLINE | ID: mdl-28396546

RESUMO

HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATP (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Produtos do Gene pol/antagonistas & inibidores , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Zalcitabina/uso terapêutico , Zidovudina/uso terapêutico , Cristalografia por Raios X , Proteínas de Ligação a DNA/genética , Farmacorresistência Viral/genética , Transcriptase Reversa do HIV/genética , Vírus da Hepatite B/genética , Humanos , Mutação/genética , Conformação Proteica , Estrutura Quaternária de Proteína
10.
Brasília; CONITEC; dez. 2016.
Monografia em Português | BRISA/RedTESA | ID: biblio-837292

RESUMO

Contexto: A solicitação da exclusão dos antirretrovirais fosamprenavir (FPV) 700mg e didanosina entérica (ddI EC) 250mg e 400mg do arsenal terapêutico de antirretrovirais para tratamento do HIV/aids baseia-se na substituição desses fármacos por outros com melhor eficácia e posologia, além de menor toxicidade e menos interações medicamentosas, tendo como foco disponibilizar melhores opções de tratamento para as pessoas vivendo com HIV/aids (PVHA). Recomendação da CONITEC: Na reunião realizada no dia 30 de novembro de 2016, os membros presentes deliberaram por unanimidade recomendar a exclusão dos medicamentos antirretrovirais (ARV) na forma farmacêutica comprimido de fosamprevir (FPV) 700 mg, dianosina entérica ddI EC 250 mg e ddI EC 400 mg do arsenal terapêutico de antirretrovirais para o tratamento do HIV/aids. Recomendação da CONITEC: Na reunião realizada no dia 30 de novembro de 2016, os membros presentes deliberaram por unanimidade recomendar a exclusão dos medicamentos antirretrovirais (ARV) na forma farmacêutica comprimido de fosamprevir (FPV) 700 mg, dianosina entérica ddI EC 250 mg e ddI EC 400 mg do arsenal terapêutico de antirretrovirais para o tratamento do HIV/aids. Decisão: Excluir os medicamentos antirretrovirais (ARV) fosamprenavir (FPV) 700mg, didanosina entérica ddI EC 250mg e ddI EC 400mg do arsenal terapêutico de antirretrovirais para tratamentodo HIV/Aids, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria SCTIE-MS nº 49 publicada no Diário Oficial da União (D.O.U.) nº 246, de 23 de dezembro de 2016.


Assuntos
Humanos , Didanosina/efeitos adversos , Didanosina/uso terapêutico , HIV , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Brasil , Análise Custo-Benefício , Substituição de Medicamentos , Avaliação da Tecnologia Biomédica , Falha de Tratamento , Sistema Único de Saúde
11.
Pediatr Infect Dis J ; 35(8): e248-52, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27167116

RESUMO

BACKGROUND: Noncirrhotic portal hypertension (NCPH) has been reported in HIV-infected adults. Antiretroviral drugs, as well as genetic and thrombophilic predisposition, have been suggested as possible etiologic factors. METHODS: Clinical data were collected from 6 HIV-infected patients attending the Infectious Diseases Departments at respectively Emma Children's Hospital Academic Medical Centre in Amsterdam, The Thai Red Cross AIDS Research Centre, Bangkok, Imperial College Healthcare NHS Trust, London who were diagnosed with NCPH. All underwent extensive blood analysis, liver ultrasound, liver elastography, esophagogastroduodenoscopy and percutaneous needle liver biopsy for histological evaluation. RESULTS: We describe 6 perinatally HIV-infected adolescents, all female, who developed NCPH after prolonged exposure during childhood to a didanosine-containing antiretroviral regimen. Histology and electron microscopy showed periportal fibrosis and mitochondrial damage as key findings in their liver biopsies. One of these 6 patients required surgical intervention, the remainder have been managed conservatively to date. CONCLUSIONS: Thus, symptomatic NCPH may present in adolescence after perinatally acquired HIV-1 infection. In this case series, risk factors included female sex and prolonged exposure to antiretroviral regimens that included the nucleoside-analogue didanosine in childhood.


Assuntos
Antirretrovirais/efeitos adversos , Didanosina/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hipertensão Portal , Transmissão Vertical de Doença Infecciosa , Adolescente , Adulto , Antirretrovirais/uso terapêutico , Didanosina/uso terapêutico , Feminino , Humanos , Fígado/patologia , Adulto Jovem
12.
AIDS ; 30(11): 1771-80, 2016 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-27088320

RESUMO

BACKGROUND: It is unclear whether HIV infection is associated with liver fibrosis in the absence of chronic hepatitis B or C virus (HBV/HCV) coinfection. We compared prevalence of liver fibrosis, noninvasively assessed by the Fibrosis-4 (FIB-4) index, between HIV-infected patients and uninfected controls, and explored determinants of a higher FIB-4 score, indicative of more liver fibrosis. METHODS: FIB-4 was assessed in HIV-uninfected and HIV-1-infected, predominantly virologically suppressed participants of the AGEhIV Cohort Study without HBV and/or HCV coinfection, and aged at least 45. Using multivariable regression, we investigated associations between FIB-4 and HIV-status, HIV-disease characteristics, antiretroviral drugs and markers of microbial translocation and immune activation. RESULTS: Prevalence of advanced liver fibrosis (FIB-4 ≥ 3.25) was low: 1.4% in HIV-infected and 1.0% in HIV-uninfected participants. After adjustment for age, sex, ethnicity, detectable anti-hepatitis B core/anti-HCV antibodies and excessive alcohol intake, HIV remained significantly associated with higher FIB-4 (+4.2%, P = 0.05). Prior exposure to didanosine, longer duration of a CD4 cell count below 500 cells/µl and a lower CD4 cell count at enrollment were each associated with a higher FIB-4. Markers of immune activation (soluble CD163, activated CD8 T-lymphocytes and regulatory T-lymphocytes) were associated with a higher FIB-4 in HIV-infected but not HIV-uninfected study participants. CONCLUSION: HIV infection was independently associated with higher FIB-4 scores, indicating more advanced liver fibrosis, though the difference in FIB-4 scores between HIV-infected and HIV-uninfected was small. Higher levels of immune activation were associated with liver fibrosis in HIV-infected, even in the absence of HBV or HCV infection, but not in HIV-uninfected individuals.


Assuntos
Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Didanosina/efeitos adversos , Didanosina/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Cirrose Hepática/epidemiologia , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
13.
Arch Pharm (Weinheim) ; 349(6): 442-55, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27128998

RESUMO

A series of novel phosphorylated derivatives of didanosine were designed and docking studies were performed with a fusion protein of the Newcastle disease virus (NDV), to develop antiviral compounds against NDV. Based on the docking scores and binding affinities, three derivatives were selected. These compounds were synthesized and characterized by IR, (1) H, (13) C, (31) P, and CHN analysis and mass spectra. They were assessed for their in vitro antiviral activity in DF-1 cells; DDI-10 showed better antiviral activity as evidenced by significant reduction in plaque formation and cytopathic effects. DDI-10 was further evaluated in NDV-infected chicken; the survival rates and antioxidant enzyme levels in brain, liver, and lung tissues were estimated. Superoxide dismutase and catalase were significantly raised, and lipid peroxidation and HA titer levels were decreased upon treatment with 1.5 mg/kg body weight of DDI-10 than with 3 mg/kg body weight of DDI. Further histopathological alterations in NDV-infected tissues were restored in chicken treated with DDI-10. Thus, based on the results from in silico, in vitro, and in vivo assays, the novel phosphorylated DDI-10 might be considered as potent antiviral compound for NDV infection in chicken.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Galinhas/virologia , Didanosina/análogos & derivados , Didanosina/farmacologia , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/uso terapêutico , Encéfalo/metabolismo , Catalase/metabolismo , Células Cultivadas , Didanosina/química , Didanosina/uso terapêutico , Hemaglutinação/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Pulmão/metabolismo , Simulação de Acoplamento Molecular , Doença de Newcastle/tratamento farmacológico , Fosforilação , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/virologia , Relação Quantitativa Estrutura-Atividade , Superóxido Dismutase/metabolismo , Análise de Sobrevida
14.
J Med Virol ; 88(3): 448-54, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26291050

RESUMO

HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] + zidovudine [ZDV] vs. EFV + 3TC + ddI) among the HIV-1 CRF06_cpx infected subjects in Estonia. HIV-1 genomic RNA was sequenced; DRMs and amino acid substitutions were compared in 44 treatment naïve and 45 first-line NNRTI + 2 NRTI treatment failed patients consisting of EFV + 3TC + ZDV (n = 17) and EFV + 3TC + didanosine[ddI] (n = 21) therapy failed sub-populations. At least one DRM was found in 78% of treatment experienced patients. The most common NRTI mutations were M184V (80%), L74V (31%), L74I (17%), K219E (9%), and M184I (9%), NNRTI mutations were K103N (83%), P225H (14%), L100I (11%), and Y188L (11%), reflecting generally the similar pattern of DRMs to that seen in treatment failed subtype B viruses. Sub-population analysis revealed that EFV + 3TC + ddI failed patients had more DRMs compared to EFV + 3TC + ZDV failed patients, especially the ddI DRM L74IV and several additional NNRTI DRMs. Additionally, CRF06_cpx specific mutation E179V and substitutions R32K, K122E, and V200AE were also detected in treatment experienced population. After the failure of the first-line EFV + 3TC + ddI therapy HIV-1 CRF06_cpx viruses develop additional NRTI and NNRTI mutations compared to EFV + 3TC + ZDV regimen. Therefore the usage of EFV + 3TC + ddI in this subtype decreases the options for next regimens containing abacavir, and NNRTI class agents.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Adulto , Terapia Antirretroviral de Alta Atividade , Benzoxazinas/uso terapêutico , Didanosina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Estônia/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Lamivudina/uso terapêutico , Masculino , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico , Zidovudina/uso terapêutico
15.
Pediatr Infect Dis J ; 34(12): 1355-60, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26379163

RESUMO

BACKGROUND: AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years). METHODS: Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle. RESULTS: Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 µM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 µM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance. CONCLUSIONS: Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.


Assuntos
Benzoxazinas/uso terapêutico , Didanosina/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Pré-Escolar , Didanosina/administração & dosagem , Didanosina/farmacocinética , Emtricitabina/administração & dosagem , Emtricitabina/farmacocinética , Feminino , Infecções por HIV/epidemiologia , Humanos , Lactente , Masculino , Estudos Prospectivos
16.
Artigo em Inglês | MEDLINE | ID: mdl-26350426

RESUMO

A specific and reliable HPLC-MS/MS method was developed and validated for the simultaneous determination of 2',3'-dideoxyinosine (ddI) and the active metabolites, 2',3'-dideoxyadenosine-5'-triphosphate (ddA-TP) in human peripheral-blood mononuclear cell for the first time. The analytes were separated on a HILIC column (100mm×2.1mm, 1.7µm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was used for detection. The cell homogenates sample was prepared by the solid phase extraction. The calibration curves were linear over a concentration range of 0.5-200.0ng/mL for ddI and 0.25-100.0ng/mL for ddA-TP. The intra-day and inter-day precision was less than 15% and the relative error (RE) were all within ±15%. The validated method was successfully applied to assess the disposition characteristics of ddI and support cell pharmacokinetics after the patients with AIDS were orally administrated with ddI and tenofovir disoproxyl fumarate (TDF).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nucleotídeos de Desoxiadenina/sangue , Didanosina/sangue , Didesoxinucleotídeos/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Didanosina/farmacocinética , Didanosina/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Limite de Detecção , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
18.
Arch Endocrinol Metab ; 59(2): 116-22, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25993673

RESUMO

OBJECTIVE: This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases. MATERIALS AND METHODS: A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables. RESULTS: The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059. CONCLUSION: The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Autoanticorpos/isolamento & purificação , Hipotireoidismo/epidemiologia , Iodeto Peroxidase/imunologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Doenças da Glândula Tireoide/epidemiologia , Síndrome de Imunodeficiência Adquirida/sangue , Síndrome de Imunodeficiência Adquirida/complicações , Adulto , Antirretrovirais/uso terapêutico , Doenças Assintomáticas/epidemiologia , Doenças Assintomáticas/terapia , Contagem de Linfócito CD4 , Estudos Transversais , Didanosina/uso terapêutico , Feminino , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/imunologia , Masculino , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Doenças da Glândula Tireoide/tratamento farmacológico
19.
Arch. endocrinol. metab. (Online) ; 59(2): 116-122, 04/2015. tab
Artigo em Inglês | LILACS | ID: lil-746470

RESUMO

Objective This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases. Materials and methods A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables. Results The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059. Conclusion The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases. .


Assuntos
Adulto , Feminino , Humanos , Masculino , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Autoanticorpos/isolamento & purificação , Hipotireoidismo/epidemiologia , Iodeto Peroxidase/imunologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Doenças da Glândula Tireoide/epidemiologia , Síndrome de Imunodeficiência Adquirida/sangue , Síndrome de Imunodeficiência Adquirida/complicações , Antirretrovirais/uso terapêutico , Doenças Assintomáticas/epidemiologia , Doenças Assintomáticas/terapia , Estudos Transversais , Didanosina/uso terapêutico , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/imunologia , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Doenças da Glândula Tireoide/tratamento farmacológico
20.
Eur J Gastroenterol Hepatol ; 27(5): 577-84, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25769096

RESUMO

BACKGROUND: Many HIV antiretroviral medications have been associated with chronic liver injury. HIV-infected patients frequently develop HIV and highly active antiretroviral treatment-associated lipodystrophy syndrome (HALS), characterized by accumulation of intra-abdominal fat, insulin resistance, and hepatic steatosis. We sought to determine whether long-term exposure to specific antiretroviral medications or the presence of HALS predispose HIV-infected patients to the development of cirrhosis. METHODS: HIV-infected patients with cirrhosis who received care in the Veterans Affairs Healthcare System nationally in 2009 were matched by hepatitis C virus (HCV) coinfection status and year of first visit for HIV to the Veterans Affairs Healthcare System with HIV-infected patients without cirrhosis in a 1 : 3 ratio. RESULTS: Among HIV/HCV coinfected patients (593 with cirrhosis and 1591 matched controls), HALS was associated with a significantly increased risk for cirrhosis (adjusted odds ratio 1.6, 95% confidence interval 1.1-2.3), especially among Black patients (adjusted odds ratio 2.9, 95% confidence interval 1.6-5.2). In addition, among HIV/HCV coinfected patients, longer cumulative exposures to all antiretroviral medications, all nucleoside reverse transcriptase inhibitors, all protease inhibitors, and selected individual medications (didanosine, stavudine, and nelfinavir) were found to be significantly associated with cirrhosis. In contrast, among HIV-infected patients not coinfected with HCV (245 with cirrhosis and 658 matched controls), HALS or exposure to antiretroviral medications was found not to be significantly associated with cirrhosis, with the exception of didanosine. CONCLUSION: HALS and cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors, especially stavudine, didanosine, and nelfinavir, were found to be associated with the development of cirrhosis in HIV/HCV coinfected patients, but not in HIV-monoinfected patients.


Assuntos
Coinfecção/epidemiologia , Infecções por HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/epidemiologia , Hepatite C/epidemiologia , Cirrose Hepática/epidemiologia , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Estudos de Casos e Controles , Didanosina/uso terapêutico , Feminino , Infecções por HIV/complicações , Inibidores da Protease de HIV/uso terapêutico , Síndrome de Lipodistrofia Associada ao HIV/etnologia , Síndrome de Lipodistrofia Associada ao HIV/etiologia , Hispano-Americanos/estatística & dados numéricos , Humanos , Cirrose Hepática/etnologia , Masculino , Pessoa de Meia-Idade , Nelfinavir/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco , Estavudina/uso terapêutico , Fatores de Tempo
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