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1.
Xenobiotica ; 50(5): 570-579, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31403353

RESUMO

HIV replication in the brain is unopposed due to reduced antiretroviral drug penetration into the central nervous system (CNS). Prevalence of HIV-associated neurocognitive disorder (HAND) has increased severely in patients living with HIV despite current treatments. The aims of this study were to evaluate the brain bio-distribution of alternative nucleoside reverse transcriptase inhibitors, abacavir, stavudine and didanosine in the CNS and to determine their localization patterns in the brain.Sprague-Dawley rats received 50 mg kg-1 single i.p dose of each drug. Mass spectrometric techniques were then used to investigate the pharmacokinetics and localization patterns of these drugs in the brain using LC-MS/MS and mass spectrometric imaging (MSI), respectively.Abacavir, stavudine and didanosine reached the Brain Cmax with concentration of 831.2, 1300 and 43.37 ngmL-1, respectively. Based on MSI analysis Abacavir and Stavudine were located in brain regions that are strongly implicated in the progression of HAND.Abacavir and Stavudine penetrated into CNS, reaching a Cmax that was above the IC50 for HIV (457.6 and 112.0 ngmL-1, respectively), however, it was noted ddI showed poor entry within the brain, therefore, it is recommended that this drug cannot be considered for treating CNS-HIV.


Assuntos
Encéfalo/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Animais , Didanosina/metabolismo , Didesoxinucleosídeos/metabolismo , Infecções por HIV , Ratos , Estavudina/metabolismo , Espectrometria de Massas em Tandem
2.
BMC Infect Dis ; 19(1): 708, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399063

RESUMO

BACKGROUND: Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation. METHODS: Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome). RESULTS: prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]). CONCLUSIONS: We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.


Assuntos
Adiponectina/sangue , Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Tecido Adiposo/patologia , Adulto , Biomarcadores/sangue , Estudos Transversais , Didanosina/efeitos adversos , Feminino , Infecções por HIV/fisiopatologia , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea/efeitos dos fármacos , Timidina/análogos & derivados
3.
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
4.
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
5.
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
6.
AIDS ; 33(4): 675-683, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30585844

RESUMO

BACKGROUND: Thymidine analogs and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous adipose tissue (SAT) to visceral adipose tissue (VAT), which, in turn, is a risk factor for cardiovascular disease. We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to thymidine analogs and/or ddI, without exposure, and uninfected controls and the association with cardiovascular disease risk factors. METHODS: In all, 761 PLWH from the Copenhagen Comorbidity in HIV Infection study, and 2283 age and sex-matched uninfected controls from the Copenhagen General Population Study were included. PLWH were stratified according to prior exposure to thymidine analogs and/or ddI. VAT and SAT were determined by abdominal computed tomography scan. Hypotheses were tested using regression analyses. RESULTS: Exposure to thymidine analogs and/or ddI was associated with 21.6 cm larger VAT (13.8-29.3) compared to HIV infection without exposure. HIV-negative status was associated with similar VAT compared to HIV infection without exposure. Cumulative exposure to thymidine analogs and/or ddI [3.7 cm per year (2.3-5.1)], but not time since discontinuation [-1.1 cm per year (-3.4 to 1.1)], was associated with VAT. Prior exposure to thymidine analogs and/or ddI was associated with excess risk of hypertension [adjusted odds ratio (aOR) 1.62 (1.13-2.31)], hypercholesterolemia [aOR 1.49 (1.06-2.11)], and low high-density lipoprotein [aOR 1.40 (0.99-1.99)]. CONCLUSIONS: This study suggests a potentially irreversible and harmful association of thymidine analogs and ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation.


Assuntos
Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Didanosina/efeitos adversos , Infecções por HIV/complicações , Timidina/efeitos adversos , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Doenças Cardiovasculares/fisiopatologia , Dinamarca/epidemiologia , Didanosina/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Timidina/administração & dosagem , Timidina/análogos & derivados
7.
Cell Biochem Biophys ; 76(1-2): 111-124, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28477056

RESUMO

Anaplastic lymphoma kinase is a tyrosine kinase receptor protein belonging to insulin receptor superfamily. Gene fusions in anaplastic lymphoma kinase are associated with non-small cell lung cancer development. Hence, they are of immense importance in targeted therapies. Thus, for the treatment of non-small cell lung cancer, effective anaplastic lymphoma kinase inhibitors are of great significance. Therefore, our objective is to find hit compounds that could have better inhibitory activity than the existing anaplastic lymphoma kinase inhibitors. Keeping this in mind, in the present study pharmacophore based virtual screening was performed to identify possible anaplastic lymphoma kinase inhibitors. Initially, a five-point common pharmacophore hypothesis was generated based on twelve anaplastic lymphoma kinase inhibitors using PHASE module of Schrödinger. Subsequently, common pharmacophore hypothesis-based screening was conducted against in-trials subset of ZINC database and a total of 1000 hits were identified. The molecules obtained were further screened by three stages of docking using GLIDE software. The docking results reveal that six hit molecules showed higher glide score in comparison with the reference molecules. Finally, pharmacokinetic properties of the hit molecules were also analysed using QikProp programme. The results indicate that molecules namely videx, dexecadotril, chloramphenicol, naficillin were found to have good pharmacokinetic properties and human oral absorption. Moreover, videx, naficillin and chloramphenicol were found to have significant inhibitory activity for mutant (F1174L) anaplastic lymphoma kinase. It was also found that videx exhibited crucial interactions with the Met1199 residue of the native and mutant anaplastic lymphoma kinase protein. Furthermore, PASS algorithm predicted anti-neoplastic activity for all the four molecules. Thus these hits are found to be promising leads for anaplastic lymphoma kinase inhibitors. We believe that this study will be useful for the discovery and designing of more potent anaplastic lymphoma kinase inhibitors in the near future.


Assuntos
Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Algoritmos , Quinase do Linfoma Anaplásico , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Domínio Catalítico , Cloranfenicol/química , Cloranfenicol/metabolismo , Bases de Dados de Compostos Químicos , Bases de Dados de Proteínas , Didanosina/química , Didanosina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Conformação Molecular , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Termodinâmica , Tiorfano/análogos & derivados , Tiorfano/química , Tiorfano/metabolismo
8.
Drug Deliv Transl Res ; 8(1): 21-31, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28944416

RESUMO

Rational design of prodrugs for efficient albumin binding shows distinct advantages in drug delivery in terms of drug availability, systemic circulation, and potential targeting effect. And fatty acids are good candidates due to their high affinity to albumin. However, how the alkyl chain length of fatty acids affects the binding dynamics between prodrugs and albumin, despite its importance, is still unclear. In the present study, three prodrugs of didanosine (DDI) and fatty acids were designed and synthesized to evaluate the effect of the alkyl chain length on prodrug-albumin binding process, including capric acid-didanosine (CA-DDI), myristic acid-didanosine (MA-DDI), and stearic acid-didanosine (SA-DDI). The binding dynamics between these prodrugs with bovine serum albumin (BSA) were studied by fluorometry, circular dichroism (CD), UV analysis, and molecular docking. It turned out that DDI itself showed poor binding affinity to BSA. In contrast, CA-DDI, MA-DDI, and SA-DDI demonstrated significantly improved binding affinity. Interestingly, the binding affinity between DDI prodrugs and BSA was correlated with the alkyl chain length of fatty acids, and the binding constant significantly increased with the extension of alkyl chain length (KCA-DDI = 5.86 × 103 M-1, KMA-DDI = 8.57 × 103 M-1, and KSA-DDI = 11.42 × 103 M-1 at 298 K).


Assuntos
Fármacos Anti-HIV/química , Didanosina/química , Ácidos Graxos/química , Pró-Fármacos/química , Soroalbumina Bovina/química , Sítios de Ligação , Dicroísmo Circular , Fluorescência , Simulação de Acoplamento Molecular , Ligação Proteica
9.
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
10.
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
11.
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
12.
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
13.
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
14.
AIDS ; 31(11): 1535-1543, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28398958

RESUMO

OBJECTIVE: To determine the incidence and risk factors for developing diabetes mellitus in a cohort of Thai HIV-infected patients on long-term combination antiretroviral therapy (cART). DESIGN: Prospective study conducted between July 1996 and 30 April 2015. METHODS: A total of 1748 patients (60% men) who did not have diabetes mellitus prior to ART were assessed twice a year. Incident diabetes mellitus was defined as either having two consecutive fasting glucose levels more than 126 mg/dl, or reporting antidiabetes mellitus medication/diabetes mellitus diagnosis after starting cART. Incidence rates were calculated per 1000 person-year follow-up. Multivariate Cox regression was used to determine risk factors for the development of diabetes mellitus. RESULTS: During a median follow-up of 9 years (16 274 person-year of follow-up), 123 patients developed new-onset diabetes mellitus, resulting in an incidence rate of 7.6 (95% confidence interval 6.3-9) per 1000 person-year of follow-up. From the multivariate models, age more than 35 years, male sex, BMI at least 25 kg/m, family history of diabetes, abnormal waist circumference, lipodystrophy and exposure to didanosine were significantly associated with incident diabetes mellitus. The diabetes mellitus group had higher mortality rate (8.1 vs. 4.1%, P = 0.04). A significantly higher proportion diabetes vs. nondiabetes patients developed cardiovascular and cerebrovascular complications (8.9 vs. 3.6%, P = 0.008) or chronic kidney disease stage III (estimated glomerular filtration rate <60 ml/min/1.73 m) (15.3 vs. 1.9%, P < 0.001) over total follow-up. CONCLUSION: In addition to traditional risk factors, lipodystrophy and use of didanosine were strongly associated with development of incident diabetes. Given the higher rate of cardiovascular-cerebrovascular complications and chronic kidney disease among patients with diabetes mellitus, careful assessment and appropriate management of diabetes mellitus are essential.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/fisiopatologia , Didanosina/efeitos adversos , Infecções por HIV/fisiopatologia , Síndrome de Lipodistrofia Associada ao HIV/complicações , Obesidade Abdominal/complicações , Insuficiência Renal Crônica/prevenção & controle , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Terapia Antirretroviral de Alta Atividade , Grupo com Ancestrais do Continente Asiático , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Didanosina/administração & dosagem , Feminino , Infecções por HIV/complicações , Síndrome de Lipodistrofia Associada ao HIV/fisiopatologia , Humanos , Incidência , Masculino , Obesidade Abdominal/fisiopatologia , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/etiologia , Inibidores da Transcriptase Reversa/administração & dosagem , Fatores de Risco , Tailândia , Resultado do Tratamento
15.
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
16.
Med Mycol J ; 57(4): J155-J162, 2016.
Artigo em Japonês | MEDLINE | ID: mdl-27904061

RESUMO

The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered in order to achieve a successful outcome.


Assuntos
Neoplasias Hematológicas/complicações , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/terapia , Mucormicose/diagnóstico , Mucormicose/terapia , Anfotericina B/uso terapêutico , Didanosina , Diagnóstico Precoce , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Pneumopatias Fúngicas/etiologia , Mucormicose/etiologia , Neutropenia , Risco , Procedimentos Cirúrgicos Operatórios
17.
Retina ; 36 Suppl 1: S159-S167, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28005674

RESUMO

PURPOSE: To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature. METHODS: This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity. RESULTS: Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort. CONCLUSION: Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Doenças da Coroide/induzido quimicamente , Didanosina/efeitos adversos , Degeneração Retiniana/induzido quimicamente , Adulto , Idoso , Didanosina/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
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
19.
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
20.
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
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