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1.
AIDS Res Ther ; 17(1): 46, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703286

RESUMO

BACKGROUND: The COVID-19 has been a severe pandemic all around the world. Nowadays the patient with co-infection of HIV and SARS-CoV-2 was rarely reported. Here we reported a special case with HIV and SARS-CoV-2 co-infection, which showed a prolonged viral shedding duration. CASE PRESENTATION: The patient was infected with HIV 8 years ago through sexual transmission and had the normal CD4+T cell count. She was found SARS-CoV-2 positive using real-time Polymerase Chain Reaction (RT-PCR) during the epidemic. Most importantly, the patient had a prolonged viral shedding duration of SARS-CoV-2 about 28 days. CONCLUSION: The viral shedding duration may be prolonged in people living with HIV. The 14 days isolation strategy might not be long enough for them. The isolation or discharge of these patients needs further confirmation for preventing epidemics.


Assuntos
Antirretrovirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por HIV/complicações , Pneumonia Viral/diagnóstico , Eliminação de Partículas Virais , Benzoxazinas/administração & dosagem , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/análise , Contagem de Linfócito CD4 , Calafrios , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Fadiga , Feminino , Febre , HIV/crescimento & desenvolvimento , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina M/sangue , Lamivudina/administração & dosagem , Pessoa de Meia-Idade , Pandemias , Faringite , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real , Escarro/virologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Eliminação de Partículas Virais/imunologia , Zidovudina/administração & dosagem
2.
Medicine (Baltimore) ; 99(22): e20487, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481459

RESUMO

Simultaneous therapeutic drug monitoring (TDM) of combination antiretroviral therapy (cART) is critical during pregnancy in order to improve clinical follow-up, monitor viral load, and patient adherence to treatment.A modified simple and fast ultra-high performance liquid chromatography coupled with tandem mass spectrometry and electrospray ionization (UPLC-ESI-MS/MS) method was developed and validated according to national and international guidelines for the simultaneous determination of lamivudine (LMV), zidovudine (ZDV), lopinavir (LPV), and ritonavir (RTV) concentrations in 100-µL plasma sample of Human Immunodeficiency Virus (HIV)-positive pregnant women. Protein precipitation using 0.1% formic acid in cold acetonitrile was used for sample preparation. The chromatographic separation was achieved with a run-time of 3.0 minutes and 3-µL injection on an ethylene bridged hybrid C18 column (2.1 µm × 50 mm, 1.7 µm), under gradient conditions using acetonitrile and formic acid (0.1%).The chromatographic method was used to analyze 10 plasma samples from 8 HIV pregnant women as a clinical patient routinely follow-up by applying TDM criteria.The protonated precursor/product ion transitions for LMV (230.18/112.08), ZDV (268.22/127.10), LPV (629.55/447.35), and RTV (721.50/296.20) were recorded in multiple-reaction-monitoring (MRM) mode. The calibration curve was linear in the range of 50-3,000, 75-4,500, 250-15,000, and 25-1,500-ng/mL for LMV, ZDV, LPV, and RTV, respectively. The range of accuracy was 97.2% to 100.1% and precision 3.4% to 12.7%. The method showed specificity and matrix effect values of < 15%. Minimum absolute recovery percentages (%CV) were 90.5 (5.4), 90.8 (5.0), 95.4 (3.5), and 93.7 (6.9), for LMV, ZDV, LPV, and RTV, respectively. Drug concentrations in patient samples had high inter-individual variability with %CV of 91.98%, 77.54%, 53.80%, and 92.16% for ZDV, LMV, LPV, and RTV, respectively. Two of the 8 patients showed no adherence due to the absence of Protease Inhibitors (PIs) levels in plasma.This technique demonstrated to be effective in therapeutic drug monitoring and is intended to be used in population pharmacokinetics specifically for HIV-positive pregnant women.


Assuntos
Fármacos Anti-HIV/sangue , Monitoramento de Medicamentos , Soropositividade para HIV/tratamento farmacológico , Lamivudina/sangue , Lopinavir/sangue , Ritonavir/sangue , Zidovudina/sangue , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Segurança do Paciente , Gravidez , Espectrometria de Massas em Tandem , Carga Viral
3.
Medicine (Baltimore) ; 99(24): e20516, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541474

RESUMO

Symptomatic cerebrospinal fluid (CSF) viral escape (sCVE) is reported in people with HIV, who are on ritonavir-boosted protease inhibitor (PI/r) containing antiretroviral therapy (ART). Management of sCVE includes performing genotypic HIV-1 resistance testing (GRT) on CSF and plasma HIV and changing ART accordingly. Neither GRT nor newer drugs (Dolutegravir and Darunavir/ritonavir) are routinely available in India. As a result, management of sCVE includes 2 modalities: a) ART intensification by adding drugs that reach therapeutic concentrations in CSF, like Zidovudine, to existing ART or b) Changing to a regimen containing newer boosted PI/r and integrase strand transfer inhibitor (INSTI) as per GRT or expert opinion. In this retrospective study, we report the outcomes of above 2 modalities in treatment of sCVE in Pune, India.Fifty-seven episodes of sCVE in 54 people with HIV taking PI/r-containing ART were identified. Clinical, demographic, laboratory and ART data were recorded. Forty-seven cases had follow-up data available after ART change including measurement of plasma and CSF viral load (VL).Of the 47 cases, 23 received zidovudine intensification (Group A, median VL: plasma- 290, CSF- 5200 copies/mL) and 24 received PI/INSTI intensification (Group B, median VL: plasma- 265, CSF-4750 copies/mL). CSF GRT was performed in 16 participants: 8 had triple class resistance. After ART change, complete resolution of neurologic symptoms occurred in most participants (Group A: 18, Group B: 17). In Group A, follow-up plasma and CSF VL were available for 21 participants, most of whom achieved virologic suppression (VL < 20 copies/mL) in plasma (17) and CSF (15). Four participants were shifted to the PI/INSTI intensification group due to virologic failure (plasma or CSF VL > 200 copies/mL). In Group B, follow-up plasma and CSF VL were available for 23 participants, most of whom also achieved virologic suppression in plasma (21) and CSF (18). Four deaths were noted, 2 of which were in individuals who interrupted ART.This is a unique sCVE cohort that was managed with 1 of 2 approaches based on treatment history and the availability of GRT. At least 75% of participants responded to either approach with virologic suppression and improvement in symptoms.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/tratamento farmacológico , Zidovudina/uso terapêutico , Adulto , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Eur. j. anat ; 24(3): 193-203, mayo 2020. tab, ilus, graf
Artigo em Inglês | IBECS | ID: ibc-ET2-5389

RESUMO

The degenerative and inflammatory changes were reported in cardiac tissues of rats exposed to zidovudine (ZDV). This study was designed to ex-amine the histochemical changes in the myocardi-um of adult Wistar rats exposed to ZDV and ad-ministered with methanolic extract of Buchholzia coriacea (MEBC) seed. Forty-eight healthy Wistar rats weighing 150-155 g. were randomly assigned into eight groups of six rats each. Group A served as control and received distilled water; group B received 100 mg/kg of ZDV; group C received 600 mg/kg of MEBC; group D received 100 mg/kg of vitamin C; group E received 100 mg/kg of vitamin C and ZDV; group F received 150 mg/kg of MEBC and 100 mg/kg of ZDV; group G received 300 mg/kg of MEBC and 100 mg/kg of ZDV, and group H received 600 mg/kg of MEBC and 100 mg/kg of ZDV. Treatment lasted for a period of 56 days. Blood was collected separately into clean capped plain tubes for biochemical parameters. Heartswere excised, fixed in 10% formal saline and pro-cessed for histology. ZDV induced a significant increase in the serum concentration of Nitric Oxide (NO) and Cardiac Troponin I (cTnI) in the ZDV-alone group when compared to control (p < 0.05). Also, there was reduction in activity of the Glutathi-one reductase (GR) enzyme in the ZDV-alone group relative to control (P = 0.0006, F = 7.0). Distor-tion of the cross banding pattern of cardiac muscle fibres in ZDV-alone group was manifested. These effects were reversed by administration of MEBC compared to vitamin C group


No disponible


Assuntos
Animais , Ratos , Ventrículos do Coração/anatomia & histologia , Metanol/administração & dosagem , Zidovudina/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/veterinária , Coração/anatomia & histologia , Capparaceae , Extratos Vegetais/administração & dosagem , Ventrículos do Coração/efeitos dos fármacos , Zidovudina/administração & dosagem , Ratos Wistar/anatomia & histologia , Coração/efeitos dos fármacos , Técnicas Histológicas , Fotomicrografia , Antioxidantes/administração & dosagem , Sementes
5.
BMC Infect Dis ; 20(1): 123, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046664

RESUMO

BACKGROUND: The rate of S68G mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has increased and is closely related to the K65R mutation among CRF01_AE-infected patients who failed treatment. We aimed to explore the temporal association of S68G and K65R mutations and disclose the role of the former on susceptibility to nucleotide/nucleoside reverse transcriptase inhibitor (NRTI) and viral replication with the K65R double mutations among CRF01_AE-infected patients who failed treatment. METHODS: The occurrence of S68G and K65R mutations was evaluated among HIV-1 of various subtypes in the global HIV Drug Resistance Database. The temporal association of S68G and K65R mutations was analyzed through next-generation sequencing in four CRF01_AE-infected patients who failed treatment with tenofovir/lamivudine/efavirenz. The impact of the S68G mutation on susceptibility to NRTI and replication fitness was analyzed using pseudovirus phenotypic resistance assays and growth competition assays, respectively. RESULTS: The frequency of the S68G mutation increased by 1.4-9.7% in almost all HIV subtypes and circulating recombinant forms in treatment-experienced patients, except subtype F. The S68G mutation often occurred in conjunction with the K65R mutation among RTI-treated patients, with frequencies ranging 21.1-61.7% in various subtypes. Next-generation sequencing revealed that the S68G mutation occurred following the K65R mutation in three of the four CRF01_AE-infected patients. In these three patients, there was no significant change detected in the half maximal inhibitory concentration for zidovudine, tenofovir, or lamivudine between the K65R and K65R/S68G mutations, as demonstrated by the phenotypic resistance assays. Virus stocks of the K65R and K65R/S68G mutations were mixed with 4:6, 1:1, and 9:1 and cultured for 13 days, the K65R/S68G mutants outgrew those of the K65R mutants irrespective of the input ratio. CONCLUSIONS: S68G may be a natural polymorphism and compensatory mutation of K65R selected by NRTIs in the CRF01_AE strain of HIV-1. This mutation does not affect susceptibility to NRTI; however, it improves the replication fitness of K65R mutants. This study deciphers the role of the S68G mutation in the HIV reverse transcriptase of the CRF01_AE strain and provides new evidence for the interpretation of drug-resistant mutations in non-B subtypes of HIV-1.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/genética , Mutação , Fármacos Anti-HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/uso terapêutico , Taxa de Mutação , Polimorfismo Genético , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Falha de Tratamento , Replicação Viral/efeitos dos fármacos , Zidovudina/uso terapêutico
6.
BMC Infect Dis ; 20(1): 68, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964348

RESUMO

BACKGROUND: Cryptococcal meningitis (CCM) is a common and deadly disease among HIV-infected patients. Notable about CCM is its association with the immune reconstitution inflammatory syndrome (IRIS). Though it has been posited a switch from first to second-line antiretroviral therapy (ART) can induce CCM IRIS, a case presentation of CCM IRIS has not been published. CASE PRESENTATION: A 10-year-old, HIV-infected girl who initially presented with severe headache and new-onset seizures, with cerebrospinal fluid that returned antigen, India Ink, and culture positive for Cryptococcus neoformans. Notably, 8 weeks prior to seizures, she had switched from first line to second-line ART (abacavir-lamivudine-efavirenz to zidovudine-lamivudine-lopinavir/ritonavir) due to virologic failure, with a viral load of 224,000 copies/milliliter. At time of seizures and 8 weeks on second-line ART, her viral load had reduced to 262 copies/milliliter. Her hospital course was prolonged, as she had ongoing headaches and developed bilateral cranial nerve VI palsies despite clearance of Cryptococcus from cerebrospinal fluid on antifungal therapy and therapeutic lumbar punctures. However, symptoms stabilized, and she was discharged with oral fluconazole. Cranial nerve palsies resolved 10 weeks post discharge and she has remained disease free. CONCLUSIONS: We describe a case of CCM IRIS in a 10-year-old HIV infected child after changing to second-line ART. This case provides evidence that screening for cryptococcal antigenaemia prior to switch from first-line to second-line ART could be an important measure to prevent cryptococcal disease.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Cryptococcus neoformans/isolamento & purificação , HIV/efeitos dos fármacos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Meningite Criptocócica/diagnóstico , Ritonavir/uso terapêutico , Zidovudina/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Antifúngicos/uso terapêutico , Antígenos de Fungos/sangue , Benzoxazinas/uso terapêutico , Criança , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Feminino , Fluconazol/uso terapêutico , HIV/isolamento & purificação , Humanos , Síndrome Inflamatória da Reconstituição Imune/etiologia , Lamivudina/efeitos adversos , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/etiologia , Ritonavir/efeitos adversos , Resultado do Tratamento , Carga Viral , Zidovudina/efeitos adversos
7.
PLoS One ; 15(1): e0227473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978137

RESUMO

INTRODUCTION: Loss to follow up after the initiation of antiretroviral therapy (ART) is common in Africa, particularly in Ethiopia and it is a considerable obstacle for the effectiveness of the ART program. Mortality is a competing risk of loss to follow up but it is often overlooked and there is limited evidence about the incidence and predictors of loss to follow up in the presence of competing events. OBJECTIVE: To assess the Incidence and predictors of loss to follow up among adult HIV patients on ART in University of Gondar Comprehensive Specialized Hospital between January 1, 2015, and December 31, 2018. METHODS: Institution based retrospective follow up study was conducted in University of Gondar Comprehensive Specialized Hospital. A Gray's test and cumulative incidence curve were used to compare the cumulative incidence function of loss to follow up. Bivariable and multivariable competing risk regression models were fitted to identify the predictors of lost to follow up and those variables with p-value <0.05 in the multivariable analysis was considered as significant predictors of lost to follow up. RESULT: A total of 531 adult HIV patients on ART were included in the analysis. The incidence rate of loss to follow up in this study was 10.90 (95% CI: 8.9-13.2) per 100 person years. Being age group 15-30 years (aSHR = 2.01; 95%CI;1.11-3.63), being daily laborer(aSHR = 2.60; 95%CI;1.45-4.66), not receiving cotrimoxazole preventive therapy (aSHR = 2.66; 95%CI;1.68-4.21), not receiving isoniazid preventive therapy(aSHR = 4.57; 95% CI;1.60-13.08), ambulatory functional status (aSHR = 1.61; 95% CI; 1.02-2.51) and taking AZT-3TC-NVP medication at start of ART(aSHR = 2.01; 95% CI; 1.16-3.78) were significant predictors of lost to follow up. CONCLUSION: In this study the incidence of lost to follow up was high. Young people, daily laborer, ambulatory patients and those taking AZT-3TC-NVP as well as those who did not take opportunistic prophylaxis were at higher risk of loss to follow up. Therefore, giving special attention to the high-risk groups for lost to follow up highlighted in this study could decrease the rate of LTFU.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Perda de Seguimento , Adolescente , Adulto , Assistência Ambulatorial , Quimioterapia Combinada , Feminino , Seguimentos , Hospitais Especializados , Humanos , Incidência , Lamivudina/uso terapêutico , Masculino , Nevirapina/uso terapêutico , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem , Zidovudina/uso terapêutico
8.
Environ Pollut ; 258: 113700, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31838398

RESUMO

Dissolved organic matter (DOM) is the most important light absorber that may induce indirect photolytic transformation of organic pollutants in natural waters. In this study, effects of DOM derived from freshwater and seawater on the photodegradation of three antiviral drugs acyclovir, lamivudine and zidovudine were investigated. Results show that the photodegradation of acyclovir is promoted mainly by excited triplet states DOM (3DOM*), and the photodegradation of lamivudine is accelerated by 3DOM*, •OH and 1O2 together; however, the photodegradation of zidovudine is inhibited by DOM mainly via light screening. Compared with DOM from freshwater, promotion effect of DOM extracted from seawater (SDOM) on the photodegradation of acyclovir and lamivudine is weaker, which is attributed to lower productivity of reactive intermediates. On the other hand, inhibitory effect of SDOM on the photodegradation of zidovudine is also weaker, which is due to weaker light screening caused by lower light absorption. Photodegradation half-lives of the three antiviral drugs are predicted to be all more than 20 days in freshwater and seawater bodies of the Yellow River estuarine region. These findings are significant for understanding the phototransformation processes of antiviral drugs and other organic pollutants in estuarine and coastal regions.


Assuntos
Antivirais/química , Substâncias Húmicas , Fotólise , Poluentes Químicos da Água/química , Aciclovir , Água Doce/química , Lamivudina , Água do Mar/química , Zidovudina
9.
Braz J Infect Dis ; 24(1): 65-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31835018

RESUMO

Antiretroviral therapy (ART) has modified the outcome of patients with HIV infection, providing virological control and reducing mortality. However, there are several reasons as to why patients may discontinue their antiretroviral therapy, with adverse events being one of the main reasons reported in the literature. This is a case-control nested in a cohort of people living with HIV/AIDS, conducted to identify the incidence of ART modification due to adverse events and the associated factors, in two referral services in Recife, Brazil, between 2011 and 2014. Of the modifications occurred in the first year of ART, 25.7% were driven by adverse events. The median time elapsed between initiating ART and the first modification due to adverse events was 70.5 days (95% CI: 26-161 days). The main adverse events were dermatological, neuropsychiatric and gastrointestinal. Dermatological events were the earliest to appear after initiating ART. Efavirenz was the most prescribed and most modified drug during the study period. The group of participants who used zidovudine, lamivudine, and efavirenz had a 2-fold greater chance (adjusted OR: 2.16 95% CI: 1.28-3.65) of switching ART due to adverse events when compared to the group that used tenofovir with lamivudine and efavirenz.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Síndrome de Imunodeficiência Adquirida/mortalidade , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/efeitos adversos , Brasil , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Lamivudina/efeitos adversos , Modelos Logísticos , Lopinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ritonavir/efeitos adversos , Tenofovir/efeitos adversos , Fatores de Tempo , Adulto Jovem , Zidovudina/efeitos adversos
10.
J Pharm Biomed Anal ; 178: 112911, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31627078

RESUMO

Zidovudine (ZDV) and efavirenz (EFV), which belong to two separate classes of antiretroviral drugs, viz., NRTI and NNRTI, respectively, were subjected to different stability test conditions alone and in solid mixtures to evaluate possibility of interaction among them. The exposed samples were analyzed by high performance liquid chromatography (HPLC) using a C18 column and a PDA detector. Two new peaks were observed in the sample in which 50 µl CH3CN was added to increase the contact among the drugs, and which was subjected in open beaker to accelerated stability test condition of 40 °C/75%RH for 15 d. Subsequently, liquid chromatography-high resolution mass spectrometric (LC-HRMS) studies were carried out to obtain their accurate mass. The products were also isolated, and subjected to 1H, 13C, DEPT-135, COSY, HSQC and HMBC nuclear magnetic resonance (NMR) studies. The collective information allowed their structural characterization as isomeric cycloaddition products of the two drugs. As these were novel compounds, they were subjected to testing for cytotoxicity and in vitro anti-HIV-1 activity against primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C) in TZM-bl cell line. The two were found to show weak activity against the standard drugs. The reason was sought through molecular docking studies, which highlighted that it was perhaps their comparative bigger molecular size than the drugs of both classes used currently in HIV therapy. Being previously unknown molecules, their in silico physicochemical and ADMET properties were also evaluated using ADMET Predictor™ and TOPKAT software.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Zidovudina/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Combinação de Medicamentos , Estabilidade de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular
11.
S Afr Med J ; 109(12): 919-926, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31865953

RESUMO

BACKGROUND: World Health Organization guidelines recommend that HIV patients who do not achieve viral suppression on efavirenz-based first-line antiretroviral therapy (ART) should be changed to a protease inhibitor (PI)-based regimen. In South Africa (SA), ~200 000 people are on second-line treatment, but little is known about these patients. OBJECTIVES: To describe second-line black African patients in a large urban area. METHODS: A quantitative retrospective study of 825 second-line patients in central Johannesburg, SA (subdistrict F), was performed with data extracted from government databases. Demographic characteristics, treatment status and laboratory information were gathered, then analysed with CD4+ cell count, viral load (VL) and retention-in-care data as outcome variables. RESULTS: The average recorded time to VL measurement after the switch to a PI-based ART regimen was 20 months, and 83.1% (570/686) of patients with a recent VL achieved viral suppression while on second-line treatment. The most recent median CD4+ cell count for the cohort was 286 cells/µL (interquartile range 160 - 478), which represented a 177 cells/µL increase from the baseline count at the start of first-line ART. Slightly less than three-quarters (72.4%) of the population remained active in care in the study clinics from initiation on first-line ART. Demographic characteristics such as being <25 years of age, male sex and geographical transfer (started initial treatment in a different region) independently predicted low CD4+ cell counts and virological failure on second-line treatment. Patients with virological failure were most likely (odds ratio (OR) 3.13, 95% confidence interval (CI) 1.50 - 6.56) to be lost to follow-up after the switch, while patients from Hillbrow Community Health Centre (OR 0.27, 95% CI 0.16 - 0.44), South Rand Hospital (OR 0.24, 95% CI 0.12 - 0.47) and Jeppe Clinic (OR 0.38, 95% CI 0.16 - 0.88), three larger sites, were most likely to remain active in care. CONCLUSIONS: VL suppression was high in patients on second-line treatment, but one-fifth of patients were lost to follow-up. Younger age, male sex and transfer from other treatment sites predicted poor treatment outcomes, highlighting opportunities for prioritisation of adherence interventions.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Carga Viral , Adulto , Fatores Etários , Contagem de Linfócito CD4 , Bases de Dados Factuais , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Humanos , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Fatores Sexuais , Tenofovir/uso terapêutico , Falha de Tratamento , Organização Mundial da Saúde , Zidovudina/uso terapêutico
12.
Biopharm Drug Dispos ; 40(9): 341-349, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31693190

RESUMO

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 µmol min/L, Cmax 6.46 ± 0.74 µmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 µmol/min/L, Cmax 6.10 µmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.


Assuntos
Recém-Nascido Prematuro/metabolismo , Modelos Biológicos , Zidovudina/farmacocinética , Fármacos Anti-HIV/farmacocinética , Idade Gestacional , Humanos , Recém-Nascido
13.
AAPS PharmSciTech ; 21(1): 1, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712905

RESUMO

The SeDeM diagram expert system has been applied to study Zidovudine and some excipients. From the obtained diagrams, a pharmaceutical formula has been designed. SeDeM diagram ascertains the critical parameters that are suitable for a direct compression. The formula is compressed using a rotary tablet press simulator which emulates rotary tablet press' compression profiles. From these compressions, we study the formula behavior under different industrial production conditions but saving a huge amount of material. The study is done at different compression forces and compression speeds and taking into account the influence of the pre-compression force. The differences observed between the compression profiles are hereby described. The results indicate that the formulation is able to be compressed adequately with the emulated compression profiles and no differences are observed between the final products. Therefore, we can assure that the SeDeM diagram expert system is accurate and robust. Moreover, its results are comparable with the compression results in a rotary tablet press, which has never been described in the pharmaceutical literature before. From the obtained results, it is possible to select the best rotary press to scale-up this formulation.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Composição de Medicamentos/instrumentação , Composição de Medicamentos/métodos , Sistemas Especialistas , Comprimidos , Zidovudina/administração & dosagem , Composição de Medicamentos/normas , Indústria Farmacêutica , Excipientes , Testes de Dureza , Pós
14.
Acta Med Indones ; 51(3): 253-257, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31699949

RESUMO

This is the first report of HIV drug resistance in RSUPN Dr. Cipto Mangunkusumo. We tested We reviewed eleven new cases of HIV patients who had virologic failure after 6 months first-line antiretroviral therapy. With the sequencing method, analysis of gene mutations encoded HIV drug resistance. Genotypic resistance results and HIV-1 subtype were interpreted by Stanford DR database. Of ten plasma samples that were successfully amplified and sequenced, all samples were resistant to at least one antiretroviral drug. Genotypic resistance towards the antiretroviral drugs being used was observed in lamivudine (90%), tenofovir (83%), nevirapine (100%) dan efavirenz (100%). It is interesting that no zidovudine resistance were found, including in four patients receiving zidovudine in their HAART. The common NRTI mutations were M184VI and K65R, while NNRTI mutations were Y181CFGVY, K103N, A98AG, E138GQ and G190AGS. No mayor PI mutations were found. Based on these findings, we supports the need for appropriate virology monitoring and HIV drug resistance survey in clinical practice and access to drug options in case of virology failure.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adulto , Terapia Antirretroviral de Alta Atividade , Benzoxazinas , Feminino , Infecções por HIV/virologia , HIV-1/genética , Humanos , Lamivudina , Masculino , Tenofovir , Falha de Tratamento , Carga Viral , Zidovudina
15.
J Fluoresc ; 29(5): 1257-1263, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31620936

RESUMO

Autofluorescence of the bone extracellular matrix (ECM) has not been widely explored although the ECM plays a very important role in bone development. In our research we focused on examining the bone matrix of very young animals due to the intense growth process during the first month of life. Structure images and fluorescence spectra of the bone surface were carried out using confocal fluorescence microscope Eclipse Ti-S inverted CLSM (NIKON, Japan) for compact tibia of healthy 7-, 14- and 28-day-old rat newborns after prenatal zidovudine administration in comparison with control. Spectral features of ECM autofluorescence were analyzed statistically by taking into consideration p < 0.05. The CLSM technique allows for simultaneous examination of the structure and autofluorescence from selected areas of the bone surface. Excessive autofluorescence of ECM after prenatal zidovudine administration influences bone growth incommensurably to the newborns' age. Therefore the possibility of an additional non-enzymatic mechanism of collagen cross-linking in the first two weeks of life of newborn rats prenatally treated with zidovudine has been considered. Our results suggest that ECM autofluorescence can be an indicator of bone development in the normal and pathological state.


Assuntos
Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Tíbia/citologia , Tíbia/crescimento & desenvolvimento , Zidovudina/farmacologia , Animais , Ratos , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Fatores de Tempo
16.
Clinics (Sao Paulo) ; 74: e318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531571

RESUMO

OBJECTIVE: The present literature review aims to highlight gaps in the treatment of preventative mother-to-child HIV transmission and the risk factors in Brazil. METHODS: Among the 425 articles identified in SciELO and PubMed searches, 59 articles published between 1994 and 2016 were selected for reading and data extraction, and 33 articles were included in the present review. RESULTS: The rates of vertical HIV transmission described in the studies varied widely, from 1.8% to 27.8%, with a significant reduction over the years. However, recent rates were also found to be variable in different regions of Brazil, and despite the significant reduction in mother-to-child transmission, many gaps remain in prevention services. A failure to attend prenatal care is the main factor associated with the increased risk of vertical transmission of HIV, hindering early maternal diagnosis and the completion of preventative measures during the prenatal period and, often, the peripartum and postnatal periods. A small number of studies discussed the sociodemographic factors, including a low level of education for pregnant women and the inadequacies of health services, such as difficulties scheduling appointments and undertrained staff, associated with vertical transmission. As such, the current challenge is to better define the sociodemographic and infrastructural factors that increase the risk of mother-to-child transmission of HIV to provide the necessary investments to promote an earlier inclusion of these populations in prevention services. CONCLUSIONS: This review may serve as a guide for future programs to focus efforts on the prevention of vertical HIV transmission.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Brasil , Quimioterapia Combinada , Feminino , Infecções por HIV/prevenção & controle , Humanos , Gravidez , Cuidado Pré-Natal , Fatores de Risco , Zidovudina/uso terapêutico
17.
Eur J Pharm Biopharm ; 144: 91-100, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521715

RESUMO

We have previously demonstrated that the ester conjugation of zidovudine (AZT) with ursodeoxycholic acid (UDCA) allows to obtain a prodrug (U-AZT) which eludes the active efflux transporters (AET). This allows the prodrug to more efficiently permeates and remains in murine macrophages than the parent compound. Here we demonstrate that U-AZT can be formulated, by a nanoprecipitation method, as nanoparticle cores coated by bile acid salt (taurocholate or ursodeoxycholate) corona, without any other excipients. The U-AZT nanoparticles appeared spherical with a mean diameter of ∼200 nm and a zeta potential of ∼-55 mV. During the incubation (5 h) in fetal bovine serum, the ursodeoxycholate-coated nanoparticle size did not change. Differently, taurocholate-coated particle size was firstly reduced and then increased up to 800 µm, thus suggesting the high aptitude of these nanoparticles to interact with serum proteins. The in vitro uptake of taurocholate coated particles by murine macrophages was strongly higher than that of ursodeoxycholate-coated particles or free U-AZT (∼500% and ∼7000%, respectively). AZT was also detected in macrophages following the prodrug uptake, with the greatest amounts observed after the taurocholate-coated nanoparticle incubation. As macrophages in the subarachnoid spaces of cerebrospinal fluid (CSF) constitute one of the most unreachable HIV sanctuaries in the body, we also tested the ability of taurocholate-coated nanoparticles (i.e., nanoparticles highly internalized by macrophages) to reach them after their nasal administration in the presence or absence of chitosan. The results indicate that chitosan allowed to obtain a relatively high uptake (up to 4 µg/ml) of U-AZT in CSF. Taking into account that chitosan may promote the direct brain nanoparticle uptake, these findings can be considered an initial step toward the in vivo targeting of the subarachnoid macrophages by U-AZT prodrug.


Assuntos
Ácidos e Sais Biliares/química , Encéfalo/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Mucosa Nasal/metabolismo , Pró-Fármacos/farmacologia , Zidovudina/farmacologia , Administração Intranasal , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Quitosana/química , Portadores de Fármacos/química , Excipientes/química , Camundongos , Nariz , Tamanho da Partícula , Ácido Ursodesoxicólico/química
18.
Mol Cell Biochem ; 462(1-2): 41-50, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31432386

RESUMO

Antiretroviral therapy (ART) has remarkably decreased HIV-related mortality. However, drug-resistant HIV variants pose a potential threat to the long-term success of ART. Both HIV mutants and host factors can cause HIV drug resistance. Using susceptible ACH2 cells chronically infected with HIV-1, we examined the effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication that can be activated by HIV-1 superinfection. We found that HIV-1 superinfection induced more viral production, which was diminished by p38 inhibitor, SB203580, and by AZT in cells infected with non-AZT-resistant HIV-1 strain MN. p38α expression can resist action of AZT in inhibition of HIV-1 replication with increased expression of transcription factor, NF-ĸBp65, SP1, and c-Fos through activation of TCR-related pathways with upregulation of CD3, TCRα, TCRß, Zap-70, PKC, PLCγ1, GRB2, and PI3K/Akt expression. In HIV-1 MN superinfection under AZT treatment, expression of p38α led to HIV vif expression and inhibited APOBEC3G expression. We also investigated effects of p38α on gp130/JAK-STAT pathways, in which p38α increased expression of protein, gp130, EGFR, Jak2, STAT1, STAT3, STAT5, ras, and TF. p38α could induce apoptotic pathways with upregulation of Fas, FADD, Caspase-8, p53, and Bax, and downregulation of Bcl2 expression. These results indicate that p38α plays a positive role in reactivation of viral replication from HIV-1 latent infection and leads to HIV-1 AZT resistance. In conclusion, MAPKp38α can activate HIV-1 replication inhibited by AZT from HIV-1 latent infection and may be used as a latency reversal agent. The activation involves induction of several cell signaling pathways that are required for HIV-1 replication, which may be integrated into future viral remission strategies.


Assuntos
Farmacorresistência Viral/efeitos dos fármacos , HIV-1/fisiologia , Replicação Viral/efeitos dos fármacos , Zidovudina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Receptor gp130 de Citocina/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Janus Quinases/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
19.
Pediatr Infect Dis J ; 38(10): 1045-1050, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31365477

RESUMO

BACKGROUND: Combination antiretroviral drug regimens are increasingly preferred for neonatal postexposure prophylaxis (PEP) among HIV-exposed infants with high-risk of transmission. We evaluated the adverse events associated with the use of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP) for neonatal PEP during the first 6 weeks of life. METHODS: A prospective cohort of non-breast-fed HIV-exposed infants was conducted at 5 clinical sites in Thailand. Study population included 100 high-risk HIV-exposed infants (maternal HIV RNA > 50 copies/mL prior to delivery or received antiretroviral therapy less than 12 weeks) and 100 low-risk HIV-exposed neonates. High-risk infants received ZDV/3TC/NVP for 6 weeks whereas low-risk HIV-exposed neonates received a 4-week regimen of ZDV. Complete blood count, aspartate transaminase and alanine transaminase were assessed at birth, 1, 2 and 4 months of life. RESULTS: From October 2015 to November 2017, 200 infants were enrolled, of which 18.5% had low birth weight < 2500 g. The proportion of infants with anemia grade 2 or higher at 1 and 2 months of life between ZDV/3TC/NVP and ZDV prophylaxis was 48.5% vs 32.3% (P=0.02); nevertheless, severe anemia (grade 3) was not significantly different; 9.2% vs 10.2% (P=0.81), respectively. At 1 month old, infants on ZDV/3TC/NVP prophylaxis had significantly higher grade 2 anemia versus infants on ZDV alone (33.0% vs 13.4%; P=0.001); however, no difference was observed at 2 months old. No differences in neutropenia or hepatotoxicity between infant prophylactic regimens were observed. CONCLUSIONS: Triple antiretroviral neonatal PEP with ZDV/3TC/NVP for 6 weeks in high-risk HIV-exposed infants did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy prophylaxis.


Assuntos
Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Quimioprevenção/efeitos adversos , Quimioprevenção/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Infecções por HIV/prevenção & controle , Profilaxia Pós-Exposição/métodos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Masculino , Nevirapina/administração & dosagem , Nevirapina/efeitos adversos , Estudos Prospectivos , Tailândia , Resultado do Tratamento , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos
20.
J Int AIDS Soc ; 22(8): e25386, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31441211

RESUMO

INTRODUCTION: Adolescents with perinatally acquired HIV (PHIV) are at risk of chronic disease due to long-standing immune suppression, HIV disease and antiretroviral therapy (ART) exposure. However, there are few data on multisystem disease in this population. We investigated the overlapping burden of neurocognitive, cardiovascular, respiratory and/or renal impairment among PHIV positive (PHIV+) adolescents. METHODS: In this cross-sectional analysis, participants aged 9 to 14 years on ART for >6 months were recruited from seven sites across Cape Town from July 2013 through March 2015, together with age-matched HIV-negative (HIV-) adolescents. Impairment at enrolment was assessed across neurocognitive functioning (using the youth-International HIV Dementia Scale); cardiac function (echocardiogram abnormality); respiratory function (abnormal spirometry) and renal function (abnormal glomerular filtration rate). RESULTS AND DISCUSSION: Overall, 384 PHIV+ and 95 HIV- adolescents were included (mean age, 11.9 years; 49% female). Median age of ART initiation was 4.2 years (IQR: 1.7 to 7.6) and median CD4 count was 709 (IQR: 556 to 944) with 302 (79%) of PHIV+ adolescents virologically suppressed. Abacavir and Zidovudine were the most commonly used nucleoside reverse transcriptase inhibitors (NRTIs) with 60% of adolescents on non-nucleoside reverse transcriptase inhibitors (NNRTI) and 38% on a protease inhibitor (PI). Among PHIV+ adolescents, 167 (43.5%) had single system impairment only, 110 (28.6%) had two systems involved, and 39 (10.2%) had three or four systems involved. PHIV+ participants had more 2-system and 3-system impairment than HIV-, 110 (28.6%) versus 17 (17.9%), p = 0.03 and 39 (10.2%) versus 3 (4.3%), p = 0.03. PHIV+ participants who had failed a year of school (73.8% vs. 46.4%, p = 0.00) and with a viral load >1000 copies/mL at enrolment (16.8% vs. 8.1%, p = 0.03) were more likely to have dual or multisystem impairment. Of those with cardiac impairment, 86.7% had an additional system impaired. Similarly, in those with neurocognitive impairment, almost 60% had additional systems impaired and of those with respiratory impairment, 74% had additional systems impaired. CONCLUSIONS: Despite relatively early ART initiation, there is a substantial burden of multisystem chronic impairment among PHIV+ adolescents. This phenomenon needs to be further explored as this population ages and begins to engage in adult lifestyle factors that may compound these impairments.


Assuntos
Antirretrovirais/uso terapêutico , Doenças Cardiovasculares/etiologia , Transtornos Cognitivos/etiologia , Infecções por HIV/complicações , Nefropatias/etiologia , Doenças Respiratórias/etiologia , Adolescente , Contagem de Linfócito CD4 , Criança , Estudos Transversais , Didesoxinucleosídeos/uso terapêutico , Feminino , Infecções por HIV/congênito , Infecções por HIV/tratamento farmacológico , Humanos , Transmissão Vertical de Doença Infecciosa , Masculino , África do Sul , Carga Viral , Zidovudina/uso terapêutico
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