Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 520
Filtrar
1.
J Neurol Sci ; 397: 146-149, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30634130

RESUMO

Lower limb neuropathic pain in HIV patients is a common manifestation of sensory neuropathy (HIV-SN), but can be seen in patients who do not meet standard definitions of HIV-SN. The drug stavudine is a risk factor for HIV-SN, but some patients treated without stavudine experience HIV-SN, and the prevalence and risk factors influencing neuropathic pain in this setting are unknown. A cross sectional study at Cipto Mangunkusumo Hospital Jakarta tested 197 HIV patients treated for >12 months without stavudine. HIV-SN was defined using the AIDS Clinical Trial Group Brief Peripheral Neuropathy Screening Test (ACTG-BPNST). A validated Indonesia translation of Douleur Neuropathique en 4 (DN4) questionnaire was used to assess lower limb neuropathic pain. Nerve conduction studies assessed large nerve fiber function and Stimulated Skin Wrinkle (SSW) tests were performed to assess small nerve fibers. The prevalence of neuropathic pain was 6.6%. BPNST+HIV-SN was diagnosed in 14.2% of the cohort and 38.5% of patients with pain. Use of protease inhibitors and ART duration <2 years associated with neuropathic pain in univariate (p = .036, p = .002, resp.) and multivariable analyses (model p < .001). SSW tests were abnormal in 53.8% of subjects with neuropathic pain and only 25.5% without pain (p = .05). Patients with pain without BPNST+HIV-SN had begun ART more recently than those with both diagnoses. Overall this preliminary study showed that neuropathic pain associated with protease inhibitors and a shorter duration of ART in Indonesian HIV patients, and may be an early symptom of small fiber neuropathy in this context.


Assuntos
Antirretrovirais/efeitos adversos , Infecções por HIV/tratamento farmacológico , Neuralgia/induzido quimicamente , Estavudina/efeitos adversos , Adulto , Antirretrovirais/uso terapêutico , Estudos Transversais , Feminino , Humanos , Indonésia , Masculino , Neuralgia/epidemiologia , Prevalência , Fatores de Risco , Estavudina/uso terapêutico
2.
Inflammopharmacology ; 27(2): 387-396, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30600474

RESUMO

Human immuno-deficiency virus (HIV) associated sensory neuropathy (SN) is a frequent complication of HIV infection. It is extremely difficult to alleviate and hence the quality of life of affected individuals is severely and adversely impacted. Stavudine (d4T) is an antiretroviral drug that was widely used globally prior to 2010 and that is still used today in resource-limited settings. Its low cost and relatively good efficacy when included in antiretroviral dosing regimens means that there is a large population of patients with d4T-induced antiretroviral toxic neuropathy (ATN). As there are no FDA approved drugs for alleviating ATN, it is important to establish rodent models to probe the pathobiology and to identify potentially efficacious new drug treatments. In the model establishment phase, d4T administered intravenously at a cumulative dose of 375 mg/kg in male Wistar Han rats evoked temporal development of sustained mechanical allodynia in the hindpaws from day 10 to day 30 after initiation of d4T treatment. As this d4T dosing regimen was also well tolerated, it was used for ATN model induction for subsequent pharmacological profiling. Both gabapentin at 30-100 mg/kg and morphine at 0.3-2 mg/kg given subcutaneously produced dose-dependent relief of mechanical allodynia with estimated ED50's of 19 mg/kg and 0.4 mg/kg, respectively. In contrast, intraperitoneal administration of meloxicam or amitriptyline up to 30 mg/kg and 7 mg/kg, respectively, lacked efficacy. Our rat model of ATN is suitable for investigation of the pathophysiology of d4T-induced SN as well as for profiling novel molecules from analgesic drug discovery programs.


Assuntos
Antirretrovirais/efeitos adversos , Nefropatias/induzido quimicamente , Estavudina/efeitos adversos , Amitriptilina/administração & dosagem , Animais , Masculino , Meloxicam/administração & dosagem , Qualidade de Vida , Ratos , Ratos Wistar
3.
Indian J Med Res ; 148(2): 207-214, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30381544

RESUMO

Background & objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) are known to cause mitochondrial toxicity. This study was done to estimate mitochondrial DNA (mtDNA) content of peripheral blood mononuclear cells (PBMCs) among human immunodeficiency virus (HIV) infected, NRTI treated and antiretroviral therapy (ART)-naïve patients and evaluate the utility of mtDNA content as a biomarker of mitochondrial toxicity. Methods: mtDNA content in PBMCs of 57 HIV-infected ART untreated and 30 ART treated with stavudine (d4T) or zidovudine (AZT) containing regimen were compared against 24 low-risk healthy controls (LoRHC). Results: There was a significant (P=0.01) reduction in mtDNA content among HIV-infected (104; 80-135) compared to LoRHC (127; 110-167), and it was the same in both the treated (104.8; 88-130) and untreated patients (104.7; 78-142). mtDNA significantly (P=0.014) declined in ART treated patients symptomatic for toxicity (97; 74-111) than the asymptomatic patients (128; 103- 153). Interpretation & conclusions: mtDNA depletion in PBMCs was evident among HIV-infected individuals on ART. Moreover, as mtDNA content was reduced among the patients symptomatic for toxicity than the asymptomatic in both the HIV-infected groups, the current study supports mtDNA content of PBMCs to serve as a biomarker of mitochondrial dysfunction induced by NRTI and HIV. Longitudinal studies with a large sample need to be done to confirm these findings.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade , Feminino , Infecções por HIV/complicações , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Zidovudina/administração & dosagem
4.
PLoS One ; 13(10): e0204111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273369

RESUMO

BACKGROUND: The use of the HIV antiretroviral drug stavudine (d4T), a thymidine analogue, is associated with the development of mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway, could influence occurrence of d4T-related toxicity. METHODS: We examined this hypothesis in a cohort of HIV-positive South African adults exposed to d4T, including 143 cases with SN and 120 controls without SN. Ten SNPs in four genes associated with stavudine transport, and 16 SNPs in seven genes of the thymidine synthesis / phosphorylation pathway were genotyped using Agena mass spectrometry methods. Associations between sensory neuropathy and genetic variants were evaluated using PLINK by univariate and multivariable analyses. RESULTS: Age and height were significantly associated with SN occurrence. Using logistic regression with age and height as covariates, and uncorrected empirical p-values, genetic variation in SLC28A1, SAMHD1, MTHFR and RRM2B was associated with SN in South Africans using d4T. CONCLUSION: Variation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway may influence occurrence of d4T-related SN. These data contribute to the characterisation of African pharmacogenetic variation and its role in adverse response to antiretroviral therapy.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Estavudina/efeitos adversos , Adulto , Grupo com Ancestrais do Continente Africano , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Feminino , Infecções por HIV/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/genética , Ribonucleotídeo Redutases/genética , Proteína 1 com Domínio SAM e Domínio HD/genética , África do Sul , Estavudina/uso terapêutico
5.
PLoS One ; 13(9): e0203530, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183766

RESUMO

INTRODUCTION: Estimating the incidence of antiretroviral discontinuations due to adverse drug reactions (ADRs) is important to inform antiretroviral treatment (ART) regimen recommendations, and to guide prescribing and monitoring policies. Routinely collected clinical data is a useful source of pharmacovigilance data. We estimated the incidences of first-line antiretroviral discontinuations due to ADRs using routine clinical data, and compared them with incidences estimated using data enhanced by folder review, in two South African cohorts. METHODS: We included patients 16 years and older on first-line ART. We selected a stratified random sample of 25% for checking of ART prescription data and reasons for antiretroviral discontinuations retrospectively, including folders reviews where required (enhanced-data sample). We estimated the incidence of antiretroviral discontinuations using Kaplan-Meier and competing risk analyses. RESULTS: In 15396 patients, 40% had a first-line antiretroviral discontinuation by three years on ART. We could determine the reason for 65% of discontinuations using routine data only, and 84% of discontinuations, in the enhanced-data sample of 3837 patients. ADR was the most common reason for discontinuations. In the enhanced-data sample, the cumulative incidence of discontinuations due to ADRs by three years was 30.4% (95% CI: 24.4-36.6) for stavudine; 2.0% (95% CI: 1.5-2.6) for tenofovir, and 1.3% (95% CI: 0.8-2.1) for efavirenz. Using routine data only, the cumulative incidences of discontinuations due to ADRs by three years for stavudine, tenofovir, and efavirenz respectively were 23.9% (95% CI: 20.3-27.7), 1.2% (95% CI: 0.9-1.4) and 0.5% (95% CI: 0.3-0.7). CONCLUSIONS: Although the relative rankings were similar using routine or enhanced data, lack of checking for missing reasons for discontinuation resulted in underestimates of the incidence of antiretroviral discontinuations due to ADRs. Systems to improve data collection of reasons for regimen changes prospectively would increase the capacity of routine data to answer pharmacovigilance questions.


Assuntos
Antirretrovirais/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Adulto , Benzoxazinas/efeitos adversos , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Estudos Retrospectivos , África do Sul , Estavudina/efeitos adversos , Tenofovir/efeitos adversos
6.
Artigo em Inglês | MEDLINE | ID: mdl-30104267

RESUMO

Stavudine remains a useful replacement option for treatment for HIV+ children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine triphosphate levels in children receiving a reduced dose of 0.5 to 0.75 mg/kg of body weight twice daily to investigate whether a similar dose optimization can safely be made. A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine triphosphate in 23 HIV+ children and 24 HIV+ adults who received stavudine at 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. Simulations were employed to optimize the pediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30 mg twice daily. A biphasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine triphosphate. The use of allometric scaling with fat-free mass characterized well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30 mg twice daily in adults predicted median (interquartile range [IQR]) stavudine triphosphate minimum drug concentration (C min) and maximum drug concentration (C max) values of 13 (10 to 19) and 45 (38 to 53) fmol/106 cells, respectively. Targeting this exposure, simulations in HIV+ children were used to identify a suitable weight-band dosing approach (0.5 to 0.75 mg/kg), which was predicted to achieve median (IQR) C min and C max values of 13 (9 to 18) and 49 (40 to 58) fmol/106 cells, respectively. Weight-band dosing using a stavudine dose of 0.5 to 0.75 mg/kg is proposed, and it shows comparable exposures to adults receiving the current WHO-recommended dose of 30 mg twice daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2 years would have a reduced toxic effect while retaining antiretroviral efficacy.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Polifosfatos/farmacocinética , Estavudina/efeitos adversos , Estavudina/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polifosfatos/administração & dosagem , Estavudina/administração & dosagem , Adulto Jovem
7.
Lab Chip ; 18(17): 2510-2522, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-29992215

RESUMO

Drug development is currently hampered by the inability of animal experiments to accurately predict human response. While emerging organ on chip technology offers to reduce risk using microfluidic models of human tissues, the technology still mostly relies on end-point assays and biomarker measurements to assess tissue damage resulting in limited mechanistic information and difficulties to detect adverse effects occurring below the threshold of cellular damage. Here we present a sensor-integrated liver on chip array in which oxygen is monitored using two-frequency phase modulation of tissue-embedded microprobes, while glucose, lactate and temperature are measured in real time using microfluidic electrochemical sensors. Our microphysiological platform permits the calculation of dynamic changes in metabolic fluxes around central carbon metabolism, producing a unique metabolic fingerprint of the liver's response to stimuli. Using our platform, we studied the dynamics of human liver response to the epilepsy drug Valproate (Depakine™) and the antiretroviral medication Stavudine (Zerit™). Using E6/E7LOW hepatocytes, we show TC50 of 2.5 and 0.8 mM, respectively, coupled with a significant induction of steatosis in 2D and 3D cultures. Time to onset analysis showed slow progressive damage starting only 15-20 hours post-exposure. However, flux analysis showed a rapid disruption of metabolic homeostasis occurring below the threshold of cellular damage. While Valproate exposure led to a sustained 15% increase in lipogenesis followed by mitochondrial stress, Stavudine exposure showed only a transient increase in lipogenesis suggesting disruption of ß-oxidation. Our data demonstrates the importance of tracking metabolic stress as a predictor of clinical outcome.


Assuntos
Dispositivos Lab-On-A-Chip , Análise do Fluxo Metabólico/instrumentação , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Estavudina/efeitos adversos , Ácido Valproico/efeitos adversos
8.
BMC Pharmacol Toxicol ; 19(1): 28, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871665

RESUMO

BACKGROUND: Human Immunodeficiency Virus (HIV) is one of the main causes of morbidity and mortality; because of this it continues to be a major global public health concern. It has believed to kill more than 34 million lives so far. Sub Saharan Africa constitutes about 70% of people living with HIV among the 37 million on the globe. This region, accounted for more than two third of the global new HIV infections and about 15 million (40%) were receiving antiretroviral therapy (ART) at the end of 2014 throught the world. ART has fundamentally changed the treatment of HIV and transformed this infection from a disease of high mortality to chronic and medically managed disease. The issues of drug induced toxicities & complexity of current highly active antiretroviral therapy (HAART) regimens has remained of great concern. The aim of this study was to determine factors leading to antiretroviral regimen changes among HIV/AIDS Patients in the study area. METHODS: A facility based retrospective cross-sectional study was conducted from April 28, 2017 to May 30, 2017 in the ART clinics of east and west Wollega zone health institutions using a pre-tested data collecting form and chart review. The sample included the 243 patients whose medication had been switched. RESULTS: Majority 145 (59.67%) of the patients had been on ART for > 10 years duration. More than half 126(51.9%) of the patients had received tuberculosis (TB) treatment and almost three out of five patients (57.2%) had received isoniazid & cotrimoxazole prophylaxis. The most common reason for regimen change was peripheral neuropathy 146(60.1%) and the most common medication for this reason was stavudine, lamivudine and neverapine based 108(44.44%). CONCLUSIONS: The number of patients who changed ARV drug in our resource constrained setting present a challenge to the restricted treatment choices that we currently own. Less toxic and better-tolerated HIV treatment options should be available and used more frequently.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Substituição de Medicamentos/estatística & dados numéricos , Infecções por HIV/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas , Estudos Transversais , Etiópia , Humanos , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Nevirapina/administração & dosagem , Nevirapina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Retrospectivos , Estavudina/administração & dosagem , Estavudina/efeitos adversos
9.
PLoS One ; 13(6): e0198447, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29912896

RESUMO

BACKGROUND: Nearly all newly infected children acquire Human Immunodeficiency virus (HIV) via mother-to-child transmission (MTCT) during pregnancy, labour or breastfeeding from untreated HIV-positive mothers. Antiretroviral therapy (ART) is the standard care for pregnant women with HIV. However, evidence of ART effectiveness and harms in infants and children of HIV-positive pregnant women exposed to ART has been largely inconclusive. The aim of our systematic review and network meta-analysis (NMA) was to evaluate the comparative safety and effectiveness of ART drugs in children exposed to maternal HIV and ART (or no ART/placebo) across different study designs. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (inception until December 7, 2015). Primary outcomes were any congenital malformations (CMs; safety), including overall major and minor CMs, and mother-to-child transmission (MTCT; effectiveness). Random-effects Bayesian pairwise meta-analyses and NMAs were conducted. After screening 6,468 citations and 1,373 full-text articles, 90 studies of various study designs and 90,563 patients were included. RESULTS: The NMA on CMs (20 studies, 7,503 children, 16 drugs) found that none of the ART drugs examined here were associated with a significant increase in CMs. However, zidovudine administered with lamivudine and indinavir was associated with increased risk of preterm births, zidovudine administered with nevirapine was associated with increased risk of stillbirths, and lamivudine administered with stavudine and efavirenz was associated with increased risk of low birth weight. A NMA on MTCT (11 studies, 10,786 patients, 6 drugs) found that zidovudine administered once (odds ratio [OR] = 0.39, 95% credible interval [CrI]: 0.19-0.83) or twice (OR = 0.43, 95% CrI: 0.21-0.68) was associated with significantly reduced risk of MTCT. CONCLUSIONS: Our findings suggest that ART drugs are not associated with an increased risk of CMs, yet some may increase adverse birth events. Some ART drugs (e.g., zidovudine) effectively reduce MTCT.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Assistência Perinatal/economia , Complicações Infecciosas na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/epidemiologia , Fármacos Anti-HIV/economia , Benzoxazinas/efeitos adversos , Benzoxazinas/economia , Criança , Anormalidades Congênitas , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/economia , Feminino , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/efeitos adversos , Lamivudina/economia , Meta-Análise em Rede , Nevirapina/efeitos adversos , Nevirapina/economia , Gravidez , Estavudina/efeitos adversos , Estavudina/economia , Natimorto/epidemiologia , Zidovudina/efeitos adversos , Zidovudina/economia
10.
PLoS One ; 13(4): e0194132, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617438

RESUMO

BACKGROUND: Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy (LA) and/or lipohypertrophy (LH). Following phasing-out of stavudine, incidence of newly-diagnosed LA and LH declined dramatically. However, the natural history of existing cases should be explored, particularly with prolonged protease inhibitor exposure. METHODS: The Collaborative HIV Paediatric Study (CHIPS) is a multicentre cohort study of most HIV-infected children in the United Kingdom and Ireland. Those on ART with a LA/LH assessment recorded in 2003-2011 were included. Assessments were completed annually by consultant physicians. Using the 0-3 grading system, LA or LH was defined as grade 2 or 3. Resolution was defined as return to grade 1 or 0 in all body regions. RESULTS: Of 1345 children followed for median (IQR) 5.5 (2.9, 8.2) years after ART initiation, 30 developed LA and 27 developed LH, all at least 2 years after ART initiation. Median age at LA diagnosis was 11 (10, 13) years and at LH diagnosis was 13 (11, 15) years. Children with LA were more likely white (p<0.0001); lower height-for-age z-score at ART initiation (p = 0.02); initiated ART earlier (p = 0.04), with longer ART exposure (p = 0.04). Children with LH were similar to those without. Analysis of individual drugs revealed that LA was associated with greater duration of exposure to stavudine and didanosine; while LH was associated with greater duration of exposure to stavudine and ritonavir (given alone or in combination with another protease inhibitor). Median time in follow-up following ART switch was 2.8 (1.9, 4.9) and 2.5 (1.6, 4.7) years respectively. Resolution occurred in 10 (30%) of LA cases (median time to resolution 2.3 [1.8, 3.6] years) and 3 (11%) of LH cases (median time to resolution 2.0 [1.7, 2.1] years). CONCLUSIONS: Prevalence of LA and LH were low, with some resolution noted, especially for LA. More long-term data are needed.


Assuntos
Lipodistrofia/epidemiologia , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Adolescente , Criança , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Irlanda/epidemiologia , Lipodistrofia/complicações , Estudos Longitudinais , Masculino , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Resultado do Tratamento , Reino Unido/epidemiologia
11.
J Pediatric Infect Dis Soc ; 7(3): e70-e77, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-29373687

RESUMO

Objectives: Abacavir has replaced stavudine in antiretroviral therapy (ART) regimens because it has largely been phased out as a result of toxicity concerns; this loss has reduced further the already-limited drug options for children. Few data regarding virologic and metabolic outcomes among children who undergo substitution of stavudine exist. We evaluated the effects of preemptive substitution of abacavir for stavudine in children initially without lipodystrophy and virally suppressed on a stavudine-containing regimen. Methods: At Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa, virally suppressed human immunodeficiency virus (HIV)-infected children ≥36 months of age without lipodystrophy were randomly assigned to continue taking stavudine as part of their ART regimen (n = 106) or to have abacavir substituted for stavudine (n = 107). The children were followed for 56 weeks after randomization in the context of a larger trial of treatment options for ART-experienced children. Results: The mean age of the children was 4.3 years, and the mean duration of ART before random assignment was 3.5 years. No differences in virological outcomes, CD4 response, growth, or dyslipidemia were noted between the stavudine and abacavir groups. By 56 weeks, children in the abacavir group had less clinically detected lipodystrophy (4.7% vs 16%, respectively), a higher proportion of leg fat relative to total fat (0.243 vs 0.230, respectively; P = .006), and a lower trunk/leg-skinfold ratio (0.547 vs 0.569, respectively; P = .003) than the children in the stavudine group. Conclusion: Substituting abacavir for stavudine did not compromise virological response to treatment and was associated with significantly less lipodystrophy. These results support recommendations that favor abacavir in this population.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Estavudina/uso terapêutico , Carga Viral , Antropometria , Fármacos Anti-HIV/efeitos adversos , Composição Corporal , Contagem de Linfócito CD4 , Pré-Escolar , Didesoxinucleosídeos/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/imunologia , Humanos , Lactente , Lipodistrofia/induzido quimicamente , Masculino , África do Sul , Estavudina/efeitos adversos
12.
Biomed Res Int ; 2017: 7481597, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28293638

RESUMO

Protease inhibitor (PI) may cause abnormal glucose metabolism, abnormal lipid metabolism, and metabolic syndrome in HIV-infected adults but less well studied in Asian adolescents. This cross-sectional study evaluated anthropometric factors, oral glucose tolerance test, and lipid profiles of perinatally HIV-infected Thai adolescents who had received PI-based antiretroviral therapy for at least 6 months. Eighty adolescents were enrolled [median (IQR) age 16.7 (14.6-18.0) years, 42 males]. Metabolic syndrome, prediabetes, and type 2 diabetes mellitus (T2DM) were found in 8 (10%), 17 (22.1%), and 3 (3.8%) adolescents, respectively. Dyslipidemia was found in 56 (70%) adolescents, with hypertriglyceridemia being the most common type. In multivariate analysis, presence of lipohypertrophy (OR: 25.7, 95% CI: 3.2-202.8; p = 0.002) and longer duration of PI use (OR: 1.04, 95% CI: 1.00-1.08; p = 0.023) were associated with metabolic syndrome. Obesity (OR: 7.71, 95% CI: 1.36-43.7; p = 0.021), presence of lipohypertrophy (OR: 62.9, 95% CI: 4.97-795.6; p = 0.001), and exposure to stavudine for ≥6 months (OR: 8.18, 95% CI: 1.37-48.7; p = 0.021) were associated with prediabetes/T2DM, while exposure to tenofovir for ≥6 months reduced the risk (OR: 0.17, 95% CI: 0.04-0.78; p = 0.022). Metabolic disorders were commonly found in adolescents receiving PI. Careful monitoring and early intervention to modify cardiovascular risk should be systematically implemented in this population particularly those with exposure to stavudine.


Assuntos
Infecções por HIV/tratamento farmacológico , Doenças Metabólicas/epidemiologia , Inibidores de Proteases/uso terapêutico , Adolescente , Antropometria , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Glicemia/química , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/epidemiologia , Feminino , Infecções por HIV/complicações , Humanos , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , Síndrome Metabólica/epidemiologia , Análise Multivariada , Obesidade/epidemiologia , Estado Pré-Diabético/epidemiologia , Prognóstico , Inibidores de Proteases/efeitos adversos , Estavudina/efeitos adversos , Estavudina/uso terapêutico , Centros de Atenção Terciária
13.
AAPS PharmSciTech ; 18(3): 697-709, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27222026

RESUMO

The objectives of this research work were to develop optimized nanoparticulate formulations of poly (d,l-lactic-co-glycolic acid) (PLGA) (85:15) with an anti-AIDS drug stavudine and to evaluate their in-vitro uptake by the macrophages and hepatotoxicity in-vivo. Nanoparticles were prepared by nanoprecipitation method based on a factorial design with varying parameters such as the amounts of polymer and stabilizer used. Physicochemical characterizations such as drug-excipient interaction, surface morphology, particle size, and zeta potential measurements were carried out. The best formulation was selected and tagged with fluorescein isothiocyanate (FITC) for cellular uptake study of the formulation. In-vitro uptake of nanoparticles by macrophages was carried out. Formulation-induced hepatotoxicity was assessed by analyzing some serum hepatotoxic parameters and hepatic histology following 10-day treatment in comparison with the free drug. Nanoparticles exhibited smooth surface with particle size 84-238 nm, high entrapment efficiency (approx 85%), and negative surface charge. Formulations showed a sustained drug release pattern over the study period. In-vitro uptake study by macrophages exhibited a time-dependent profile. In-vivo studies on rats showed improvement in the serum parameters and maintenance of the integrity of the hepatic architecture indicating decreased hepatotoxicity with the formulations as compared to the free drug. The experimental results showed a positive outcome in the development of antiretroviral drug carrier exhibiting sustained drug release, macrophage-targeted delivery characteristics, and having reduced hepatoxicity. This could be beneficial for the management of early stage of HIV infection besides reducing the drug load for effective treatment, thereby offering an attractive option in AIDS therapy.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Nanopartículas/química , Estavudina/química , Estavudina/farmacologia , Animais , Fármacos Anti-HIV/efeitos adversos , Química Farmacêutica/métodos , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Ácido Láctico/química , Macrófagos/efeitos dos fármacos , Masculino , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-Dawley , Estavudina/efeitos adversos
14.
Afr J AIDS Res ; 15(3): 243-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27681148

RESUMO

South Africa has one of the highest prevalences of HIV and AIDS in the world. HIV/AIDS patients face countless challenges, one of which is the risk of adverse drug reactions (ADRs). This study aimed to describe the ADRs reported in South Africa with reference to the type of ADRs, antiretrovirals (ARVs) implicated, seriousness of the ADRs and patient demographics associated with specific ADRs. A retrospective quantitative study was carried out using ADR reports submitted to the National Department of Health (NDoH) from 1 January 2010 to 31 December 2014. A descriptive and inferential analysis was carried out to determine the strength of the relationships between different variables. A total of 2 489 reports were analysed. This study found evidence of ADRs among patients on regimens based on stavudine (n = 1 256, 50.46%), efavirenz (n = 572, 22.98%), zidovudine (n = 209, 8.40%), tenofovir (n = 203, 8.16%) and nevirapine (n = 153, 6.15%). The 10 most common ADRs reported with the use of ARVs were peripheral neuropathy (n = 472, 19%), lipodystrophy (n = 471, 18.9%), serious skin reactions (n = 266, 10.7%), gynaecomastia (n = 219, 8.8%), renal failure (n = 140, 5.6%), dizziness (n = 133, 5.3%), hyperlactatemia (n = 118, 4.7%), psychosis/hallucinations (n = 47, 1.9%), sleep disturbances (n = 44, 1.8%) and vomiting (n = 44, 1.8%). Female patients were more likely to experience peripheral neuropathy, lipodystrophy, skin rash, anaemia and hyperlactatemia, while male patients were more prone to experience gynaecomastia and peripheral neuropathy. In addition, patients aged 30-44 years reported the most ADRs. Most reactions resulted from the use of stavudine, efavirenz, zidovudine, nevirapine and tenofovir in the population groups identified in this study.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Exantema/induzido quimicamente , Ginecomastia/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Lipodistrofia/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Insuficiência Renal/induzido quimicamente , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Tontura/induzido quimicamente , Tontura/fisiopatologia , Exantema/fisiopatologia , Feminino , Ginecomastia/patologia , Infecções por HIV/virologia , Humanos , Lipodistrofia/patologia , Masculino , Pessoa de Meia-Idade , Nevirapina/administração & dosagem , Nevirapina/efeitos adversos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Insuficiência Renal/fisiopatologia , Estudos Retrospectivos , África do Sul , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos
15.
Clin Infect Dis ; 63(2): 205-13, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27143668

RESUMO

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have a higher risk of cardiovascular disease, potentially partly mediated by a higher prevalence of hypertension. We therefore examined the prevalence and determinants of hypertension in HIV-1-infected patients compared with appropriate HIV-negative controls. METHODS: Data from 527 HIV-1-infected and 517 HIV-uninfected participants at the time of enrollment into the ongoing AGEhIV Cohort Study were analyzed. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, and/or self-reported use of antihypertensive drugs. RESULTS: Hypertension prevalence was higher among HIV-1-infected individuals compared with controls (48.2% vs 36.4%; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.27-2.09). In logistic regression models adjusted for age, sex, ethnicity, family history of hypertension, smoking, alcohol use, physical activity, and body mass index, the association between HIV and hypertension remained statistically significant (ORHIV, 1.65; 95% CI, 1.25-2.19), but was attenuated after additional adjustment for waist-to-hip ratio (ORHIV, 1.29; 95% CI, .95-1.76). Among HIV-1-infected individuals, particularly among those with mono/dual nucleoside reverse transcriptase inhibitor therapy prior to combination antiretroviral therapy, stavudine exposure was independently associated with hypertension (ORstavudine, 1.54; 95% CI, 1.04-2.30). This association was attenuated after additional adjustment for either waist-to-hip ratio (ORstavudine, 1.30; 95% CI, .85-1.96) or hip circumference (ORstavudine, 1.40; 95% CI, .93-2.11). CONCLUSIONS: Our findings suggest that changes in body composition, involving both abdominal obesity and stavudine-induced peripheral lipoatrophy, might contribute to the higher prevalence of hypertension in HIV-1-infected patients. CLINICAL TRIALS REGISTRATION: NCT01466582.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Composição Corporal , Infecções por HIV/complicações , HIV-1 , Hipertensão/etiologia , Estavudina/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Estudos Transversais , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estavudina/uso terapêutico , Circunferência da Cintura
16.
Malawi Med J ; 28(1): 6-9, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-27217910

RESUMO

AIM: Lighthouse Trust in Lilongwe, Malawi serves approximately 25,000 patients with HIV antiretroviral therapy (ART) regimens standardized according to national treatment guidelines. However, as a referral centre for complex cases, Lighthouse Trust occasionally treats patients with non-standard ART regimens (NS-ART) that deviate from the treatment guidelines. We evaluated factors contributing to the use of NS-ART and whether patients could transition to standard regimens. METHODS: This was a cross-sectional study of all adult patients at Lighthouse Trust being treated with NS-ART as of February 2012. Patients were identified using the electronic data system. Medical charts were reviewed and descriptive statistics were obtained. RESULTS: One hundred six patients were initially found being treated with NS-ART, and 92 adult patients were confirmed to be on NS-ART after review. Mean patient age was 42.4 ± 10.3 years, and 52 (57%) were female. Mean duration of treatment with the NS-ART being used at the time of data collection was 2.1 ± 1.5 years. Eight patients (9%) were on modified first-line NS-ART and 84 (91%) were on modified second-line NS-ART, with 90 patients (98%) having multiple factors contributing to NS-ART use. Severe toxicity from one medication contributed in 28 cases (30%) and toxicity from multiple medications contributed in 46 cases (50%), while 22 patients (24%) were transitioned to NS-ART following a stockout of their original medication. Following clinical review, 84 patients (91%) were transitioned to standard regimens, and eight (9%) were maintained on NS-ART because of incompatibility of their clinical features with the latest national guidelines. CONCLUSIONS: Primary factors contributing to NS-ART use were medication toxicities and medication stockouts. Most patients were transitioned to standard regimens, although the need for NS-ART remains.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Quimioterapia Combinada/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/provisão & distribução , Estudos Transversais , Feminino , Humanos , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Malaui , Masculino , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Estavudina/efeitos adversos , Estavudina/uso terapêutico , Resultado do Tratamento , Confiança , Adulto Jovem
17.
Chem Biol Interact ; 252: 82-6, 2016 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-27041070

RESUMO

Lon protease, an ATP dependent mitochondrial protease, is important in mitochondrial protein maintenance. Disruption of protein homeostasis and mitochondrial dysfunction is associated with lipodystrophy, metabolic syndrome and accelerated aging, and are commonly observed in patients on long term antiretroviral therapy. Sirtuin 3 (SIRT3) is a post-translational regulator of Lon and regulates antioxidant response. We previously showed the nucleoside analogues (NRTIs), Zidovudine (AZT; 7.1 µM), Stavudine (d4T; 4 µM), and Tenofovir (TFV; 1.2 µM) induced oxidative stress and mitochondrial dysfunction in human hepatoma (HepG2) cells at 24 h (h) and 120 h. We conducted a mitochondrial proteomic assessment of homeostasis in the same model, using the same NRTIs. Protein expression of Lon, SIRT3, heat shock protein (HSP) 60, phospho-eukaryotic translation initiation factor 2α (p-eIF2α; Ser51) and phospho-c-jun N-terminal kinase (p-JNK; Thr183/Tyr185) were quantified by western blots. The data showed all stress responses were significantly increased in HepG2 cells by all antiretroviral drugs at 24 h (p < 0.0001); however, at 120 h, a significant depletion in the ATP-dependent proteins Lon (p = 0.00013) and HSP60 (p < 0.0001) was observed. Proteins initiated by endoplasmic reticulum stress: p-eIF2α (p = 0.001) and p-JNK (p = 0.0029), were significantly reduced following prolonged treatment. SIRT3 was maintained at elevated levels in the treated cells following prolonged exposure (p < 0.001). We conclude that the ATP dependent proteins are more relevant to acute toxicity, while SIRT3 confers protection over prolonged periods of toxicity.


Assuntos
Antirretrovirais/efeitos adversos , Fator de Iniciação 2 em Eucariotos/metabolismo , Hepatócitos/efeitos dos fármacos , Protease La/metabolismo , Estavudina/efeitos adversos , Tenofovir/efeitos adversos , Zidovudina/efeitos adversos , Chaperonina 60/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 3/metabolismo , Estresse Fisiológico/efeitos dos fármacos
18.
Neuropharmacology ; 105: 543-552, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26898292

RESUMO

UNLABELLED: Although antiretroviral agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. The antiretroviral toxic neuropathy induces debilitating and extremely difficult to treat pain syndromes that often lead to discontinuation of antiretroviral therapy. Due to the critical need for the identification of novel therapeutic targets to improve antiretroviral neuropathic pain management, we investigated the role of the JNK signalling pathway in the mechanism of antiretroviral painful neuropathy. Mice were exposed to zalcitabine (2',3'-dideoxycytidine, ddC) and stavudine (2',3'-didehydro-3'-deoxythymidine, d4T) that induced a persistent mechanical allodynia and a transient cold allodynia. Treatment with the JNK blocker SP600125 before antiretroviral administration abolished mechanical hypersensitivity with no effect on thermal response. A robust spinal JNK overphosphorylation was observed on post-injection day 1 and 3, along with a JNK-dependent increase in p-c-Jun and ATF3 protein levels. Co-immunoprecipitation experiments showed the presence of a heterodimeric complex between ATF3 and c-Jun indicating that these transcription factors can act together to regulate transcription through heterodimerization. A rise in BDNF and caspase-3 protein levels was detected on day 1 and BDNF sequestration prevented both caspase-3 and p-JNK increase. These data suggest that BDNF plays a role in the early stages of ddC-induced allodynia by promoting apoptotic events and the activation of a hypernociceptive JNK-mediated pathway. We illustrated the activation of a BDNF-mediated JNK pathway involved in the early events responsible for the promotion of neuropathic pain, leading to a better knowledge of the mechanisms involved in the antiretroviral neuropathy. SUMMARY: JNK blockade prevents antiretroviral-induced pain hypersensitivity. This may represent a potential prophylactic treatment of neuropathic pain to improve antiretroviral tolerability.


Assuntos
Antirretrovirais/efeitos adversos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hiperalgesia/prevenção & controle , MAP Quinase Quinase 4/antagonistas & inibidores , Neuralgia/prevenção & controle , Medula Espinal/efeitos dos fármacos , Animais , Antracenos/farmacologia , Caspase 3/metabolismo , Temperatura Baixa , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , Neuralgia/induzido quimicamente , Neuralgia/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Distribuição Aleatória , Medula Espinal/enzimologia , Estavudina/efeitos adversos , Tato , Zalcitabina/efeitos adversos
20.
PLoS One ; 11(1): e0147724, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26807589

RESUMO

BACKGROUND: In Thailand, the combined generic anti-retroviral drug stavudine/lamivudine/nevirapine (d4T/3TC/NVP) has been used to treat human immunodeficiency virus (HIV)-infected individuals since 2001. Due to relatively frequent adverse effects, d4T gradually has been replaced with tenofovir disoproxil fumarate (TDF). Although the frequency of adverse drug effects with TDF is lower than that with d4T, TDF is known to induce kidney dysfunction, especially in the proximal tubules. It has been reported that renal tubular transporters, including members of the multi-drug resistant (MDR) protein family, are implicated in tenofovir extrusion and may, therefore, confer susceptibility to TDF-induced kidney tubular dysfunction (KTD). We have explored the association between KTD and polymorphisms in genes that encode adenosine triphosphate-binding cassette (ABC)-type MDRs. METHODS: HIV-infected patients receiving TDF-containing antiretroviral regimens for at least one year were enrolled in the study. The levels of beta2-microglobulin in urine and creatinine (Cr) were measured. Three single-nucleotide polymorphisms, ABCC2 C-24T (rs717620), ABCC2 G1429A (rs2273697), and ABCC4 T4976C (rs1059751), were analyzed using TaqMan SNP genotyping assays. RESULTS: A total of 273 HIV-infected patients were recruited. The median number of years of TDF treatment was 5.04 with interquartile range (IQR) of 3.9-6.7. Despite the length of treatment with TDF, 98.5% patients maintained an estimated glomerular filtration rate (eGFR) of >60 mL/min as calculated by the CKD-EPI formula. Fifty-four patients (19.8%) showed beta2-microglobulinuria (median 2636 µg/g Cr with IQR of 1519-13197 µg/g Cr). The allele frequency of ABCC4 T4976C among those 54 patients was 0.602, compared to 0.475 among the 219 remaining patients (p = 0.018). CONCLUSIONS: Approximately 20% of HIV-infected patients receiving TDF showed beta2-microglobulinuria. The C allele at position 4976 of the ABCC4 gene was associated with beta2-microglobulinuria in this population. This polymorphism may help to identify patients at greater risk for developing TDF-associated KTD.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/genética , Nefropatias/induzido quimicamente , Nefropatias/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Tenofovir/efeitos adversos , Adulto , Feminino , Frequência do Gene , Interação Gene-Ambiente , Genótipo , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Estavudina/efeitos adversos , Estavudina/uso terapêutico , Tenofovir/uso terapêutico , Tailândia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA