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1.
Antiviral Res ; 180: 104857, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32562705

RESUMO

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2' or 3' modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses' exonuclease activity. We examined these nucleotide analogues for their ability to be incorporated by the RdRps in the polymerase reaction and to prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (triphosphates of Carbovir, Ganciclovir, Stavudine and Entecavir; 3'-OMe-UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2'-OMe-UTP), and 3 did not terminate the polymerase reaction (2'-F-dUTP, 2'-NH2-dUTP and Desthiobiotin-16-UTP). The coronaviruses possess an exonuclease that apparently requires a 2'-OH at the 3'-terminus of the growing RNA strand for proofreading. In this study, all nucleoside triphosphate analogues evaluated form Watson-Crick-like base pairs. The nucleotide analogues demonstrating termination either lack a 2'-OH, have a blocked 2'-OH, or show delayed termination. Thus, these nucleotide analogues are of interest for further investigation to evaluate whether they can evade the viral exonuclease activity. Prodrugs of five of these nucleotide analogues (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA-approved medications for treatment of other viral infections, and their safety profiles are well established. After demonstrating potency in inhibiting viral replication in cell culture, candidate molecules can be rapidly evaluated as potential therapies for COVID-19.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/virologia , Nucleotídeos/farmacologia , Pneumonia Viral/virologia , RNA Replicase/antagonistas & inibidores , Vírus da SARS/enzimologia , Síndrome Respiratória Aguda Grave/virologia , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Betacoronavirus/genética , Cidofovir/química , Cidofovir/farmacologia , Cidofovir/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Didesoxinucleosídeos/química , Didesoxinucleosídeos/farmacologia , Didesoxinucleosídeos/uso terapêutico , Ganciclovir/química , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Guanina/análogos & derivados , Guanina/química , Guanina/farmacologia , Guanina/uso terapêutico , Nucleotídeos/química , Nucleotídeos/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , RNA Viral/antagonistas & inibidores , RNA Viral/biossíntese , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Estavudina/química , Estavudina/farmacologia , Estavudina/uso terapêutico , Valganciclovir/química , Valganciclovir/farmacologia , Valganciclovir/uso terapêutico
2.
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
3.
Niger Postgrad Med J ; 26(4): 195-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621657

RESUMO

Background: The presence of human leukocyte antigen (HLA) B*57:01 allele predicts hypersensitivity reaction (HSR) to abacavir (ABC), a nucleoside reverse-transcriptase inhibitor used for human immunodeficiency virus (HIV) treatment. However, the prevalence of this allele amongst Nigerians with HIV is yet to be established. We aimed to determine the prevalence of HLA-B*57:01 allele amongst Nigerians with HIV infection. Methods: We conducted a multicentre cross-sectional epidemiologic survey. Between April 2016 and April 2017, patients were enrolled across five HIV treatment facilities in Nigeria. Participants' demographic information and their history of ABC exposure were obtained, and venous blood was obtained for HLA typing. Results: One thousand five hundred and four (1504) adults were enrolled, with a mean age of 44.6 ± 10.7 years, 1078 (71.7%) were female. 1463 (97.3%) were on antiretroviral therapy. ABC use was reported by 12 (0.8%) participants and none reported HSR. Of 1500 blood samples that were processed, 1458 (97.2%) were successfully typed. Of these, 132 (9.1%) were HLA-B*57 positive using non-specific low-resolution HLA-B*5701 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*5701 allele. Conclusion: HLA-B*5701allele is rare amongst Nigerians.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Hipersensibilidade a Drogas/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Antígenos HLA-B/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Estudos Transversais , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/genética , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Antígenos HLA-B/sangue , Antígenos HLA-B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos
4.
Top Antivir Med ; 27(3): 123-127, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31634859

RESUMO

Antiretroviral therapy (ART) should be started as soon as possible after HIV diagnosis. Recommended starting ART regimens in patients with any baseline viral load include ictegravir plus tenofovir alafenamide (TAF)/emtricitabine (FTC), dolutegravir (DTG) plus abacavir/lamivudine, DTG plus TAF (or TDF)/FTC, or DTG plus 3TC. Initial laboratory evaluation includes CD4+ cell count, plasma HIV-1 RNA, and testing for HIV reverse transcriptase and protease resistance mutations. ART regimens do not need to be altered for virologic blips due to release of virus from chronically latently infected cells in patients otherwise exhibiting viral suppression. Patients with continuously undetectable viral load on ART pose virtually no risk of transmitting infection through sexual contact. This article is based on a case-based presentation by Michael S. Saag, MD, at the 2018 Clinical Conference at the National Ryan White Conference on HIV Care & Treatment in December 2018 and intended for clinicians who are new to HIV disease management.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/transmissão , Transcriptase Reversa do HIV/efeitos dos fármacos , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Inibidores de Integrase/uso terapêutico , Lamivudina/uso terapêutico , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mutação , RNA Viral/sangue , Tenofovir/uso terapêutico , Carga Viral
5.
Ultrastruct Pathol ; 43(4-5): 220-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31578116

RESUMO

Combined antiretroviral therapy (cART) consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz, is still the first-line treatment in resource-limited settings. However, efavirenz has shown strong prominence of disadvantages with variance in plasma concentration and central nervous side effects. Our study presents HIV infected, drug naïve, female patient with relatively low BMI, CYP2B6 516G>T (rs3745274) genotype with high efavirenz plasma concentration. In this case report, the patient was admitted at the hospital 6 months after cART initiation with drug-induced severe hepatotoxicity. Furthermore, pathophysiological findings proved confluent parenchymal necrosis after aspiration liver biopsy, with mild to moderate inflammation in portal tracts with focal interface hepatitis. All other possible causes were excluded. Thus, we conclude that efavirenz has a potential harmful effect in patients with low BMI, specific genotyping and interindividual pharmacokinetics affecting high plasma concentration.


Assuntos
Benzoxazinas/efeitos adversos , Índice de Massa Corporal , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Doença Hepática Induzida por Substâncias e Drogas/patologia , Didesoxinucleosídeos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Lamivudina/uso terapêutico
6.
PLoS One ; 14(9): e0222650, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560700

RESUMO

BACKGROUND: Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge. METHODS: Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients. RESULTS: In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/µL in raltegravir and 239 cells/µL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled. CONCLUSIONS: Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/µL at week 48. TRIAL REGISTRATION: EUDRACT number: 2011-005973-21.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Darunavir/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Raltegravir Potássico/uso terapêutico , Ritonavir/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Darunavir/administração & dosagem , Diagnóstico Tardio , Didesoxinucleosídeos/administração & dosagem , Feminino , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Raltegravir Potássico/administração & dosagem , Ritonavir/administração & dosagem
7.
Infect Dis (Lond) ; 51(11-12): 838-846, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556765

RESUMO

Background: Despite suppressive antiretroviral therapy (ART), many HIV-infected individuals have low-level persistent immune activation in the central nervous system (CNS). There have been concerns regarding the CNS efficacy of tenofovir alafenamide fumarate (TAF) because of its low cerebrospinal fluid (CSF) concentrations and because it is a substrate of the active efflux transporter P-glycoprotein. Our aim was to investigate whether switching from emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or abacavir (ABC)/lamivudine (3TC) to FTC/TAF would lead to changes in residual intrathecal immune activation, viral load, or neurocognitive function. Methods: Twenty HIV-1-infected neuro-asymptomatic adults (11 on ABC/3TC and 9 on FTC/TDF) were included in this prospective study. At baseline, all participants changed their nucleoside analogues to FTC/TAF without any other changes in their ART regimen. We performed lumbar punctures, venipunctures, and neurocognitive testing at baseline and after three and 12 months. Results: During follow-up, there were no significant changes in CSF or plasma HIV RNA, CSF neopterin, CSF ß2-microglobulin, IgG index, albumin ratio, CSF NFL, or neurocognitive function in assessed by Cogstate in any of the groups. Conclusion: This small pilot study indicates that switching to FTC/TAF from ABC/3TC or FTC/TDF has neither a positive, nor a negative effect on the HIV infection in the CNS.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/virologia , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Idoso , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Feminino , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Tenofovir/uso terapêutico , Carga Viral
8.
Indian Pediatr ; 56(8): 685-686, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31477651

RESUMO

We studied 48 children receiving abacavir-based HAART regimen, over a period of one-year for side effects and failure rates. None of the children developed hypersensitivity reaction. The CD4 count significantly improved from the time of enrolment till 12 months of therapy while the failure rate was 14.5%.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adolescente , Terapia Antirretroviral de Alta Atividade , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento
9.
Sensors (Basel) ; 19(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416185

RESUMO

Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.


Assuntos
Técnicas Biossensoriais/métodos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Antígenos HLA-B/análise , Leucócitos Mononucleares/metabolismo , Alelos , Anticorpos Imobilizados/química , Anticorpos Imobilizados/imunologia , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Didesoxinucleosídeos/uso terapêutico , Hipersensibilidade a Drogas/etiologia , Técnicas Eletroquímicas , Eletrodos , Infecções por HIV/tratamento farmacológico , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos
10.
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
11.
J Int AIDS Soc ; 22(7): e25324, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31294931

RESUMO

INTRODUCTION: Dolutegravir (DTG) is recommended as part of first-line antiretroviral therapy (ART) for people living with HIV(PLHIV). We sought to determine the rate of adverse events (AEs) and discontinuations among Thais treated during acute HIV infection (AHI) and switched to DTG-based regimens. METHODS: Thai participants in the SEARCH010/RV254 cohort who initiated ART during AHI and switched to DTG for at least 48 weeks were prospectively observed and included in the analysis. Rates and characteristics of DTG-related AEs and discontinuations were described. RESULTS: A total of 313 Thai participants were included in the analysis. The median age was 29 years, 96% were male, 64% had a Bachelor's degree or higher and 16% had a body mass index (BMI) <18.5 kg/m2 . Participants were on ART for a median of 124 weeks before switching to DTG. The median (IQR) body weight increased from 63 (56 to 70) kg before to 65 (58 to 73) kg (p < 0.0001) after 48 weeks of DTG. Forty-nine (16%) developed DTG-related AEs, corresponding to an incidence of 16.6 per 100 person-years. Neuropsychiatric symptoms were most frequently encountered (n = 25, 8%), followed by laboratory abnormalities (n = 16, 5%). Six (2%) discontinued DTG, corresponding to an incidence of 2.4 per 100 person-years. All discontinuations were due to increased liver enzymes in the presence of hepatitis C virus coinfection. In the multivariate analysis, incident hepatitis C virus infection was the only risk factor for discontinuing DTG (hazard ratio 59.4, 95% CI 8.5 to 297.9, p < 0.0001). Neither low BMI nor concurrent abacavir therapy was associated with discontinuation. CONCLUSIONS: DTG was well tolerated with few discontinuations in this cohort of young men. Incident hepatitis C virus infection was a driver of liver-related AEs leading to discontinuations. In populations at risk, regular testing for hepatitis C virus during ART is recommended to anticipate possible AEs, guide management and improve safety.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Estudos de Coortes , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/uso terapêutico , Feminino , HIV-1 , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tailândia/epidemiologia , Adulto Jovem
12.
Clin Exp Nephrol ; 23(11): 1272-1279, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31327092

RESUMO

BACKGROUND: Chronic kidney disease (CKD) has become one of the most frequent non-infectious comorbidities in the aging HIV-infected population on long-standing combination antiretroviral therapy (cART). METHODS: We conducted a retrospective, cross-sectional study including HIV-infected adult patients attending our HIV outpatient clinic during the years 2017 and 2018 to assess prevalence and associated risk factors of CKD. Estimated glomerular filtration rate (eGFR) was measured by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. CKD was diagnosed and classified according to the National Kidney Foundation guidelines. Logistic regression was employed to identify factors associated with CKD. RESULTS: We enrolled 2339 HIV-infected patients (91% were Caucasian) with a mean age of 45.3 years and a mean current CD4 lymphocyte count of 531 cells/mm3. CKD was diagnosed in 311 subjects (13.3%). Overall, 294 (12.6%) patients had albuminuria, 108 (4.6%) had eGFR < 60 mL/min/1.73 m2, and 78 (3.3%) had albuminuria plus eGFR < 60 mL/min/1.73 m2. Stages 4-5 of CKD were documented in 23 (1%) cases. Age greater than 50 years, male gender, hypertension, diabetes mellitus, high triglycerides, nadir CD4 cell count < 200 cells/mm3, current use of tenofovir disoproxyl fumarate (TDF) and of TDF plus a ritonavir-boosted protease inhibitors were independently associated with CKD, while current use of abacavir plus one integrase inhibitor was associated with a reduced risk of CKD. CONCLUSION: There is a significant prevalence of CKD among HIV-infected persons in association with both traditional and HIV-specific risk factors, requiring a careful periodic monitoring of renal function in these patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Insuficiência Renal Crônica/epidemiologia , Adulto , Fatores Etários , Albuminúria/etiologia , Contagem de Linfócito CD4 , Estudos Transversais , Diabetes Mellitus/epidemiologia , Didesoxinucleosídeos/uso terapêutico , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/virologia , Humanos , Hipertensão/epidemiologia , Hipertrigliceridemia/epidemiologia , Inibidores de Integrase/uso terapêutico , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Proteção , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Ritonavir/uso terapêutico , Fatores Sexuais , Tenofovir/uso terapêutico
13.
BMC Infect Dis ; 19(1): 583, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277607

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. METHODS: We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. RESULTS: The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy. CONCLUSIONS: The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Razão de Chances
14.
Infect Dis (Lond) ; 51(9): 691-693, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31272264

RESUMO

Introduction: Generic drugs are helpful to enhance the efficiency of the sanitary system. A generic coformulation of abacavir (ABC) and lamivudine (3TC) is available since 2016 in Spain. A report of our experience with its use is exposed. Methods: Patients between February 2017 and June 2017 who were taking Triumeq® were switched to the generic ABC + 3TC plus DTG. Efficacy, safety, reasons for discontinuation and costs savings were evaluated at 48 weeks. Results: Switch was made in 93 patients, with a median age of 47 years and a mean time of 12.33 years with HIV infection. Six patients (6.5%) discontinued the new ART, being toxicity of the central nervous system the most frequent reason. The effective saving derived from the change after 1 year of treatment was 151.127 €. Conclusions: The change from Triumeq® to a generic regimen of ABC + 3TC and another pill of DTG seems to be safe and efficient at 48 weeks.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Substituição de Medicamentos , Medicamentos Genéricos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lamivudina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha
16.
Int J STD AIDS ; 30(5): 467-471, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30999834

RESUMO

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Lamivudina/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Colesterol/sangue , Didesoxinucleosídeos/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Testes de Função Renal , Lamivudina/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Raltegravir Potássico/efeitos adversos , Resultado do Tratamento , Triglicerídeos/sangue
17.
Medicine (Baltimore) ; 98(17): e15149, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027057

RESUMO

RATIONALE: With the existence of the human immunodeficiency virus (HIV) infection as a chronic disease, more often adverse effects of its treatment with the various antiretroviral therapies (ARTs) available have been recognized. Going further, Triumeq has been associated with a myriad of adverse effects, of which rhabdomyolysis is rarely reported in the literature. PATIENT CONCERNS: The patient presented with muscle tenderness over the lower limbs and dark brown-to-red colored urine. DIAGNOSIS: Given the presenting symptoms, as well as the laboratory testing, including elevated serum creatine kinase and liver enzymes, the diagnosis of rhabdomyolysis was made. INTERVENTIONS: Improvement was achieved rapidly after starting intravenous fluid therapy and with discontinuation of Triumeq. OUTCOMES: After discharge, repeated creatine kinase levels in the clinic have been normal and decision was made to initiate another ART and until now, no further episodes of rhabdomyolysis have developed. Regular outpatient follow-up has been ongoing for over 1 year and no complications have been identified. LESSONS: This case aims to recognize rhabdomyolysis as a rare, but possible adverse effect associated with the use of Triumeq for HIV-infected patients and therefore clinicians prescribing this combination should be aware of this potential side effect and counsel their patients accordingly.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Lamivudina/efeitos adversos , Rabdomiólise/etiologia , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Rabdomiólise/diagnóstico , Rabdomiólise/terapia
18.
Artigo em Inglês | MEDLINE | ID: mdl-30803969

RESUMO

In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Emtricitabina/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Adenina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico
19.
Int J STD AIDS ; 30(5): 447-452, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30630396

RESUMO

Hyperparathyroidism has been described in people living with HIV undergoing tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART), but differences in calcium levels have never been investigated in detail. We aimed to compare the prevalence of hypocalcemia between patients with and without TDF-containing ART. The patients and methods were a retrospective cohort study in HIV-infected adult patients receiving dolutegravir and either abacavir (ABC)/lamivudine (3TC) or TDF/emtricitabine in a single center in Munich, Germany. Of 172 patients, 126 (73.3%) were male and the median age was 48.5 years (interquartile range 42-54). Average calcium levels were 2.24 (2.21-2.29) mmol/l and 2.21 (2.16-2.26) mmol/l (P < 0.001) with a prevalence of at least one episode of total calcium <2.12 mmol/l of 16.2 and 34.4% in the groups treated with ABC/3TC and TDF/emtricitabine, respectively (P = 0.006). TDF use was independently associated with the occurrence of albumin-corrected calcium levels of <2.12 mmol/l (odds ratio: 6.7 [1.3-35.6]; P = 0.025). Hypocalcemia seems to occur more often in TDF-treated patients. Further research into hypocalcemia with TDF and potential cardiovascular effects may be of benefit based on these findings.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Didesoxinucleosídeos/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Hipocalcemia/induzido quimicamente , Lamivudina/efeitos adversos , Tenofovir/efeitos adversos , Adulto , Fármacos Anti-HIV/uso terapêutico , Cálcio/sangue , Estudos de Coortes , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/epidemiologia , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Tenofovir/uso terapêutico , Resultado do Tratamento
20.
HIV Med ; 20(3): 214-221, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632660

RESUMO

OBJECTIVES: As more HIV-positive individuals receive antiretroviral therapy (ART), payers are seeking options for covering these increased and sustained drug costs. Strategic use of available generic antiretroviral (ARV) formulations may be feasible. De-simplifying a single-tablet co-formulation (STF) into two or more tablets using both brand and generic drugs has been proposed. We determine if voluntary de-simplification of one STF could be utilized as a cost-saving strategy. We report on the challenges, uptake, outcomes and cost savings of this initiative. METHODS: Patients stable on the most commonly used STF (Triumeq® ) were offered the option of remaining on Triumeq® or switching to generic abacavir/lamivudine and Tivicay® between 1 January 2015 and 1 January 2018; those starting ART consisting of abacavir/lamivudine/doulutegravir in the same period were offered the option of starting Triumeq® or generic abacavir/laminvudine and Tivicay® . No incentives were provided. We examined the acceptance/decline rates, patient satisfaction, health care outcomes and annual cost savings. RESULTS: Of 626 patients receiving Triumeq® , 321 were approached; 177 (55.1%) agreed to de-simplify. Of patients initiating ART, 62.7% chose the generic co-formulation. Patients switching to or starting on the generic co-formulation were more likely to be male, > 45 years old, Caucasian, men who have sex with men (MSM) and more HIV-experienced, and to have more comorbidities (all P < 0.05). Preference for STF was cited for declining de-simplification. No concern about generic ARVs was expressed. The rate of viral load > 500 HIV-1 RNA copies/mL after baseline was 2.7% in switched patients compared with 7.0% in those declining to switch. No de novo resistance occurred. A saving of Cdn$1 319 686 was achieved in the first year. CONCLUSIONS: Reliance on altruism, while respecting patient autonomy, achieved de-simplification in > 50% of patients approached, and generated immediate cost savings with no increased risk of adverse events, viral breakthrough or resistance.


Assuntos
Antirretrovirais/economia , Didesoxinucleosídeos/economia , Medicamentos Genéricos/economia , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/economia , Lamivudina/economia , Adulto , Fatores Etários , Idoso , Antirretrovirais/uso terapêutico , Canadá , Comorbidade , Redução de Custos , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Medicamentos Genéricos/uso terapêutico , Feminino , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Satisfação do Paciente , Comprimidos , Resultado do Tratamento
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