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1.
BMC Infect Dis ; 20(1): 443, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576136

RESUMO

BACKGROUND: Liangshan Yi Autonomous Prefecture is one of the areas that most severely affected by human immunodeficiency virus (HIV) in China, and virological failure on antiretroviral therapy (ART) is serious in this area. Analyses of prevalence and determinants of ART failure, the genetic diversity and drug resistance among people living with HIV (PLWH) helps improve HIV treatment efficiency and prevent HIV transmission. METHODS: A total of 5157 PLWH were recruited from 2016 to 2017. The venous blood samples were subjected to RT-PCR, followed by sequencing of the HIV-1 pol gene, targeting the protease and reverse transcriptase fragments. HIV-1 diversity was analyzed using the DNAStar software and drug resistance mutations were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: A total of 2156 (41.81%) PLWH showed virological failure on ART. Males (ORm = 1.25), heterosexual behaviors and drug injection (ORm = 1.44) and mother to child transmission routes (ORm = 1.58), the clinical stage of AIDS (ORm = 1.35), having used illicit drugs and shared the needles (1-4 times: ORm = 1.34; more than 5 times: ORm = 1.52), having ever replaced ART regimen (ORm = 1.48) increased the risk of virological failure among PLWH, while higher education lever (ORm = 0.77) and ≥ 12 months on ART (12 ~ 36 months: ORm = 0.72; ≥36 months: ORm = 0.66) was associated with lower likelihood of virological failure. The data revealed that CRF07_BC (1508, 95.62%) were the most common strains, and the drug-resistant rate was 32.10% among PLWH with virological failure in this area. The high frequencies of drug resistance were found in EFV and NVP of NNRTIs, ABC, FTC and 3TC of NRTIs, and TPV/r in PIs. The most common mutations in NNRTIs, NRTIs and PIs were K103N/KN (64.69%), M184V/MV/I (36.29%) and Q58E/QE (4.93%), respectively. CONCLUSION: We concluded that surveillance of virological failure, HIV-1 subtypes, and drug resistance to understand HIV-1 epidemiology and guide modification of ART guidelines, and target prevention and control strategies should be formatted to reduce the virological failure and drug resistance to promote viral suppression and prevent HIV-1 transmission.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Variação Genética , HIV-1/genética , Grupos Minoritários , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome de Imunodeficiência Adquirida/sangue , Síndrome de Imunodeficiência Adquirida/transmissão , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , China/epidemiologia , Feminino , Genes pol , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Masculino , Mutação , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Adulto Jovem
2.
Infection ; 48(2): 249-258, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31893354

RESUMO

PURPOSE: Recommended regimens for pregnant women with HIV-1 are composed of two nucleoside reverse transcriptase inhibitors (NRTI) plus either a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (ISTI), with non-nucleoside reverse transcriptase inhibitors (NNRTI) representing an alternative drug class. The study's purpose was to compare these three options in terms of pregnancy outcomes. METHODS: Data from a national observational study of pregnant women with HIV-1 were used. The analysis included all pregnancies reported between 2008 and 2018, ending in live births and exposed within 32 weeks of gestation to three-drug regimens composed of a NRTI backbone plus a PI, a NNRTI or a ISTI, without class switching during pregnancy. Clinical and laboratory outcomes were evaluated in univariate and multivariable analyses. RESULTS: Overall, 794 exposed pregnancies were analyzed (PI 78.4%, NNRTI 15.4%, ISTI 6.2%). Almost all outcomes had similar rates in the three groups. Women who received PI in pregnancy were less likely to be virologically suppressed at third trimester. PI use was associated with higher bilirubin and triglyceride levels, and ISTI use with a lower rate of low birthweight. The differences in viral suppression at third trimester and in low birthweight were not maintained in multivariable analyses that were adjusted for confounders. DISCUSSION: We found no major differences in a wide range of outcomes relevant for pregnant women with HIV. Such results are reassuring, and this information may be helpful in a context of preconception counseling when therapeutic choices for pregnancy are discussed between women and care providers.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase/uso terapêutico , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Peso ao Nascer , Feminino , HIV-1 , Humanos , Inibidores de Integrase/efeitos adversos , Análise Multivariada , Gravidez , Resultado da Gravidez , Inibidores de Proteases/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos
3.
Ann Pharmacother ; 54(1): 64-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31416335

RESUMO

Objective: To compare and contrast doravirine (DOR) with other agents in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class, review safety and efficacy data from both completed and ongoing clinical trials, and outline the potential place in therapy of DOR. Data Sources: A literature search using the PubMed database (inception to June 2019) was conducted using the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Study Selection and Data Extraction: Clinical data were limited to those published in the English language from phase 2 or 3 clinical trials. Ongoing trials were identified through ClinicalTrials.gov. Data Synthesis: DOR was approved by the US Food and Drug Administration on the strength of 2 phase 3 randomized, double-blind, noninferiority clinical trials with additional studies currently underway examining its utility in other clinical scenarios. Relevance to Patient Care and Clinical Practice: The role of NNRTIs as part of antiretroviral (ARV) therapy has diminished in recent years given the introduction of more tolerable individual ARV agents and regimens. Despite this, new agents are still needed in the therapeutic arena because treatment failure as well as intolerance can still occur with many first-line therapies. The optimal place in therapy of DOR remains to be defined. Conclusions: DOR is a new NNRTI that represents a potential treatment option for treatment-naïve patients, without many of the previously described untoward effects of the NNRTI class.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Triazóis/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Humanos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos
4.
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
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.
Medicine (Baltimore) ; 98(43): e17585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651864

RESUMO

This study sought to examine the human immunodeficiency virus type 1 (HIV-1) genetic diversity on drug resistance among men who have sex with men (MSM) with virologic failure in antiretroviral therapy (ART), and investigate linking-associated factors for genetic transmission networks.Seven hundred and thirty-four HIV-positive MSM with virologic failure in ART were recruited into our study from 2011 to 2017. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The drug resistance mutations were determined using the Stanford University HIV Drug Resistance Database. The genetic transmission networks were analyzed for CRF01_AE and CRF07_BC sequences by the genetic distance-based method.Of 734 subjects, 372 (50.68%) showed drug resistance, in which CRF01_AE and CRF07_BC were the predominating subtypes. Drug resistance more frequently occurred in non-nucleoside reverse transcriptase inhibitors (NNRTIs) treatment (48.64%), and followed by nucleoside reverse transcriptase inhibitors (NRTIs) (36.51%) and PIs (4.03%). The most common drug resistance-associated mutations in protease inhibitors (PIs), NRTIs and NNRTIs were K20I/R, M184V/I and K103N/KN, respectively. For 283CRF01_AE sequences, 64 (22.61%) fell into clusters at a genetic distance of 0.011, resulting in 17 clusters ranging in size from 2 to 16 individuals. For 230 CRF07_BC sequences, 66 (28.69%) were connected to at least one other sequence with 0.005 genetic distances, resulting in 8 clusters ranging in size from 2 to 52 individuals. Individuals who showed drug resistance to ART were less likely to fall into clusters than those who did not. The genetic linkage was robust by the exclusion of sites associated with drug resistance.CRF01_AE and CRF07_BC were the main strains among MSM with virologic failure in ART, and the drug resistance more frequently occurred in NNRTIs, followed by NRTIs and PIs. Genetic transmission networks revealed a complexity of transmission pattern, suggesting early-diagnosis and in-time intervention among MSM.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/efeitos adversos , Adolescente , Adulto , China , Homossexualidade Masculina , Humanos , Masculino , Minorias Sexuais e de Gênero/estatística & dados numéricos , Falha de Tratamento , Adulto Jovem
7.
PLoS Med ; 16(9): e1002895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539371

RESUMO

BACKGROUND: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). METHODS AND FINDINGS: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. CONCLUSION: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. TRIAL REGISTRATION: clinicaltrials.gov NCT02245022.


Assuntos
Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , HIV/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Feminino , HIV/genética , HIV/crescimento & desenvolvimento , Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Troca Materno-Fetal , Leite Humano/metabolismo , Gravidez , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , África do Sul , Resultado do Tratamento , Uganda , Carga Viral , Adulto Jovem
8.
Expert Opin Drug Metab Toxicol ; 15(10): 813-829, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31556749

RESUMO

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy against HIV-1 infections. Here, we provide a comprehensive overview of approved and emerging NNRTIs. Areas covered: This review covers the latest trend of NNRTIs regarding their pharmacodynamics, pharmacokinetics, mechanisms of drug action, drug resistance as well as new applications such as two-drug regimens and long-acting formulations. Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. The latter three compounds with favorable pharmacodynamic profiles and minimal adverse effects are often combined with one integrase inhibitor or two NRTIs in once-daily fixed-dose tablets. NNRTI-anchored regimens have been approved as initial therapies in treatment-naïve patients (efficacy: 72% to 86%) or maintaining therapies in virologically-suppressed patients (efficacy: 91% to 95%). Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Preparações de Ação Retardada , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Humanos , Adesão à Medicação , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética
10.
BMC Infect Dis ; 19(1): 715, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409277

RESUMO

BACKGROUND: Gynecomastia is known to occur in some men taking an efavirenz-based antiretroviral therapy (ART) regimen. However, the incidence and outcomes of gynecomastia are not known in Zimbabwe. We described the characteristics and outcomes of gynecomastia among male patients on an efavirenz-based ART regimen. METHODS: We conducted a retrospective cohort review of data of all male patients aged ≥18 years taking an efavirenz-based regimen at Newlands Clinic, Harare, Zimbabwe before 31 March 2017. The primary outcome was gynecomastia as defined by breast/nipple enlargement reported by patient and confirmed by clinical palpation. Routinely collected data on demographics, baseline CD4, body mass index, duration on efavirenz, clinical presentation and outcomes were extracted from the clinic database and analysed using STATA 12.1. We investigated for any associations with concomitant medicines using cox regression. RESULTS: We analysed data for 1432 men with a median age of 40 years (IQR: 33-48). Half of the patients were in WHO stage 1 at ART commencement. Median body mass index and CD4 count at efavirenz commencement was 21 (IQR: 19-23) and 260 cells/mm3 (IQR: 126-412) respectively. The incidence of gynecomastia was 22/1000 person-years (IQR: 17.3-27.8). Over half of the cases (58%) were bilateral and 75% of all cases developed within two years of starting efavirenz. There were no significant associations with concomitant use of isoniazid (HR: 0.95, p = 0.87) or amlodipine (HR: 0.43, p = 0.24). Gynecomastia resolved in 83.5% of cases following withdrawal of efavirenz with a median time to resolution of 3 months (IQR: 2-9). CONCLUSION: The incidence of gynecomastia among patients taking efavirenz-based ART was low with most cases developing early on during treatment. Most cases resolved completely after withdrawing efavirenz.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ginecomastia/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Adulto , Anlodipino/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Ginecomastia/epidemiologia , Humanos , Incidência , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/efeitos adversos , Zimbábue/epidemiologia
11.
PLoS One ; 14(7): e0218649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269034

RESUMO

BACKGROUND: Tenofovir-containing regimens comprise the preferred first-line antiretroviral therapy (ART) in many countries including South Africa, where utilization of second-line regimens is limited. Considerable HIV drug resistance has occurred among persons failing tenofovir-containing first-line ART. We evaluated drug resistance at the population level using mathematical modeling. SETTING: Heterosexual HIV epidemic in KwaZulu-Natal, South Africa. METHODS: We constructed a stochastic individual-based model and simulated scenarios of ART implementation, either CD4-based (threshold < 500 cells/mL) or Fast-track (81% coverage by 2020), with consideration of major drug-associated mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using base case and uncertainty analyses, we assessed (majority) drug resistance levels. RESULTS: By 2030, the median total resistance (proportion of HIV-infected persons with drug resistance) is predicted to reach 31.4% (interquartile range (IQR): 16.5%-50.2%) with CD4-based ART, decreasing to 14.5% (IQR: 7.7%-25.8%) with Fast-track implementation. In both scenarios, we find comparably high prevalence (~80%) of acquired NNRTI-associated, M184V and K65R mutations. Over 48% of individuals with acquired resistance harbor dual, 44% triple and 7% just single drug mutations. Drug-resistant HIV is predicted to comprise 40% (IQR: 27%-50%) of incident infections, while 70% of prevalent transmitted resistance is NNRTI-associated. At 2018, the projected total resistance is 15% (IQR: 7.5%-25%), with 18% (IQR: 13%-24%) of incident infections from transmitted drug-resistant HIV. CONCLUSIONS: WHO-recommended preferred first-line ART could lead to substantial drug resistance. Effective surveillance of HIV drug resistance and utilization of second-line as well as alternative first-line regimens is crucial.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Modelos Teóricos , Adulto , Antígenos CD4/efeitos dos fármacos , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Heterossexualidade , Humanos , Masculino , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , África do Sul/epidemiologia , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico , Carga Viral/efeitos dos fármacos
12.
Protein Sci ; 28(9): 1664-1675, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31301259

RESUMO

The retrovirus HIV-1 has been a major health issue since its discovery in the early 80s. In 2017, over 37 million people were infected with HIV-1, of which 1.8 million were new infections that year. Currently, the most successful treatment regimen is the highly active antiretroviral therapy (HAART), which consists of a combination of three to four of the current 26 FDA-approved HIV-1 drugs. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. One class of RT inhibitors is nucleoside reverse transcriptase inhibitors (NRTIs), a crucial component of the HAART. Once incorporated into DNA, NRTIs function as a chain terminator to stop viral DNA replication. Unfortunately, treatment with NRTIs is sometimes linked to toxicity caused by off-target side effects. NRTIs may also target the replicative human mitochondrial DNA polymerase (Pol γ), causing long-term severe drug toxicity. The goal of this work is to understand the discrimination mechanism of different NRTI analogues by RT. Crystal structures and kinetic experiments are essential for the rational design of new molecules that are able to bind selectively to RT and not Pol γ. Structural comparison of NRTI-binding modes with both RT and Pol γ enzymes highlights key amino acids that are responsible for the difference in affinity of these drugs to their targets. Therefore, the long-term goal of this research is to develop safer, next generation therapeutics that can overcome off-target toxicity.


Assuntos
Polimerase do DNA Mitocondrial/química , Emtricitabina/farmacologia , Transcriptase Reversa do HIV/química , Lamivudina/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Motivos de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Polimerase do DNA Mitocondrial/metabolismo , Emtricitabina/efeitos adversos , Emtricitabina/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Lamivudina/efeitos adversos , Lamivudina/química , Modelos Moleculares , Conformação Proteica , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
13.
Horm Res Paediatr ; 91(4): 262-270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256164

RESUMO

BACKGROUND: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. OBJECTIVE: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. METHODS: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity. RESULTS: We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect. CONCLUSION: The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.


Assuntos
Hiperplasia Suprarrenal Congênita , Benzoxazinas , Infecções por HIV/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Nascimento Prematuro , Efeitos Tardios da Exposição Pré-Natal , Inibidores da Transcriptase Reversa , Esteroide 21-Hidroxilase/antagonistas & inibidores , Hiperplasia Suprarrenal Congênita/induzido quimicamente , Hiperplasia Suprarrenal Congênita/enzimologia , Adulto , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Linhagem Celular , Feminino , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/enzimologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Esteroide 21-Hidroxilase/metabolismo
14.
Int J Antimicrob Agents ; 54(4): 487-490, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31195121

RESUMO

OBJECTIVES: The aim of this study was to compare the tolerability and viro-immunological efficacy of dolutegravir-based regimens (DTG group) with regimens based on EVG, RAL, PI or NNRTI (NODTG group) in patients with acute HIV-1 infections (AHI). METHODS: All patients diagnosed with AHI and on antiretroviral therapy (ART) between January 2015 and December 2017 from five centers in Italy were included and followed-up to 30th April 2018. AHI was defined by the presence of the positive p24 antigen with negative or indeterminate western blot. RESULTS: Forty-three patients were enrolled: 20 in the DTG group, 23 in the NODTG group. Nine patients (20.9%; four in the DTG group, five in the NODTG group) were prescribed a four-drug regimen. In the cohort, 81.4% were Italian and 83.7% were male, with a median age of 41 years (interquartile range [IQR] 31-48). Median time between HIV diagnosis and ART initiation was 12 days (IQR 5-28). Seven patients harbored a virus with transmitted mutations at baseline (16.2%), all were in the DTG group (P=0.005). All patients had undetectable HIV-RNA at the end of follow-up except two patients, one of whom had 57 copies and one who was lost to follow-up. In Kaplan-Meier analysis, time to virological suppression was similar in the two groups (log rank: P= 0.7155). After achieving virological suppression, four patients stopped ART because of toxicity: two on DTG, two on EVG for neurological and gastrointestinal toxicity, respectively. CONCLUSION: In our setting, ART in AHI is started very early. DTG showed good viro-immunological efficacy even in the presence of NRTI-transmitted mutations. DTG interruptions were rare.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Contagem de Linfócito CD4 , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
16.
Pediatr Infect Dis J ; 38(8): 828-834, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30985518

RESUMO

BACKGROUND: Minimal data exist related to neurodevelopment after in utero exposure to Efavirenz (EFV). We sought to compare neurodevelopmental outcomes in HIV-exposed/uninfected (HEU) children with in utero exposure to EFV-based triple antiretroviral treatment (ART) versus non-EFV-based ART, and to examine whether timing of initial EFV exposure is associated with neurodevelopment deficits. METHODS: Women living with HIV who had received EFV-based ART during pregnancy and whose HEU newborn participated in a prior study were reconsented for their HEU toddler to undergo neurodevelopmental testing at 24 months old. We administered the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Developmental Milestones Checklist (DMC) and Profile of Social Emotional Development (PSED). We compared outcomes to previously-collected data from a cohort of 24-month-old HEU children with in utero exposure to non-EFV-based ART. Adjusted general linear models were used to compare mean outcomes. RESULTS: Our analysis included 493 HEU children (126 EFV-exposed, 367 EFV-unexposed). Adjusted mean scores for the EFV-exposed group were worse than the EFV-unexposed group on BSID-III Receptive Language (adjusted means = 21.5 vs. 22.5, P = 0.05), DMC Locomotor (30.7 vs. 32.0, P < 0.01) and Fine Motor scales (17.8 vs. 19.2, P < 0.01); and PSED (11.7 vs. 9.9, P = 0.02); but better on the DMC Language scale (17.6 vs. 16.5, P = 0.01). Earlier (vs. later) EFV exposure was associated with worse scores on the BSID-III Receptive Language scale (20.7 vs. 22.2, P = 0.02). CONCLUSIONS: HEU children exposed in utero to EFV-based ART may be at higher risk for neurodevelopmental and social-emotional deficits than HEU children exposed to non-EFV-based ART.


Assuntos
Benzoxazinas/efeitos adversos , Desenvolvimento Infantil , Infecções por HIV/epidemiologia , Exposição Paterna/efeitos adversos , Complicações Infecciosas na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal , Inibidores da Transcriptase Reversa/efeitos adversos , Benzoxazinas/uso terapêutico , Botsuana/epidemiologia , Criança , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Inibidores da Transcriptase Reversa/uso terapêutico
18.
Int J Antimicrob Agents ; 54(1): 35-42, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30905695

RESUMO

Prolonged exposure to regimens containing protease inhibitors (PIs) as second-line therapy for human immunodeficiency virus (HIV) infection may have a negative impact on metabolic profiles and increase the risk of cardiovascular diseases. Real-world experience with dolutegravir (DTG)-based regimens as alternatives to PI-based regimens is limited in antiretroviral-experienced patients with previous failure or intolerance to first-line therapy. The current study included HIV-positive patients receiving PI-containing regimens with viral suppression for ≥6 months. Virological response and lipid profiles were compared between patients who were subsequently switched to DTG-based therapy plus nucleoside reverse transcriptase inhibitors (NRTIs) and those remaining on their PI-containing regimen at Week 48. In total, 189 patients were switched to DTG-based regimens and 313 remained on PI-containing regimens during the observation period. Patients in the DTG group were younger (mean age 40.0 years vs. 44.6 years) and were more likely to have a previous history of virological failure (44.4% vs. 19.5%) than those in the PI group. At Week 48, 1.1% of the DTG group and 3.8% of the PI group had virological non-response (HIV-RNA load >50 copies/mL) (difference, -2.7%, 95% CI -5.5% to 0.5%). The presence of M184V/I mutation and other NRTI resistance-associated mutations (RAMs) did not increase the risk of virological failure in either group. Patients switched to DTG-based therapy had statistically significant improvement of lipid profiles. Among virally suppressed HIV-positive patients, a switch to DTG-based therapy was non-inferior to continuation of PI-based therapy in virological effectiveness at Week 48, even in the presence of NRTI RAMs.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Quimioterapia de Manutenção/métodos , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Quimioterapia de Manutenção/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
19.
Infez Med ; 27(1): 103-105, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882388

RESUMO

Glucose intolerance and diabetes are becoming increasingly common in HIV-infected patients in the cART era. Many factors are associated with the development of diabetes in HIV-infected individuals who receive cART, one of which is the assumption of specific antiretroviral classes or agents. We describe a case in a 72-year-old Caucasian man with long-term HIV infection. We observed the development of unbalanced diabetes treated with insulin and metformin which improved when we replaced zidovudine with rilpivirine. This switch improved diabetes to such an extent that insulin suspension was required. In several countries zidovudine has long been used due to its low cost, although several side effects have been observed, especially in the long term. In this case, the switch to rilpivirine was shown to be able to improve the toxicity of zidovudine on glucose metabolism, representing a good option to be used.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Diabetes Mellitus/induzido quimicamente , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos , Rilpivirina/uso terapêutico , Zidovudina/efeitos adversos , Idoso , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Hemoglobina A Glicada/metabolismo , Humanos , Masculino
20.
Pharmacogenomics ; 20(2): 105-111, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30628547

RESUMO

As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must be activated to be efficacious against HIV, the enzymes responsible for this activation have not been well characterized. The purpose of this review is to summarize and clarify the scientific knowledge regarding the enzymes that phosphorylate and activate this clinically important drug.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Variação Genética , HIV/efeitos dos fármacos , HIV/genética , HIV/patogenicidade , Infecções por HIV/genética , Infecções por HIV/patologia , Humanos , Inibidores da Transcriptase Reversa/efeitos adversos , Tenofovir/efeitos adversos
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