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2.
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
3.
Medicine (Baltimore) ; 98(32): e16721, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393378

RESUMO

The aim of this retrospective cohort study was to compare safety, efficacy and rates and reasons of discontinuation of the 3 currently approved integrase strand transfer inhibitors (INSTIs) elvitegravir (EVG), dolutegravir (DTG), and raltegravir (RAL) in HIV-infected treatment-naïve and -experienced patients in a real-world cohort. One hundred four treatment-naïve patients were prescribed an INSTI-based combined antiretroviral therapy (cART)-regimen (first-line group) and 219 patients were switched to an INSTI-based cART-regimen from another treatment regimen (switch group) at our institution between May 2007 and December 2014. Twelve months after initiation of treatment, 92% of patients in the first-line group (EVG: 96%, n = 22/23; DTG: 92%, n = 34/37; RAL: 90%, n = 28/31) and 88% of patients in the switch group (EVG: 94%, n = 32/34; DTG: 90%, n = 69/77; RAL: 85%, n = 67/79) showed full virological suppression (viral load <50 copies/mL). Side effects of any kind occurred in 12% (n = 12/104) of patients in the first-line group, and 10% (n = 21/219) of patients in the switch group. In the switch group neuropsychiatric side effects (depression, vertigo, and sleep disturbances) occurred more frequently in patients treated with DTG (11%, n = 10) compared to the 2 other INSTI-based cART-regimen (EVG: 2%, n = 1; RAL: 1%, n = 1). Side effects only rarely led to discontinuation of treatment (first-line-group: 2%, n = 2/104; switch-group: 1%, n = 3/219). In this real-world setting, INSTI-based ART-regimens were highly efficacious with no significant differences between any of the 3 INSTIs. Overall, side effects were only rarely observed and generally mild in all subgroups. In light of a slightly higher incidence of vertigo and sleep disturbances in patients switched to DTG, awareness of the potential onset of psychiatric symptoms is warranted during follow-up in those patients.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Quinolonas/administração & dosagem , Raltegravir Potássico/administração & dosagem , Adulto , Idoso , Antirretrovirais , Terapia Antirretroviral de Alta Atividade/métodos , Feminino , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Raltegravir Potássico/efeitos adversos , Estudos Retrospectivos , Carga Viral/efeitos dos fármacos , Adulto Jovem
4.
N Engl J Med ; 381(9): 816-826, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31339676

RESUMO

BACKGROUND: An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings. METHODS: We conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points. RESULTS: A total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], -1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, -4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%). CONCLUSIONS: In HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 ClinicalTrials.gov number, NCT02777229.).


Assuntos
Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adulto , Benzoxazinas/efeitos adversos , Quimioterapia Combinada , Feminino , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/administração & dosagem , Masculino , Obesidade/induzido quimicamente , Gravidez , RNA Viral/sangue , Tenofovir/administração & dosagem , Carga Viral/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
6.
N Engl J Med ; 381(9): 827-840, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31329379

RESUMO

BACKGROUND: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies. METHODS: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals. RESULTS: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87). CONCLUSIONS: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).


Assuntos
Antirretrovirais/efeitos adversos , Anormalidades Congênitas/epidemiologia , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Defeitos do Tubo Neural/induzido quimicamente , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Antirretrovirais/uso terapêutico , Botsuana/epidemiologia , Quimioterapia Combinada , Feminino , Feto/efeitos dos fármacos , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Recém-Nascido , Defeitos do Tubo Neural/epidemiologia , Vigilância da População , Gravidez , Prevalência , Fatores Socioeconômicos
7.
Infect Dis Clin North Am ; 33(3): 681-692, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31239093

RESUMO

With the second-generation integrase inhibitors (dolutegravir and bictegravir) extending the attributes of earlier integrase inhibitors, three-drug regimens containing integrase inhibitors plus two nucleos(t)ide reverse transcriptase inhibitors are now widely recommended for first-line (initial) treatment of human immunodeficiency virus-1 infection. Led by dolutegravir plus lamivudine, two-drug therapy is emerging as a way to reduce antiretroviral therapy cost and adverse effects without compromising treatment options should virologic failure occur. Initial two-drug therapy has limitations, including the relative incompatibility with the coemerging concept of same-day antiretroviral therapy initiation.


Assuntos
Antirretrovirais/administração & dosagem , Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacologia , Antirretrovirais/efeitos adversos , Antirretrovirais/economia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/economia , HIV-1/efeitos dos fármacos , Humanos , Resultado do Tratamento
8.
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
10.
J Acquir Immune Defic Syndr ; 81(4): 481-486, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31021990

RESUMO

BACKGROUND: Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women. SETTING: Nation-wide database cohort analysis. METHODS: We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir. RESULTS: We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect. CONCLUSIONS: Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Gravidez/efeitos dos fármacos , Adulto , Antirretrovirais/efeitos adversos , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Farmacorresistência Viral/efeitos dos fármacos , Feminino , França , Infecções por HIV/complicações , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Defeitos do Tubo Neural/epidemiologia , Farmacovigilância , Quinolonas/uso terapêutico , Raltegravir Potássico/uso terapêutico , Resultado do Tratamento , Adulto Jovem
11.
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
12.
AIDS Rev ; 21(1): 4-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30899113

RESUMO

Neuropsychiatric adverse events (NPAEs) observed with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) are usually mild to moderate. The most prevalent symptoms are insomnia and sleep disorders, but the spectrum also includes dizziness, anxiety, depression, headache, paraesthesia, muscle-skeletal pain, poor concentration, and slow thinking. In recent cohort studies involving >6400 patients in different countries, discontinuation rates due to NPAEs were observed in around 3.5% (range, 1.4-7.2%) of subjects treated with DTG. These rates have been higher than those seen in randomized clinical trials and were also higher than with other INSTIs such as elvitegravir or raltegravir. Elderly, female patients and those who initiate abacavir simultaneously appear to be more vulnerable in some cohorts. It remains unclear if NPAEs are driven by an increased DTG exposure. With heightened awareness of health-care providers and patients, reports of NPAEs will probably increase in the future.


Assuntos
Doenças do Sistema Nervoso Central/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Fatores de Risco
13.
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
14.
Medicine (Baltimore) ; 98(10): e14828, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30855509

RESUMO

In 2017, the Ministry of Health Brazilian started using dolutegravir (DTG) 50 mg to all people living with HIV who began antiretroviral therapy (ART) or rescue regimens. Although DTG is thought to have better tolerability levels and a lower possibility of causing adverse reactions, it is necessary to continuously evaluate the safety profile of the drug in the population. Therefore, an active pharmacovigilance project for DTG was implemented. The objective of this study was to describe the Brazilian experience of implementing pharmacovigilance and the results obtained during the period between April and December 2017.Active pharmacovigilance was implemented through patient interviews and an online questionnaire developed in the Medication Logistics Control System (SICLOM).Of the total number of people on DTG in Brazil (79,742) 90.33% participated in the project, and 2.24% of those who participated reported adverse reactions to the drug; of those who reported adverse reactions, 73.86% were on first-line ART regimens, and 26.13% were on third-line regimens. The mean age of the patients who had adverse reactions to DTG was 39 years; 68.79% were male, and 31.21% were female. Of the adverse reactions reported, 50.39% were considered persistent. The 3 most frequent reactions were nausea (13.34%), diarrhea (9.83%), and headaches (9.23%).The Brazilian experience with this project has been deemed successful by federal and local managers, and the online tool to collect data has proved to be an important strategy for the pharmacovigilance of DTG as well as that of other drugs.


Assuntos
Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Farmacovigilância , Adulto , Brasil , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Avaliação de Programas e Projetos de Saúde
15.
PLoS One ; 14(1): e0210384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30625208

RESUMO

Antiretroviral agents are approved in Japan based on non-clinical and clinical data reported from overseas. Neither the long-term tolerability nor the effectiveness of raltegravir or other integrase strand transfer inhibitors in Japan is known. This study reports on the long-term tolerability and effectiveness of raltegravir in Japanese clinical practice using data collected through approximately 9 years of post-marketing surveillance. This observational survey used data on human immunodeficiency virus (HIV) infected patients initiated treatment with raltegravir between 2008 and 2017 in the HIV-related drug (HRD) cooperative survey to assess the safety and effectiveness of raltegravir in real world clinical practice. There were totally 1,303 patients prescribed raltegravir across 30 institutions; 1,293 patients and 1,178 patients were included for the safety and effectiveness analyses, respectively. The overall risk of adverse drug reaction was 17.25%, with abnormal hepatic function and hyperlipidaemia (<1.5%) having the highest proportion. Median HIV-1 RNA viral loads rapidly decreased below 40 copies/mL after 3 months of raltegravir use in treatment-naïve patients, and consistently sustained below 40 copies/mL after the start of raltegravir use in treatment-experienced patients. Among the patients who were treated for 7 years, 92.00% (95% CI: 73.97-99.02) maintained HIV-1 RNA viral load below 50 copies/mL. Additionally, CD4+ cell counts exceeded >500 cells/µL in treatment-naïve and treatment-experienced patients after 3 years and 4 years of treatment, respectively. In Japanese HIV patients, long-term treatment with raltegravir is well-tolerated and effective at viral suppression as measured by HIV-1 RNA levels and subsequent change in CD4+ cell counts. Such benefits can be expected for not only treatment-naïve but also treatment-experienced patients.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1 , Raltegravir Potássico/uso terapêutico , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , RNA Viral/sangue , Raltegravir Potássico/efeitos adversos , Segurança , Fatores de Tempo , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
16.
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
17.
Lancet HIV ; 6(2): e116-e127, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30503325

RESUMO

BACKGROUND: The integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains. METHODS: We used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted. FINDINGS: The greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving. INTERPRETATION: Using a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adolescente , Adulto , África ao Sul do Saara , Deficiências do Desenvolvimento/induzido quimicamente , Deficiências do Desenvolvimento/epidemiologia , Farmacorresistência Viral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Medição de Risco , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral , Adulto Jovem
19.
Expert Rev Clin Pharmacol ; 12(1): 31-44, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30513008

RESUMO

Introduction: Treatment of HIV infection has consistently evolved in the last three decades. A steady improvement in efficacy tolerability, safety, and practical aspects of treatment intake has made HIV infection much easier to manage over the long term, and in optimal treatment conditions the life expectancy of persons living with HIV infection now approaches the values of the general population. The last category of antiretrovirals to be fully developed for clinical use is the one of strand-transfer integrase inhibitors (INSTIs). Areas covered: In this review, the evolution of the knowledge on INSTIs use in the clinical setting is reviewed, analyzed, and interpreted. Emphasis is placed on the properties possibly accounting for several superiority results achieved by INSTIs in non-inferiority designed comparative clinical trials, which led to their inclusion as first line options in all versions of HIV therapeutic guidelines. Expert commentary: Some unprecedented clinical-pharmacological properties of INSTIs, such as their rapid and sustained action against HIV replication, the optimal tolerability and safety profile and a clinically proven robust genetic barrier are the main factors justifying the successful clinical use of INSTIs. Based on these unique features, novel INSTIs-based treatment modalities are being developed, including the reduction of antiretroviral regimens to two drugs only.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Replicação Viral/efeitos dos fármacos , Animais , Desenvolvimento de Medicamentos/métodos , Quimioterapia Combinada , Infecções por HIV/enzimologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacologia , Humanos , Expectativa de Vida , Guias de Prática Clínica como Assunto
20.
Lancet HIV ; 5(12): e715-e722, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527329

RESUMO

BACKGROUND: Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection. METHODS: In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label raltegravir-adult tablets, chewable tablets, and granules for oral suspension-were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log10 from baseline or HIV-1 RNA <400 copies per mL) at week 240. The primary analysis group for safety and efficacy comprised patients treated only with the final selected dose of raltegravir. This trial is registered with ClinicalTrials.gov, number NCT00485264. FINDINGS: Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1-60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9-90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5-98·3) of 15 patients receiving oral granules. Among patients with virological failure, raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing. INTERPRETATION: Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy. FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/isolamento & purificação , Raltegravir Potássico/administração & dosagem , Raltegravir Potássico/efeitos adversos , Administração Oral , Adolescente , Américas , Botsuana , Criança , Pré-Escolar , Feminino , Seguimentos , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacocinética , Humanos , Lactente , Masculino , Raltegravir Potássico/farmacocinética , Resultado do Tratamento
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