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2.
Lancet HIV ; 7(10): e666-e676, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010240

RESUMO

BACKGROUND: ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study. METHODS: This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262. FINDINGS: Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common. INTERPRETATION: Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study. FUNDING: USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adenina/administração & dosagem , Adenina/análogos & derivados , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Composição Corporal , Peso Corporal , Duração da Terapia , Emtricitabina/administração & dosagem , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/administração & dosagem , Resultado do Tratamento , Carga Viral , Adulto Jovem
3.
Ann Epidemiol ; 49: 1-7, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32951802

RESUMO

PURPOSE: Oral emtricitabine/tenofovir disoproxil fumarate was approved for use as pre-exposure prophylaxis (PrEP) by the U.S. Food and Drug Administration in 2012. We used national pharmacy data to examine trends of PrEP use in U.S. counties from 2012 to 2018. METHODS: Using multi-level small-area spatio-temporal modeling, we calculated the estimated annual percentage change (EAPC) in prevalence of PrEP use in the general population from 2012 to 2018. We also used a proxy measure for prevalence of PrEP use among men who have sex with men (MSM) to evaluate trends of use among MSM, the PrEP use-to-MSM ratio (PmR) or number of male PrEP users per 1000 MSM population. RESULTS: The prevalence of PrEP use and PmR increased (EAPC range: (+26.9%, +71.0%) and (+28.4%, +158.7%), respectively) in all counties with varying magnitude of increase. Counties of the Midwest and the upper South and upper West had the slowest increase in prevalence of PrEP use (EAPC range: (+26.9%; +52.9%)). Counties of the northern part of the South had the lowest PmR (EAPC range: (+28.4%; +76.0%)). Counties of the most populous core-based statistical areas had a relatively faster increase in population prevalence of PrEP use but slower increase in PmR. CONCLUSIONS: All counties in the U.S. have witnessed an increase in PrEP use with important geographic variabilities. Identifying areas with slow improvement in PrEP use, as well as "model counties" with the fastest pace of progress in PrEP coverage, is critical to inform local and state-level policies and program evaluation for PrEP scale up, particularly among MSM at higher risk for HIV.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/estatística & dados numéricos , Adesão à Medicação/estatística & dados numéricos , Profilaxia Pré-Exposição/estatística & dados numéricos , Tenofovir/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Profilaxia Pré-Exposição/tendências , Prevalência , Análise de Pequenas Áreas , Análise Espaço-Temporal , Estados Unidos/epidemiologia
4.
Lancet HIV ; 7(6): e389-e400, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32504574

RESUMO

BACKGROUND: In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. METHODS: We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. FINDINGS: 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. INTERPRETATION: These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. FUNDING: Gilead Sciences.


Assuntos
Adenina/análogos & derivados , Didesoxinucleosídeos/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Lamivudina/administração & dosagem , Tenofovir/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Idoso , Didesoxinucleosídeos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/virologia , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Tenofovir/efeitos adversos , Resultado do Tratamento , Adulto Jovem
5.
Medicine (Baltimore) ; 99(21): e20063, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481273

RESUMO

BACKGROUND: Measuring adherence to PrEP (pre-exposure prophylaxis) remains challenging. Biological adherence measurements are reported to be more accurate than self-reports and pill counts but can be expensive and not suitable on a daily basis in resource-limited countries. Using data from a demonstration project on PrEP among female sex workers in Benin, we aimed to measure adherence to PrEP and compare self-report and pill count adherence to tenofovir (TFV) disoproxil fumarate (TDF) concentration in plasma to determine if these 2 measures are reliable and correlate well with biological adherence measurements. METHODS: Plasma TFV concentrations were analyzed in samples collected at day 14 follow-up visit and months 6, 12, 18, and 24 (or at last visit when follow-up was shorter). Self-reported adherence was captured at day 14 follow-up visit and then quarterly by asking participants to report the number of missed pills within the last week. For pill count, medications were refilled monthly and participants were asked to bring in their medication bottles at each follow-up visit. Using generalized estimating equations adherence measured by self-report and pill count was compared to plasma drug concentrations. RESULTS: Of 255 participants, 47.1% completed follow-up. Weighted optimal adherence combining data from all visits was 26.8% for TFV concentration, 56.0% by self-report and 18.9% by pill count. Adherence measured by both TFV concentrations and self-report decreased over time (P = .009 and P = .019, respectively), while the decreasing trend in adherence by pill count was not significant (P = .087). The decrease in adherence was greater using TFV concentrations than the other 2 adherence measures. CONCLUSION: With high levels of misreporting of adherence using self-report and pill count, the objective biomedical assessment of adherence via laboratory testing is optimal and more accurately reflects PrEP uptake and persistence. Alternative inexpensive and accurate approaches to monitor PrEP adherence should be investigated.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Adesão à Medicação/estatística & dados numéricos , Profilaxia Pré-Exposição/métodos , Tenofovir/administração & dosagem , Adulto , Fármacos Anti-HIV/sangue , Benin , Feminino , Infecções por HIV/prevenção & controle , Humanos , Pessoa de Meia-Idade , Autorrelato , Profissionais do Sexo , Tenofovir/sangue
6.
Medicine (Baltimore) ; 99(18): e19907, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358357

RESUMO

There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/administração & dosagem , Adulto , Alanina Transaminase/sangue , Esquema de Medicação , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Soroconversão/efeitos dos fármacos , Resposta Viral Sustentada , Fatores de Tempo
7.
Am J Gastroenterol ; 115(8): 1217-1225, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32355123

RESUMO

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adulto , Antivirais/administração & dosagem , Densidade Óssea , Método Duplo-Cego , Esquema de Medicação , Feminino , Guanina/administração & dosagem , Guanina/uso terapêutico , Vírus da Hepatite B , Hepatite B Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , República da Coreia , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico , Resultado do Tratamento , Carga Viral
8.
JAAPA ; 33(6): 12-17, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32384293

RESUMO

HIV preexposure prophylaxis (PrEP) is an opportunity for clinicians to curb the 40,000 HIV infections occurring annually in the United States. PrEP is medication used by HIV-negative patients to reduce their risk of acquiring the virus. This article provides a baseline understanding of PrEP indications, prescribing, and monitoring, including a review of previously approved medication and an update on newly approved drugs, including emtricitabine/tenofovir alafenamide (F/TAF). Sexual and gender minorities are often underrepresented in the literature about PrEP, but clinicians should address risk focused on specific behaviors rather than population-level characteristics. As one of few professions with prescriptive authority, PAs have an obligation to understand and manage PrEP.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/prevenção & controle , Assistentes Médicos , Profilaxia Pré-Exposição/métodos , Atenção Primária à Saúde , Tenofovir/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/economia , Antivirais/efeitos adversos , Antivirais/economia , Emtricitabina/efeitos adversos , Emtricitabina/economia , Feminino , Infecções por HIV/transmissão , Humanos , Masculino , Profilaxia Pré-Exposição/economia , Tenofovir/efeitos adversos , Tenofovir/economia , Resultado do Tratamento
10.
Ann Epidemiol ; 44: 1-7.e2, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32279914

RESUMO

PURPOSE: Preexposure prophylaxis (PrEP) in the form of daily emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) is effective for preventing HIV infection. Implementation has been limited by an inability to systematically evaluate uptake and use. All-Payer Claims Databases (APCDs) provide an opportunity to evaluate population-level PrEP implementation. METHODS: We used 2012-2017 data from Rhode Island's APCD and developed an algorithm to identify individuals prescribed FTC/TDF for PrEP. We describe PrEP implementation by patient demographics and provider type and mapped PrEP implementation across ZIP codes. We compared APCD data to electronic medical record data and comprehensive pharmaceutical claims data (AIDSVu.org). RESULTS: The Rhode Island APCD represented approximately 87% of the state's population. PrEP use increased 31-fold from 2012 to 2017. Users were predominantly privately insured, male, and concentrated in Providence County (76.6%). Infectious diseases providers had 3.2 times the odds of being a PrEP prescriber compared to primary care providers. Compared to other pharmaceutical and electronic medical record data, the APCD underestimated the number of PrEP users in Rhode Island but improved in capturing users over time. CONCLUSIONS: APCDs are a useful data source for characterizing PrEP use across a state. There is a need to increase PrEP prescribing among primary care providers, especially in areas with underserved populations.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição/estatística & dados numéricos , Tenofovir/administração & dosagem , Adulto , Feminino , Humanos , Revisão da Utilização de Seguros , Masculino , Profilaxia Pré-Exposição/métodos , Rhode Island
11.
Emerg Microbes Infect ; 9(1): 843-850, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32267205

RESUMO

Reduced doses of antiretroviral (ARV) drugs may lower toxicity while preserving efficacy. We aimed to evaluate the efficacy of reduced doses of both tenofovir disoproxil fumarate (TDF) and efavirenz for the treatment of HIV-1 infection. In this open-label, non-inferiority trial, HIV-1-infected antiretroviral-naive adults were randomly assigned to receive either a lower dose anti-retroviral regimen comprised of TDF (200 mg), efavirenz (400 mg), and standard dose lamivudine (300 mg) or the standard dose regimen. The primary endpoint was the proportion of participants with HIV-1 RNA≤ 50 copies/mL at week 48 using a non-inferiority margin of -10%. At week 48, 79 of 92 (85.9%) participants in the lower dose regimen group and 78 of 92 (84.8%) in the standard dose regimen group achieved HIV-1 RNA≤ 50 copies/mL (treatment difference 1.1%, 95% CI -9.1 to 11.3) in the intention-to-treat analysis. Drug-related adverse events occurred more frequently in the participants receiving the standard dose regimen compared with the lower dose one (63.0% vs 80.4%). Changes in estimated glomerular filtration rate and bone mineral density were comparable between the two groups. The non-inferior efficacy and better safety profile of the lower dose ARV regimen support its use as alternative initial therapy for HIV-1 infected patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Tenofovir/administração & dosagem , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Densidade Óssea/efeitos dos fármacos , China , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Masculino , RNA Viral/sangue , Tenofovir/efeitos adversos , Resultado do Tratamento
15.
AAPS PharmSciTech ; 21(3): 91, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060665

RESUMO

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antirretrovirais/farmacocinética , Lamivudina/farmacocinética , Piridonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Antirretrovirais/administração & dosagem , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos , Tenofovir/administração & dosagem , Triazóis/administração & dosagem , Adulto Jovem
16.
Hepatol Int ; 14(1): 105-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31898210

RESUMO

BACKGROUND: Controversy exists on whether tenofovir disoproxil fumarate (TDF) is superior to entecavir (ETV) in lowering the risk of hepatocellular carcinoma (HCC) development. This meta-analysis was performed to clarify this issue with critical clinical and methodological considerations. METHODS: PubMed, EMBASE, and Cochrane Library were searched from inception to Oct 28, 2019. Randomized control trials and observational studies reporting the impact of TDF and ETV on the risk of HCC in patients with chronic hepatitis B (CHB) were eligible. Risk ratios (RRs) calculated with cumulative incidence rate and/or annual incidence rate, or hazard ratio (HR) were pooled using random-effect models. Subgroup analyses were performed to assess the potential impact of between-study level and within-study level factors. RESULTS: A total of 32 studies with 78,136 CHB patients were included. Overall cumulative incidence rate of HCC was lower in TDF group than ETV group (3.07% vs. 5.25%; RR 0.55; 95% CI 0.42-0.72). However, this difference was not statistically significant in pooled results of hazard ratio (HR 0.87; 95% CI 0.73-1.04) and RR calculated with annual incidence rate (RR 0.88; 95% CI 0.67-1.16). Potential confounding factors at between-study level included prior nucleos(t)ide usage, disease stage at baseline and region of study. More importantly, at within-study level, disparity in follow-up duration between TDF and ETV groups may impact the result, usually favoring a treatment with shorter follow-up duration. CONCLUSIONS: Compared with ETV, TDF treatment tended to have a lower overall cumulative incidence rate of HCC. However, disparity in follow-up duration may be a key factor to influence the result.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Tenofovir/uso terapêutico , Antivirais/administração & dosagem , Guanina/administração & dosagem , Guanina/uso terapêutico , Humanos , Tenofovir/administração & dosagem
17.
Mar Drugs ; 18(1)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936439

RESUMO

Women are still at high risk of contracting the human immunodeficiency virus (HIV) virus due to the lack of protection methods under their control, especially in sub-Saharan countries. Polyelectrolyte multilayer smart vaginal films based on chitosan derivatives (chitosan lactate, chitosan tartate, and chitosan citrate) and Eudragit® S100 were developed for the pH-sensitive release of Tenofovir. Films were characterized through texture analysis and scanning electron microscopy (SEM). Swelling and drug release studies were carried out in simulated vaginal fluid and a mixture of simulated vaginal and seminal fluids. Ex vivo mucoadhesion was evaluated in bovine vaginal mucosa. SEM micrographs revealed the formation of multilayer films. According to texture analysis, chitosan citrate was the most flexible compared to chitosan tartrate and lactate. The swelling studies showed a moderate water uptake (<300% in all cases), leading to the sustained release of Tenofovir in simulated vaginal fluid (up to 120 h), which was accelerated in the simulated fluid mixture (4-6 h). The films had high mucoadhesion in bovine vaginal mucosa. The multilayer films formed by a mixture of chitosan citrate and Eudragit® S100 proved to be the most promising, with zero toxicity, excellent mechanical properties, moderate swelling (<100%), high mucoadhesion capacity, and Tenofovir release of 120 h and 4 h in vaginal fluid and the simulated fluid mixture respectively.


Assuntos
Administração Intravaginal , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Ácidos Polimetacrílicos/química , Tenofovir/administração & dosagem , Animais , Fármacos Anti-HIV/administração & dosagem , Bovinos , Quitosana/farmacologia , Sistemas de Liberação de Medicamentos/normas , Feminino , Infecções por HIV/prevenção & controle , Humanos , Concentração de Íons de Hidrogênio , Membrana Mucosa/efeitos dos fármacos , Ácidos Polimetacrílicos/farmacologia , Vagina/efeitos dos fármacos
18.
Artigo em Inglês | MEDLINE | ID: mdl-31929405

RESUMO

BACKGROUND: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration. METHODS: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression. RESULTS: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively. CONCLUSIONS: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.


Assuntos
Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Organofosfatos/uso terapêutico , Polifosfatos/uso terapêutico , Resultado da Gravidez , Adenina/administração & dosagem , Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Estudos de Casos e Controles , Cromatografia Líquida , Combinação de Medicamentos , Emtricitabina/administração & dosagem , Feminino , Humanos , Modelos Logísticos , Lopinavir/uso terapêutico , Adesão à Medicação , Organofosfatos/administração & dosagem , Polifosfatos/administração & dosagem , Gravidez , Complicações na Gravidez , Estudos Retrospectivos , Ritonavir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico
20.
Int J Infect Dis ; 93: 108-117, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31988012

RESUMO

BACKGROUND: Tenofovir disoproxil fumarate (TDF) can cause renal and bone toxicity, which is associated with high plasma tenofovir concentrations in antiretroviral treatment of HIV-1 infected patients. Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. We aimed to assess the non-inferiority of a TAF-containing combination regimen versus a TDF-containing fixed-dose single-tablet regimen in the antiretroviral-treatment-naive, HIV-1-infected patients. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Trial Registry, from January 2001 to July 2019, using relevant keywords. Available data were extracted from eligible randomized trials (RCTs) and pooled as risk ratios (RRs) or standardized mean differences (SMDs) in a meta-analysis model using Stata/SE. RESULTS: We included seven eligible randomized controlled trials (RCTs) with a total of 6269 participants. Patients who were antiretroviral-naive adults with HIV-1 on both the TAF-containing regimens and the TDF-containing regimens had similar virologic suppression effects (RR, 1.02; 95% CI, 1.00-1.04; p > 0.05) at week 24 (93.99% vs. 94.20%), week 48 (90.71% vs. 89.54%), and week 96 (86.16% vs. 84.80%). Both groups had no significant improvements in CD4 cell count for the naive patients during 48 weeks of therapy (SMD, 0.09; 95% CI, 0.01 to 0.16; p < 0.05). Both treatments were safe and well-tolerated, and most adverse events were similar as mild to moderate in severity. Moreover, compared with the TDF-containing regimens, the TAF-containing regimens in patients had significantly smaller reductions in both hip (RR, 0.33; 95CI, 0.29-0.39; p < 0.05) and spine (RR, 0.58; 95CI, 0.51-0.65; p < 0.05). Additionally, the TAF-containing regimens in patients had significantly fewer increases for renal events than those of the TDF-containing regimens through 48 weeks (0.31; 95% CI, 0.18-0.55; p < 0.05). CONCLUSIONS: Our meta-analysis indicated that efficacy, safety, and tolerability of TAF-containing regimens were non-inferior in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection. Furthermore, compared with those receiving the TDF-containing regimens, patients on the TAF-containing regimens had significant advantages in renal function, bone parameters, and lipid profile for the naive patients.


Assuntos
Adenina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1 , Tenofovir/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Soropositividade para HIV , Humanos , Rim/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Comprimidos , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos
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