Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Adulto , Humanos , Adenina/análogos & derivados , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Negro ou Afro-Americano , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adesão à Medicação/estatística & dados numéricos , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Lamivudina , Mutação , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Feminino , Adulto , HIV-1/genética , HIV-1/efeitos dos fármacos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Carga Viral/efeitos dos fármacos , Zâmbia/epidemiologia , Estudos Transversais , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Piperazinas/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/farmacologia , Piridonas/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Emtricitabina/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Combinação de MedicamentosRESUMO
M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Mutação , Humanos , HIV-1/genética , HIV-1/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Fármacos Anti-HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , Lamivudina/uso terapêutico , Emtricitabina/uso terapêuticoRESUMO
BACKGROUND: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. METHODS: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. RESULTS: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. CONCLUSIONS: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Emtricitabina/uso terapêutico , Método Simples-Cego , HIV-1 , Complexo AIDS Demência/tratamento farmacológico , Maraviroc/uso terapêutico , Darunavir/uso terapêutico , Cobicistat/uso terapêutico , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/etiologia , Eletroencefalografia , Cognição/efeitos dos fármacosAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Emtricitabina , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Emtricitabina/uso terapêutico , Piridonas/uso terapêutico , Piperazinas/uso terapêutico , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Hepatite B/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Masculino , Feminino , AmidasRESUMO
BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Tenofovir , Carga Viral , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Feminino , Adulto , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carga Viral/efeitos dos fármacos , Emtricitabina/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Piperazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Darunavir/uso terapêutico , Alanina/uso terapêutico , Alanina/análogos & derivados , Resultado do Tratamento , RNA Viral , Sulfonamidas/uso terapêutico , Pessoa de Meia-Idade , Cobicistat/uso terapêutico , Reino Unido , Combinação de Medicamentos , Amidas , PiridonasRESUMO
BACKGROUND: Tenofovir-containing antiretroviral therapy regimens may have long-term toxicity-related side effects. This study aimed to compare the virological efficacy of co-formulated darunavir/ritonavir plus lamivudine with darunavir/ritonavir plus tenofovir and emtricitabine or lamivudine. METHODS: The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in treatment-naïve adults living with human immunodeficiency virus (HIV). Patients were randomized on a 1:1 basis to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir/ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir/ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of <50 copies/mL at week 48 in the intention-to-treat population. The US Food and Drug Administration snapshot algorithm and a non-inferiority margin of -12% were used. The secondary objective was to analyse safety in the per-protocol population. This study has been registered at ClinicalTrials.gov (NCT02770508). RESULTS: Between November 2015 and 31 October 2020, 336 participants were assigned at random to the triple therapy arm (n=165) or the dual therapy arm (n=171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the dual therapy group (91%) achieved virological suppression (difference -2.1%, 95% confidence interval -7.0 to 2.9). Drug-related adverse events were more common in the triple therapy group (P=0.04). Two toxicity-related events led to discontinuation in each group. INTERPRETATION: Co-formulated darunavir/ritonavir plus lamivudine showed non-inferiority and a safer toxicity profile compared with the standard-of-care triple therapy regimen including tenofovir in treatment-naïve patients.
Assuntos
Fármacos Anti-HIV , Darunavir , Quimioterapia Combinada , Infecções por HIV , Lamivudina , Ritonavir , Carga Viral , Humanos , Infecções por HIV/tratamento farmacológico , Darunavir/uso terapêutico , Darunavir/administração & dosagem , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Carga Viral/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , HIV-1/efeitos dos fármacos , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Resultado do TratamentoRESUMO
BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Piridonas , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Estudos Retrospectivos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Piridonas/economia , Piridonas/uso terapêutico , Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/economia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/economia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Combinação de Medicamentos , Oxazinas/uso terapêutico , Oxazinas/economia , Emtricitabina/uso terapêutico , Emtricitabina/economia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/economia , Piperazinas/economia , Piperazinas/uso terapêutico , Lamivudina/economia , Lamivudina/uso terapêutico , Inibidores de Integrase de HIV/economia , Inibidores de Integrase de HIV/uso terapêutico , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Substituição de Medicamentos/economia , Amidas , Ciclopropanos , Didesoxiadenosina/análogos & derivadosRESUMO
Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. Methods: HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Transmissão Vertical de Doenças Infecciosas , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Farmacorresistência Viral/genética , Gravidez , Fármacos Anti-HIV/uso terapêutico , Adulto , Recém-Nascido , Piperazinas/uso terapêutico , Ciclopropanos , HIV-1/genética , HIV-1/efeitos dos fármacos , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Alcinos , Piridonas/uso terapêutico , Emtricitabina/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Benzoxazinas/uso terapêutico , Oxazinas/uso terapêuticoRESUMO
This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.
Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , DNA Mitocondrial , Emtricitabina , Infecções por HIV , Mitocôndrias , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Masculino , Feminino , Adulto , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Benzoxazinas/uso terapêutico , Benzoxazinas/farmacologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Ciclopropanos/uso terapêutico , Tenofovir/uso terapêutico , Pessoa de Meia-Idade , Emtricitabina/uso terapêutico , DNA Mitocondrial/metabolismo , InflamaçãoRESUMO
BACKGROUND: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. OBJECTIVES: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). METHODS: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. RESULTS: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. CONCLUSIONS: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.
Assuntos
Emtricitabina , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Tenofovir , Animais , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Emtricitabina/farmacocinética , Tenofovir/farmacocinética , Distribuição Tecidual , Masculino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Feminino , Macaca mulattaRESUMO
PURPOSE OF REVIEW: Adherence-concentration-efficacy benchmarks have not been fully characterized for cisgender women using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) oral daily pre-exposure prophylaxis (PrEP) for HIV prevention. RECENT FINDINGS: We conducted a systematic review to investigate current evidence on the adherence-concentration-efficacy relationship of tenofovir-diphosphate (TFV-DP) derived from FTC/TDF PrEP in dried blood spots (DBS) and peripheral mononuclear cells (PBMC) in cisgender women without HIV, including during pregnancy. We searched for completed and ongoing studies published before May 2024 in PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrial.gov. Overall, 11 studies assessing adherence benchmarks focusing on (n = 5) or involving (n = 6) cisgender women were included. Women-specific median steady-state TFV-DP concentration for daily dosing ranged from 17 to 51 fmol/106 in PBMC and 1389 to 1685 fmol/punch in DBS in non-pregnant women; 50 to 71 fmol/106 in PBMC and 583 to 965 fmol/punch in DBS in pregnant women; and 618 to 1406 fmol/punch in DBS in postpartum women. DBS TFV-DP levels were 14-43% lower in pregnancy versus postpartum or non-pregnant periods, but PBMC TFV-DP levels appear to be comparable. Clinical and modeling studies demonstrate effective HIV protection for women taking at least four doses/week of oral TDF-based PrEP, and emerging evidence suggests that systemic drug levels are more likely to be predictive of efficacy than local tissue levels at the site of exposure. The preponderance of emerging evidence points to comparable efficacy and similar adherence requirement for women as men among those with detectable drug levels, although there was an indication that the highest achievable efficacy may be reached at a lower adherence level in men than women. In this review, we found evidence that women-specific TFV-DP adherence benchmarks in DBS and PBMC are within range of US-based historical thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women as it does in MSM, but more data are still needed to refine intrinsic achievable efficacy estimates for cisgender women.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adesão à Medicação , Profilaxia Pré-Exposição , Tenofovir , Humanos , Profilaxia Pré-Exposição/métodos , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Adesão à Medicação/estatística & dados numéricos , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Gravidez , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/administração & dosagem , Leucócitos Mononucleares , Adenina/análogos & derivados , OrganofosfatosAssuntos
Fármacos Anti-HIV , Infecções por HIV , Complicações Infecciosas na Gravidez , Terceiro Trimestre da Gravidez , Viremia , Humanos , Gravidez , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Alanina/administração & dosagem , Alanina/efeitos adversos , Amidas , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Tenofovir/análogos & derivados , Viremia/sangue , Viremia/diagnóstico , Viremia/tratamento farmacológico , Viremia/virologiaRESUMO
We characterized population pharmacokinetics in 42 African children receiving once-daily 25 mg (14 to <20 kg) or 50 mg (>20 kg) dolutegravir. Coadministration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95% confidence interval: 8.13%-30.8%) compared with zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/sangue , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/farmacocinética , Piperazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Criança , Masculino , Feminino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/administração & dosagem , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Pré-Escolar , Adolescente , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Didesoxinucleosídeos/farmacocinética , Didesoxinucleosídeos/uso terapêutico , Didesoxinucleosídeos/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Inibidores de Integrase de HIV/administração & dosagem , Alanina/farmacocinética , Alanina/análogos & derivados , Alanina/uso terapêutico , Disponibilidade Biológica , Quimioterapia Combinada , Zidovudina/farmacocinética , Zidovudina/uso terapêutico , Zidovudina/administração & dosagem , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Interações MedicamentosasRESUMO
AIMS: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. METHODS: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. DISCUSSION: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.
Assuntos
Adenina , Fármacos Anti-HIV , Interações Medicamentosas , Emtricitabina , Estradiol , Infecções por HIV , Piperazinas , Tenofovir , Pessoas Transgênero , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Emtricitabina/farmacocinética , Emtricitabina/administração & dosagem , Tenofovir/farmacocinética , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Adulto , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Alanina/farmacocinética , Alanina/administração & dosagem , Piridonas/administração & dosagem , Piridonas/farmacocinética , Estudos Longitudinais , Combinação de Medicamentos , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Pessoa de Meia-Idade , Adulto Jovem , Amidas/farmacocinética , Amidas/administração & dosagemRESUMO
INTRODUCTION: Rapid initiation of ART after HIV diagnosis is recommended for individual and public health benefits. However, certain clinical and ART-related considerations hinder immediate initiation of therapy. METHODS: An open-label, single-arm, single-centre 48-week prospective clinical trial involving ART-naïve HIV-diagnosed adults who started bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) within a week from the first hospital visit, before the availability of baseline laboratory and genotype results. The primary aim was to determine the proportion of people with at least one condition that would hinder immediate initiation of any recommended ART regimen other than BIC/FTC/TAF. Clinicaltrials.gov: NCT04416906. RESULTS: We included 100 participants: 79% men, 64% from Latin America, median age 32 years. According to European AIDS Clinical Society (EACS) and US Department of Health and Human Services 2023 guidelines, 11% (95%CI 6; 19) of participants had at least one condition that made any ART different from BIC/FTC/TAF less appropriate for a rapid ART strategy. Seventy-nine percent of the people started BIC/FTC/TAF within the first 48 hours of their first hospital visit. There were 16 early discontinuations (11 lost to follow-up). By week 48, 92% (95%CI 86; 98) of the participants of the ITT population with observed data achieved viral suppression. Eight grade 3-4 adverse events (AEs), five serious AEs and six ART-related AEs were identified. Adherence remained high. CONCLUSIONS: BIC/FTC/TAF is an optimal treatment for rapid initiation of ART. However, additional strategies to improve retention in care must be implemented.
Assuntos
Alanina , Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Masculino , Adulto , Estudos Prospectivos , Feminino , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Piridonas/administração & dosagem , Alanina/uso terapêutico , Alanina/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Piperazinas/administração & dosagem , Amidas/administração & dosagem , Amidas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Combinação de Medicamentos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Pessoa de Meia-Idade , Adulto Jovem , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: The ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort. METHODS: Data were pooled from retrospective and prospective cohorts of antiretroviral therapy (ART)-naïve (hereafter, TN) and ART-experienced (hereafter, TE) people with HIV (aged ≥21 years) receiving B/F/TAF in routine clinical care in the Republic of Korea, Singapore, and Taiwan. Analyses included effectiveness (primary endpoint: HIV-1 RNA <50 copies/ml, missing = excluded analysis), CD4 count, CD4/CD8 ratio, safety, treatment persistence, and patient-reported outcomes (prospective group). RESULTS: The analysis population included 328 participants (80 retrospective, 248 prospective; 65 TN, 263 TE). Participants were predominantly male (96.9% TN, 93.2% TE) with ≥1 comorbidity (52.3% TN, 57.8% TE); median age (years) was 31 (TN) and 42 (TE). Following 12 months of B/F/TAF, HIV-1 RNA was <50 copies/ml in 98.2% (54/55) of TN and 97.0% (227/234) of TE participants. Median (Q1, Q3) CD4 cell count increased by +187 (119, 291) cells/µl in the TN group (p < 0.001) and remained stable (+8 [-91, 110] cells/µl) in the TE group. B/F/TAF persistence was high in the prospective group, with 1/34 (2.9%) TN and 5/214 (2.3%) TE participants discontinuing treatment within 12 months. Drug-related adverse events occurred in 5.8% (19/328) of participants, leading to treatment discontinuation in 0.6% (2/328). CONCLUSIONS: Real-world evidence from BICSTaR supports the effectiveness, safety and tolerability of B/F/TAF in people with HIV in Asia.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , HIV-1 , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Feminino , Adulto , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Emtricitabina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Estudos Retrospectivos , Pessoa de Meia-Idade , Estudos Prospectivos , Piridonas/uso terapêutico , Resultado do Tratamento , Contagem de Linfócito CD4 , HIV-1/efeitos dos fármacos , HIV-1/genética , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Piperazinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adenina/efeitos adversos , Alanina/uso terapêutico , Alanina/análogos & derivados , Combinação de Medicamentos , Carga Viral/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Singapura/epidemiologia , Amidas/uso terapêutico , Taiwan , Estudos de Coortes , RNA Viral/sangueRESUMO
BACKGROUND: The rapid start of antiretroviral therapy (RSA) model initiates antiretroviral therapy (ART) as soon as possible after a new or preliminary diagnosis of HIV, in advance of HIV-1 RNA and other baseline laboratory testing. This observational study aims to determine if RSA with a single tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) is an effective regimen for achieving viral suppression and accepted by patients at the time of diagnosis. METHODS: Adults newly or preliminarily diagnosed with HIV were enrolled from October 2018 through September 2021. Real world advantage, measured in days between clinical milestones and time to virologic suppression, associated with B/F/TAF RSA was compared to historical controls. RESULTS: All Study RSA participants (n = 45) accepted treatment at their first visit and 43(95.6%) achieved virologic suppression by week 48. Study RSA participants had a significantly shorter time (median 32 days) from diagnosis to ART initiation and virologic suppression, in comparison to historical controls (median 181 days) (n = 42). Qualitative feedback from study RSA participants showed high acceptance positive response to RSA. CONCLUSIONS: RSA is feasible and well accepted by patients in a real-world community-based clinic setting. Promoting RSA in community-based clinics is an important tool in ending the HIV epidemic.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Projetos Piloto , Masculino , Feminino , Adulto , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Alanina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , HIV-1/efeitos dos fármacos , Piperazinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Carga Viral/efeitos dos fármacos , Amidas/uso terapêutico , RNA Viral/sangue , PiridonasRESUMO
A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).
Assuntos
Descoberta de Drogas , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Desenvolvimento de Medicamentos/métodos , Emtricitabina/uso terapêutico , SofosbuvirRESUMO
A lack of adherence to long-term antiretroviral therapy may impact viral suppression. The current study examined the relationship between medication adherence and clinical outcomes in people with human immunodeficiency virus infection (PWH) receiving bictegravir, emtricitabine, and tenofovir alafenamide fumarate (B/F/TAF). A retrospective cohort study using two Japanese claims databases was conducted. Adherence was measured by the proportion of days covered (PDC). Patients were grouped into 3 PDC category and persistence was estimated by Kaplan-Meier method. Cox regression analysis was performed to investigate whether the PDC was associated with treatment discontinuation. Among 952 patients, 820 (86.1%), 95 (10.0%), and 37 (3.9%) patients were grouped into the PDC ≥ 90%, 80- < 90%, and < 80% groups, respectively. Across all PDC groups, more than 90% of patients who received B/F/TAF were receiving treatment at 1 year. There was no significant difference in the risk of discontinuation between the lower PDC groups (80- < 90% and < 80%) and the PDC ≥ 90% group (0.400 [0.096, 1.661]; 2.244 [0.663, 7.594], hazard ratio [95% confidence interval], respectively). A drug resistance test was implemented for 15 patients, none of whom discontinued B/F/TAF after the test. The results suggest that events that could cause discontinuation, such as virologic failure, were not associated with PDC.