RESUMO
HIV pre-exposure prophylaxis trials with antiretroviral drugs have been variably successful. Even trials demonstrating the best efficacy leave room for improvement. Pharmacological data illuminate several sources of outcome variability, especially the impact of poor adherence, which is critical to manage PrEP in the clinic and to develop the next generation of PrEP candidates.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/metabolismo , Modelos Animais de Doenças , Humanos , Adesão à Medicação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
Assuntos
Fármacos Anti-HIV , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/imunologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Amplamente Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Método Duplo-Cego , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/efeitos adversos , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/isolamento & purificação , Humanos , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologiaRESUMO
HIV infection has been a severe global health burden, with millions living with the virus and continuing new infections each year. Antiretroviral therapy can effectively suppress HIV replication but requires strict lifelong adherence to daily oral medication regimens, which presents a significant challenge. Long-acting formulations of antiretroviral drugs administered infrequently have emerged as a promising strategy to improve treatment outcomes and adherence to HIV therapy and prevention. Long-acting injectable (LAI) formulations are designed to gradually release drugs over extended periods of weeks or months following a single injection. Critical advantages of LAIs over conventional oral dosage forms include less frequent dosing requirements, enhanced patient privacy, reduced stigma associated with daily pill regimens, and optimised pharmacokinetic/pharmacodynamic profiles. Several LAI antiretroviral products have recently gained regulatory approval, such as the integrase strand transfer inhibitor cabotegravir for HIV preexposure prophylaxis and the Cabotegravir/Rilpivirine combination for HIV treatment. A leading approach for developing long-acting antiretroviral depots involves encapsulating drug compounds in polymeric microspheres composed of biocompatible, biodegradable materials like poly (lactic-co-glycolic acid). These injectable depot formulations enable high drug loading with customisable extended-release kinetics controlled by the polymeric matrix. Compared to daily oral therapies, LAI antiretroviral formulations leveraging biodegradable polymeric microspheres offer notable benefits, including prolonged therapeutic effects, reduced dosing frequency for improved adherence, and the potential to kerb the initial HIV transmission event. The present manuscript aims to review the pathogenesis of the virus and its progression and propose therapeutic targets and long-acting drug delivery strategies that hold substantial promise for enhancing outcomes in HIV treatment and prevention.
Assuntos
Fármacos Anti-HIV , Preparações de Ação Retardada , Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Injeções , Adesão à Medicação , Composição de Medicamentos , Piridonas , DicetopiperazinasRESUMO
Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.
Assuntos
Terapia Combinada , Infecções por HIV/terapia , Recursos em Saúde , Necessidades e Demandas de Serviços de Saúde , Avaliação das Necessidades , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Saúde Global , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/imunologia , Humanos , Receptores CCR5/deficiência , Receptores CCR5/genética , Linfócitos T Citotóxicos/imunologiaRESUMO
Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20â mg) and elvitegravir (EVG, 16â mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.
Assuntos
Adenina , Alanina , Fármacos Anti-HIV , Quinolonas , Síndrome de Imunodeficiência Adquirida dos Símios , Tenofovir , Animais , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Feminino , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Alanina/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Fármacos Anti-HIV/administração & dosagem , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/farmacologia , Adenina/uso terapêutico , Vagina/virologia , Vagina/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Administração Intravaginal , Macaca mulatta , Modelos Animais de DoençasRESUMO
BACKGROUND: Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants. METHODS: Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50â copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200â copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30â kg/m2, lower; ≥30â kg/m2, higher). RESULTS: Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30â kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50â copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. CONCLUSIONS: CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category. CLINICAL TRIALS REGISTRATION: NCT02938520, NCT02951052, and NCT03299049.
Assuntos
Fármacos Anti-HIV , Índice de Massa Corporal , Infecções por HIV , HIV-1 , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Rilpivirina/administração & dosagem , Rilpivirina/efeitos adversos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , HIV-1/efeitos dos fármacos , Feminino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Adulto , Pessoa de Meia-Idade , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Carga Viral/efeitos dos fármacos , RNA Viral/sangue , Resultado do Tratamento , Quimioterapia Combinada , DicetopiperazinasRESUMO
BACKGROUND: Obesity is increasingly prevalent among people with human immunodeficiency virus (HIV, PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in silico trials using physiologically based pharmacokinetic (PBPK) modeling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. METHODS: Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/ overweight (body mass index [BMI] <30â kg/m2) and in obese (BMI >30â kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60â kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (area under the curve [AUC]) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25â kg/m2). RESULTS: Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35â kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40â kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration, but this was less frequent with the monthly administration. CONCLUSIONS: Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Obesidade , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Rilpivirina/uso terapêutico , Piridonas/farmacocinética , Piridonas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Índice de Massa Corporal , Simulação por Computador , DicetopiperazinasRESUMO
BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for human immunodeficiency virus type 1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merit further evaluation. METHODS: We performed an in-depth clinical, virological, and pharmacokinetic analysis on the reasons behind and the impact of VF during LA CAB/RPV therapy in 5 cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF, and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cutoff (≤Q1) were considered to be low. RESULTS: Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of nonnucleoside reverse transcriptase inhibitor-associated mutations in all cases, and integrase strand transfer inhibitor mutations in 4 cases. All cases displayed low drug levels of either CAB, RPV, or both during the treatment course, likely contributing to the occurrence of VF. In 3 cases, we were able to identify the potential mechanisms behind these low drug levels. CONCLUSIONS: This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological, and pharmacokinetic approach in case of failure.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Piridonas , Rilpivirina , Falha de Tratamento , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Masculino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/genética , Pessoa de Meia-Idade , Adulto , Feminino , Países Baixos , Carga Viral/efeitos dos fármacos , Genótipo , DicetopiperazinasRESUMO
BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV. METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV (400 mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50â copies/mL) at 48 weeks per US Food and Drug Administration Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression, and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (P < .001), respectively, discontinued treatment because of adverse effects, death, or lost to follow-up. The median increase of CD4 count was 181 and 223â cells/µL (P = .020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < .001). CONCLUSIONS: BIC/FTC/TAF was more efficacious and safer than EFV (400 mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.
Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , Emtricitabina , Infecções por HIV , Homossexualidade Masculina , Lamivudina , Tenofovir , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Adulto , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , China , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Ciclopropanos/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Alcinos/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Benzoxazinas/uso terapêutico , Alanina/uso terapêutico , Pessoa de Meia-Idade , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Contagem de Linfócito CD4 , Dioxolanos/uso terapêutico , Dioxolanos/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Carga Viral , Adulto Jovem , Combinação de Medicamentos , HIV-1/efeitos dos fármacos , Amidas , PiridonasRESUMO
A case of a male with human immunodeficiency virus with plasma genotyping detecting no resistance and a CRF02_AG subtype had a controlled HIV RNA on antiretroviral therapy since 2010. We introduced intramuscular therapy with cabotegravir and rilpivirine. One month later, his HIV RNA was 1500 copies/mL; genotyping found a subtype B with many mutations.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Piridonas , Rilpivirina , Superinfecção , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/administração & dosagem , Masculino , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/complicações , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Superinfecção/tratamento farmacológico , Superinfecção/virologia , Superinfecção/diagnóstico , Injeções Intramusculares , HIV-1/genética , HIV-1/efeitos dos fármacos , Genótipo , Adulto , Carga Viral/efeitos dos fármacos , RNA Viral/genética , DicetopiperazinasRESUMO
People with human immunodeficiency virus (HIV) are at risk for chronic kidney disease (CKD) due to HIV and antiretroviral therapy (ART) nephrotoxicity. Immediate ART initiation reduces mortality and is now the standard of care, but the long-term impact of prolonged ART exposure on CKD is unknown. To evaluate this, the Strategic Timing of Antiretroviral Treatment (START) trial randomized 4,684 ART-naïve adults with CD4 cell count under 500 cells/mm3 to immediate versus deferred ART. We previously reported a small but statistically significantly greater decline in estimated glomerular filtration rate (eGFR) over a median of 2.1 years in participants randomized to deferred versus immediate ART. Here, we compare the incidence of CKD events and changes in eGFR and urine albumin/creatinine ratio (UACR) in participants randomized to immediate versus deferred ART during extended follow-up. Over a median of 9.3 years, eight participants experienced kidney failure or kidney-related death, three in the immediate and five in the deferred ART arms, respectively. Over a median of five years of more comprehensive follow-up, the annual rate of eGFR decline was 1.19 mL/min/1.73m2/year, with no significant difference between treatment arms (difference deferred - immediate arm 0.055; 95% confidence interval -0.106, 0.217 mL/min/1.73m2). Results were similar in models adjusted for baseline covariates associated with CKD, including UACR and APOL1 genotype. Similarly, there was no significant difference between treatment arms in incidence of confirmed UACR 30 mg/g or more (odds ratio 1.13; 95% confidence interval 0.85, 1.51). Thus, our findings provide the most definitive evidence to date in support of the long-term safety of early ART with respect to kidney health.
Assuntos
Taxa de Filtração Glomerular , Infecções por HIV , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Taxa de Filtração Glomerular/efeitos dos fármacos , Pessoa de Meia-Idade , Adulto , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de Tempo , Incidência , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Rim/fisiopatologia , Rim/efeitos dos fármacos , Contagem de Linfócito CD4 , Albuminúria/epidemiologia , Tempo para o Tratamento , Creatinina/sangue , Creatinina/urina , Esquema de Medicação , Resultado do Tratamento , Fatores de Risco , Apolipoproteína L1/genéticaRESUMO
A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Masculino , Feminino , HIV-1/efeitos dos fármacos , Pessoa de Meia-Idade , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Combinação de MedicamentosRESUMO
BACKGROUND: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).
Assuntos
Fármacos Anti-HIV/administração & dosagem , Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Tenofovir/administração & dosagem , Zidovudina/administração & dosagem , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Criança , Darunavir/efeitos adversos , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Carga Viral , Adulto JovemRESUMO
OBJECTIVES: HIV pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but some seroconversions occur due to poor adherence or PrEP discontinuation. Our objective was to estimate the incidence of PrEP discontinuation and describe the reasons and factors associated with discontinuations. METHODS: A retrospective cohort was conducted in three French hospitals between January 2016 and June 2022. PrEP users who attended at least twice within 6â months during study period were included and followed up until December 2022. The incidence rate of PrEP discontinuation was estimated by censoring lost to follow up individuals. Factors associated with PrEP discontinuations were identified using a multivariate Cox model. RESULTS: A total of 2785 PrEP users were included, with 94% men and 5% transgender people. Median age was 35â years. By December 2022, 653 users had stopped PrEP (24%). The incidence rate was 10.8 PrEP discontinuations for 100 person-years (PY). The main causes of discontinuation were being in a stable relationship (32%), and not judging the treatment useful anymore (12%). Individuals who discontinued PrEP were younger [<29, HRâ=â1.45 (1.17-1.80)], and more likely to be women [HRâ=â2.44 (1.50-3.96)] or sex workers [HRâ=â1.53 (0.96-2.44)]. They were more likely to report PrEP side effects [HRâ=â2.25 (1.83-2.77)] or ≥2 sexually transmitted infections [HRâ=â1.87 (1.53-2.27)] during the last year. CONCLUSION: The incidence of PrEP discontinuations was quite low compared to rates observed in other cohorts. Users who stopped PrEP were sometimes still exposed to HIV, emphasizing the need for targeted interventions to prepare and support PrEP discontinuations and limit seroconversion risk.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Humanos , França/epidemiologia , Feminino , Masculino , Adulto , Infecções por HIV/prevenção & controle , Infecções por HIV/epidemiologia , Profilaxia Pré-Exposição/estatística & dados numéricos , Estudos Retrospectivos , Incidência , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48â weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. METHODS: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48â weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48â weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. RESULTS: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. CONCLUSIONS: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.
Assuntos
Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Masculino , Oxazinas/uso terapêutico , Feminino , Adulto , Pessoa de Meia-Idade , Metabolômica , Lipidômica , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Plasma/química , Proteômica , Terapia Antirretroviral de Alta Atividade , Substituição de Medicamentos , Triglicerídeos/sangue , Alanina/sangue , MultiômicaRESUMO
OBJECTIVES: Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study. METHODS: Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the 'ON-treatment period' (Day 3 or 4 of the 4-day treatment block) and the 'OFF-treatment period' (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96. RESULTS: W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR)â=â64-112) for 4/7 arm versus 130 ng/mL (82-160) for 7/7 arm, Pâ<â0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73-135) for 4/7 arm versus 117 ng/mL (83-160) for 7/7 arm, Pâ<â0.001; tenofovir alafenamide: 11 ng/mL (7-15) for 4/7 arm versus 14 ng/mL (11-18) for 7/7 arm, Pâ=â0.001]. Median OFF concentrations were significantly lower (Pâ<â0.001) at the 48 week analysis for all medications except for raltegravir (Pâ=â0.493) and atazanavir (Pâ=â0.105), for which the numbers of patients were very small. CONCLUSIONS: The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/sangue , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos/métodos , Terapia Antirretroviral de Alta Atividade , Quimioterapia de Manutenção/métodos , Resultado do Tratamento , Carga Viral , Tenofovir/sangue , Tenofovir/uso terapêutico , Tenofovir/farmacocinética , Tenofovir/administração & dosagemRESUMO
OBJECTIVE: Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment. METHODS: Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated. RESULTS: Sixty-seven PWH were identified. LAI treatment duration was 216â±â80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; Pâ<â0.05). No differences were found in rilpivirine (160â±â118 versus 189â±â81 ng/mL; Pâ=â0.430) and cabotegravir (1758â±â807 versus 1969â±â802 ng/mL; Pâ=â0.416) trough concentrations in males (nâ=â55) versus females (nâ=â12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (nâ=â9) versus non-obese participants (1916â±â905 versus 1606â±â576 ng/mL; Pâ=â0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load. CONCLUSIONS: At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.
Assuntos
Fármacos Anti-HIV , Dicetopiperazinas , Infecções por HIV , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Rilpivirina/uso terapêutico , Rilpivirina/sangue , Masculino , Feminino , Infecções por HIV/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Piridonas/farmacocinética , Piridonas/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Idoso , Injeções , Carga Viral/efeitos dos fármacosRESUMO
OBJECTIVES: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART. METHODS: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50â years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan-Meier curves and Cox regression models. RESULTS: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8â weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50â years had 1.83-fold (95% CI: 1.19-2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53-3.82) higher risk; there were no differences in TF according to sex.Over a median follow-up of 146.3â weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest. CONCLUSIONS: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos de 4 ou mais Anéis , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Estudos de Coortes , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Adulto , Piridonas/uso terapêutico , Resultado do Tratamento , Alanina/uso terapêutico , Amidas/uso terapêutico , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Adenina/análogos & derivados , Adenina/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Carga Viral/efeitos dos fármacos , Combinação de Medicamentos , Substituição de MedicamentosRESUMO
BACKGROUND: The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is based on the results of robust clinical trials. OBJECTIVES: To assess the effectiveness and safety of BIC/FTC/TAF in treatment-naïve (TN) and treatment-experienced (TE) people with HIV using available real-world cohort studies. METHODS: Systematic review and meta-analysis of publications and communications identified via Boolean search in Medline, PubMed and Embase, and conference abstracts reporting retrospective real-world use of BIC/FTC/TAF, published until 31 January 2024. The primary endpoint was the proportion of TN and TE people with HIV with viral load (VL)â<â50â copies/mL at 48â weeks while on treatment. RESULTS: Of the 38 identified publications and conference abstracts, for the present analysis we included 12 publications (comprising 792 TN and 6732 TE individuals). For the three publications including 507 TN participants reporting the primary outcome, VL suppression was 97% [95% confidence intervals (CI): 89-100]. For the nine publications including 4946 TE participants reporting the primary outcome, VL suppression was 95% (95% CI: 94-96), with suppression >93% in all studies. Total discontinuations at 48â weeks in TE individuals were 3% (95% CI: 2-5), 1% (95% CI: 0-2) due to side effects. A total of four publications with 151 TE individuals with previous presence of M184V substitution were identified, reporting a suppression rate at 48â weeks of 95% (95% CI: 88-100). CONCLUSIONS: Real-world studies demonstrate low discontinuation rates and high rates of virologic suppression in individuals treated with BIC/FTC/TAF, both TN and TE with and without previous detection of M184V substitution.
Assuntos
Alanina , Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis , Tenofovir , Carga Viral , Humanos , Infecções por HIV/tratamento farmacológico , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Alanina/uso terapêutico , Carga Viral/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Combinação de Medicamentos , Amidas/uso terapêutico , Piperazinas , Piridonas , Adenina/análogos & derivados , Adenina/uso terapêutico , Adenina/efeitos adversos , Adenina/administração & dosagem , Resultado do Tratamento , HIV-1/efeitos dos fármacos , HIV-1/genética , Estudos RetrospectivosRESUMO
OBJECTIVES: The inJectable Antiretroviral feasiBility Study (JABS) aimed to evaluate the implementation of long-acting regimens in a 'real world' Australian setting, with inclusion of participants with complex medical needs, social vulnerability and/or historical non-adherence. METHODS: JABS was a 12-month, single-centre, single-arm, open-label phase IV study of long-acting cabotegravir 600 mg plus rilpivirine 900 mg administered intramuscularly every 2 months to adults with treated HIV-1 infection. The primary endpoint was the proportion of attendances and administration of injections within a 14-day dosing window over 12 months, out of the total prescribed doses. Secondary endpoints included proportions of missed appointments, use of oral bridging, discontinuations, virological failures, adverse events and participant-reported outcomes. A multidisciplinary adherence programme embedded in the clinical service known as REACH provided support to JABS participants. RESULTS: Of 60 participants enrolled by May 2022, 60% had one or more complexity or vulnerability factors identified, including absence of social supports (50%), mental health issues, alcohol or drug use (30%) and financial hardship or instability (13%), among others. Twenty-seven per cent of participants had historical non-adherence to antiretroviral therapy. Out of 395 prescribed doses, 97.2% of injections were administered within correct dosing windows at clinic visits. Two courses of short-term oral bridging were required. The rate of injection site reactions was 29%, the majority being grade 1-2. There were no virological failures, no serious adverse events and only one injection-related study discontinuation. High baseline treatment satisfaction and acceptability of injections increased by month 12. Those with vulnerability factors had similar adherence to injections as those without such factors. Ninety-eight per cent of the participants who completed 12 months on the study have maintained long-acting therapy, virological suppression and retention in care. CONCLUSIONS: Long-acting cabotegravir plus rilpivirine was associated with very high adherence, maintenance of virological suppression, safety and treatment satisfaction in a diverse Australian clinic population, comparable to results of phase III randomized clinical trials. Individuals with vulnerability factors can achieve adherence to injections with individualized support. Long-acting therapies in this group can increase the subsequent engagement in clinical care.