RESUMEN
BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de la Proteasa del VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Nacimiento Prematuro , Piridonas , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/efectos adversos , Sulfato de Atazanavir/uso terapéutico , Cobicistat/efectos adversos , Cobicistat/uso terapéutico , Estudios de Cohortes , Darunavir/efectos adversos , Darunavir/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Recién Nacido , Oxazinas/efectos adversos , Oxazinas/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Embarazo , Nacimiento Prematuro/inducido químicamente , Piridonas/efectos adversos , Piridonas/uso terapéutico , Quinolonas/efectos adversos , Quinolonas/uso terapéutico , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/uso terapéutico , Rilpivirina/efectos adversos , Rilpivirina/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Estados UnidosRESUMEN
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.
Asunto(s)
Infecciones por VIH , Inhibidores de la Proteasa del VIH , VIH-1 , Humanos , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , Darunavir/farmacología , Darunavir/uso terapéutico , Sulfato de Atazanavir/farmacología , Sulfato de Atazanavir/uso terapéutico , Farmacorresistencia Viral , VIH-1/genética , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Proteasa del VIH/genética , Proteasa del VIH/metabolismoRESUMEN
BACKGROUND: Maintenance monotherapy with ritonavir-boosted darunavir has yielded variable outcomes and is not recommended. Trial samples offer valuable opportunities for detailed studies. We analysed samples from a 48 week trial in Cameroon to obtain a detailed characterization of drug resistance. METHODS: Following failure of NNRTI-based therapy and virological suppression on PI-based therapy, participants were randomized to ritonavir-boosted darunavir (n = 81) or tenofovir disoproxil fumarate/lamivudine +ritonavir-boosted lopinavir (n = 39). At study entry, PBMC-derived HIV-1 DNA underwent bulk Protease and Reverse Transcriptase (RT) sequencing. At virological rebound (confirmed or last available HIV-1 RNA ≥ 60 copies/mL), plasma HIV-1 RNA underwent ultradeep Protease and RT sequencing and bulk Gag-Protease sequencing. The site-directed mutant T375A (p2/p7) was characterized phenotypically using a single-cycle assay. RESULTS: NRTI and NNRTI resistance-associated mutations (RAMs) were detected in 52/90 (57.8%) and 53/90 (58.9%) HIV-1 DNA samples, respectively. Prevalence in rebound HIV-1 RNA (ritonavir-boosted darunavir, n = 21; ritonavir-boosted lopinavir, n = 2) was 9/23 (39.1%) and 10/23 (43.5%), respectively, with most RAMs detected at frequencies ≥15%. The resistance patterns of paired HIV-1 DNA and RNA sequences were partially consistent. No darunavir RAMs were found. Among eight participants experiencing virological rebound on ritonavir-boosted darunavir (n = 12 samples), all had Gag mutations associated with PI exposure, including T375N, T375A (p2/p7), K436R (p7/p1) and substitutions in p17, p24, p2 and p6. T375A conferred 10-fold darunavir resistance and increased replication capacity. CONCLUSIONS: The study highlights the high resistance barrier of ritonavir-boosted darunavir while identifying alternative pathways of resistance through Gag substitutions. During virological suppression, resistance patterns in HIV-1 DNA reflect treatment history, but due to technical and biological considerations, cautious interpretation is warranted.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de la Proteasa del VIH , Humanos , Darunavir/farmacología , Darunavir/uso terapéutico , Ritonavir/farmacología , Ritonavir/uso terapéutico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Lopinavir/farmacología , Lopinavir/uso terapéutico , Péptido Hidrolasas/uso terapéutico , Leucocitos Mononucleares , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , Mutación , ARN/uso terapéutico , ADN/uso terapéutico , Resistencia a Medicamentos , Carga ViralRESUMEN
BACKGROUND: Ritonavir-boosted darunavir (DRV/r) is a preferred protease inhibitor in pregnant women living with HIV. Current practice at British Columbia's referral centre (the Oak Tree Clinic) is to dose DRV/r as 800/100 mg daily throughout pregnancy, although some guidelines recommend DRV/r 600/100 mg twice daily due to altered pharmacokinetics with once-daily dosing. OBJECTIVES: We describe the effect of once-daily DRV/r on viral suppression, vertical transmission, adverse drug effects and adherence in pregnant women living with HIV. METHODS: This was a retrospective analysis of pregnant women living with HIV in British Columbia. Eligible women gave birth between January 2015 and August 2021, and took DRV/r 800/100 mg daily at any time during pregnancy. RESULTS: Thirty-four women were included in this study. The mean (SD) age was 33 (5) years. Thirty (88%) women were diagnosed with HIV prior to pregnancy, with 22 (73%) having viral suppression at baseline. Four (12%) were diagnosed in pregnancy, with a median baseline viral load of 9616 copies/mL (range 8370-165 000). Viral suppression was achieved by 16 (100%), 24 (75%) and 26 (74%) women in the first, second and third trimesters, respectively. No vertical transmission occurred. This combination was well tolerated, with adverse drug effects that did not result in discontinuation or change in therapy. Most women maintained >75% adherence to once-daily DRV/r at all times during pregnancy. CONCLUSIONS: Ritonavir-boosted darunavir 800/100 mg daily appears to be an appropriate dosing strategy for pregnant women living with HIV who are able to maintain optimal adherence.
Asunto(s)
Fármacos Anti-VIH , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Infecciones por VIH , Inhibidores de la Proteasa del VIH , VIH-1 , Humanos , Femenino , Embarazo , Adulto , Masculino , Darunavir/uso terapéutico , Ritonavir , Estudios Retrospectivos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
Asunto(s)
Carbamazepina , Darunavir , Interacciones Farmacológicas , Infecciones por VIH , Humanos , Darunavir/uso terapéutico , Darunavir/farmacocinética , Masculino , Persona de Mediana Edad , Carbamazepina/uso terapéutico , Carbamazepina/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Neuralgia del Trigémino/tratamiento farmacológico , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/administración & dosificación , Piridonas/farmacocinética , Piridonas/uso terapéutico , Piridonas/sangre , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/farmacocinética , Oxazinas/uso terapéutico , Oxazinas/farmacocinética , Relación Dosis-Respuesta a Droga , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Monitoreo de Drogas/métodosRESUMEN
Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. The aim of the study was to investigate the plasma levels of RA after 12 weeks of use and determine potential interactions of RA and selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which the RA concentrations in the plasma samples were analyzed. A detailed in silico analysis was conducted in order to elucidate the potential interactions between RA and the drugs efavirenz, darunavir and raltegravir. It was found that RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. The potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The present study suggests that the simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir or raltegravir) may affect the plasma levels of RA after prolonged supplementation.
Asunto(s)
Alquinos , Fármacos Anti-VIH , Benzoxazinas , Ciclopropanos , Infecciones por VIH , Humanos , Raltegravir Potásico/uso terapéutico , Darunavir/farmacocinética , Darunavir/uso terapéutico , Ácido Rosmarínico , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Niño , Humanos , Ritonavir/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Lopinavir/uso terapéutico , Darunavir/uso terapéutico , Tenofovir/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Antivirales/uso terapéutico , Fumaratos/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: SMILE, a multicentre randomized trial, compared the efficacy and safety of switching virologically suppressed children and adolescents with HIV to a once-daily dual regimen of dolutegravir plus ritonavir-boosted darunavir versus continuing standard ART. Within a nested pharmacokinetic (PK) substudy, we performed a population PK analysis to describe total and unbound dolutegravir plasma concentrations in children and adolescents receiving this dual therapy. METHODS: Sparse blood samples were obtained during follow-up for dolutegravir quantification. A population PK model was developed to simultaneously describe total and unbound dolutegravir concentrations. Simulations were performed and were compared with the protein-adjusted 90% inhibitory concentration (IC90) and the in vitro IC50, respectively. Dolutegravir exposures in children aged ≥12 years were also compared with values in treatment-experienced adults. RESULTS: Four hundred and fifty-five samples from 153 participants aged between 12 and 18 years were collected for this PK analysis. A one-compartment model with first-order absorption and elimination best described unbound dolutegravir concentrations. The relationship between unbound and total dolutegravir concentrations was best characterized by a non-linear model. Unbound dolutegravir apparent clearance was significantly influenced by total bilirubin concentrations and by Asian ethnicity. All children and adolescents had trough concentrations well above the protein-adjusted IC90 and the in vitro IC50 values. Dolutegravir concentrations and exposures were also similar to those obtained in adults receiving dolutegravir 50 mg once daily. CONCLUSIONS: A once-daily 50 mg dolutegravir dose for children and adolescents produces adequate total and unbound concentrations when used as part of dual therapy with ritonavir-boosted darunavir.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Adolescente , Humanos , Niño , Darunavir/uso terapéutico , Ritonavir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , Piridonas/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of the two-pill regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat as a switching strategy in heavily treatment-experienced people living with HIV (PLWH). METHODS: Multicentre, prospective, single-arm pilot clinical trial. Participants were virologically suppressed adults receiving a stable antiretroviral regimen of at least three pills from at least three drug families due to previous virological failures and/or toxicities with no documented resistance to integrase strand transfer inhibitors or darunavir (≥15 points, Stanford). Clinical and laboratory assessments were performed at 0, 4, 12, 24, 36 and 48 weeks. HIV-1 proviral DNA was amplified and sequenced by Illumina at baseline. Plasma bictegravir concentrations were determined in 22 patients using UHPLC-MS/MS. The primary study endpoint was viral load (VL)<â50 copies/mL at Week 48 (ITT). RESULTS: We enrolled 63 participants (92% men) with median baseline CD4 count of 515 cells/mm3 (IQR: 334.5-734.5), 24 years on ART (IQR: 15.9-27.8). The median number of pills was 4 (range: 3-10). At baseline, proviral DNA was amplified in 39 participants: 33/39 had resistance mutations. Three participants discontinued owing to toxicity. At 48 weeks, 95% had VLâ<â50 copies/mL by ITT and 100% by PP analysis. A modest increase was observed in the bictegravir plasma concentration, and a significant decrease in estimated glomerular filtration rate was observed only at Week 4, probably related to interaction with renal transporters. CONCLUSIONS: Our data suggest that BIC/FTC/TAFâ+âdarunavir/cobicistat is an effective, well-tolerated regimen that may improve convenience and, potentially, long-term success in stable heavily pre-treated PLWH.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Femenino , Humanos , Masculino , Adenina/uso terapéutico , Alanina/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/uso terapéutico , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , ADN/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Estudios Prospectivos , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: Our objective was to evaluate the prevalence of pre-existing neurological and/or psychiatric comorbidities (NPCs) and efficacy/safety outcomes for participants with versus without baseline NPCs in AMBER and EMERALD. METHODS: AMBER (treatment-naïve population) and EMERALD (virologically suppressed population) were phase III randomized studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. The primary objective of this post hoc analysis was to assess virological response (HIV-1 RNA <50 copies/mL) at week 48 by intent-to-treat US Food and Drug Administration snapshot analysis comparing participants with and without baseline NPCs. RESULTS: Among participants in AMBER, 88/362 (24%) in the D/C/F/TAF arm and 99/363 (27%) in the control arm had baseline NPCs; in EMERALD, 294/763 (39%; D/C/F/TAF) and 166/378 (44%; control) participants had baseline NPCs. At baseline, psychiatric NPCs were more common than neurological NPCs in both studies; the most common of each type were depression and headache, respectively. High virological response rates were achieved with D/C/F/TAF across studies regardless of baseline NPCs at weeks 48 (range 86%-95%) and 96 (range 80%-91%). No participants in either study with a baseline NPC prematurely discontinued because of a study drug-related neurological or psychiatric adverse event. CONCLUSION: D/C/F/TAF may be a suitable treatment option for individuals with HIV-1 and NPCs.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Cobicistat/efectos adversos , Darunavir/uso terapéutico , Combinación de Medicamentos , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológicoRESUMEN
OBJECTIVES: Our objective was to compare the immunological responses to commonly used antiretroviral therapy (ART) regimens among people with advanced HIV in the USA and to assess virological outcomes and regimen persistence. METHODS: This study included ART-naïve adults with advanced HIV infection (CD4 cell count <200 cells/µL) initiating ART with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), boosted darunavir (bDRV), dolutegravir (DTG), or elvitegravir (EVG/c)-containing regimens between 1 January 2018 and 31 December 2020 in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. Cox proportional hazards models and linear mixed models with random intercept were fit with inverse probability of treatment weighting. RESULTS: Overall, 1349 people with advanced HIV (816 B/F/TAF, 253 DTG, 146 EVG/c, 134 bDRV) were followed for a median of 22 months. Compared with B/F/TAF, a lower likelihood of achieving a CD4 cell count ≥200 cells/µL was observed with bDRV (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96), DTG (HR 0.82; 95% CI 0.69-0.98), and EVG/c (HR 0.73; 95% CI 0.57-0.93). All groups had a similar pattern of CD4:CD8 ratio changes: a rapid increase in the first 6 months (ranging from +0.15 to +0.16 units), followed by a slower increase thereafter. Only 40 individuals (4%) achieved CD4:CD8 ratio normalization (≥1). B/F/TAF was associated with a faster time to virological suppression (viral load <200 copies/mL) and a slower time to discontinuation compared with other regimens. CONCLUSIONS: Among people with advanced HIV infection, B/F/TAF initiation was associated with faster CD4 cell count recovery and favourable virological outcomes compared with bDRV-, DTG-, and EVG/c-based regimens, although no difference was observed in CD4:CD8 ratio changes over time across regimens.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Humanos , Infecciones por VIH/tratamiento farmacológico , Tenofovir/uso terapéutico , Combinación de Medicamentos , Darunavir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Inmunidad , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéuticoRESUMEN
As the introduction of antiretroviral therapy (ART) during primary HIV-1 infection (PHI) could restrict the establishment of HIV reservoirs, we aimed to assess the effect of three different ART regimens on HIV-DNA load in people living with HIV (PLWH), who started ART in PHI. Randomized, open-label, multicentric study, including subjects in PHI (defined as an incomplete HIV-1 Western blot and detectable plasma HIV-RNA) in the Italian Network of Acute HIV Infection cohort. Participants were randomly assigned (10:10:8) to a fixed-dose combination of tenofovir alafenamide fumarate (TAF) 10 mg plus emtricitabine (FTC) 200 mg, darunavir 800 mg, and cobicistat 150 mg once daily (group A), or TAF 25 mg plus FTC 200 mg, dolutegravir 50 mg once daily (group B), or an intensified four-drug regimen (TAF 10 mg plus FTC 200 mg, dolutegravir 50 mg, darunavir 800 mg, and cobicistat 150 mg once daily) (group C). The primary endpoint was the decrease of HIV-DNA copies/106 peripheral blood mononuclear cells (PBMCs) at weeks (W) 12 and 48. Secondary endpoints were increased in CD4+ cells and in CD4+/CD8+ ratio and percentage of PLWH reaching undetectable HIV-RNA. HIV-DNA was quantified by Droplet Digital PCR (Biorad QX100) and normalized to RPP30 reference gene. This study was registered in ClinicalTrials.gov (number NCT04225325). Among 78 participants enrolled, 30 were randomized to group 1, 28 to group 2, and 20 to group 3. At baseline, median CD4+ count was 658/µL (476-790), HIV-RNA 5.37 (4.38, 6.12) log10 copies/mL, without statistical difference in their change among groups at weeks 12 and 48 (p = 0.432 and 0.234, respectively). The trial was prematurely discontinued for slow accrual and for COVID-19 pandemic-associated restrictions. In the per-protocol analysis, PLWH (n = 72) with undetectable viral load was 54.3% at W12 and 86.4% at W48. Interestingly, the CD4/CD8 ratio progressively increased over time, up to normalization in almost half of the cohort by week 48, despite a deflection in group 3; no difference was observed by the Fiebig stage (I-III vs. IV-VI). HIV-DNA decreased from 4.46 (4.08, 4.81) log10 copies/106 PBMCs to 4.22 (3.79, 4.49) at week 12, and 3.87 (3.46, 4.34) at week 48, without difference among groups. At multivariable analysis, HIV-DNA delta at W48 was associated only with the increase of CD4+ count by 100 cells/mm3 but not with the Fiebig stage, the CD4+/CD8+ ratio, and treatment arm, despite a higher decrease in group 3. Six adverse events were recorded during our study, which did not cause any withdrawal from the study. We observed a decrease in HIV-DNA from baseline to W48 in PLWH treated during PHI, associated with an increase in CD4+ count, unrelated to the treatment arm.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Leucocitos Mononucleares , ARN/sangre , Tenofovir/uso terapéutico , Carga ViralRESUMEN
Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Raltegravir Potásico/uso terapéutico , Darunavir/uso terapéutico , Ritonavir/uso terapéutico , VIH-1/genética , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Seropositividad para VIH/tratamiento farmacológico , ARN , Carga Viral , Farmacorresistencia Viral , Resultado del TratamientoRESUMEN
INTRODUCTION: In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants. METHODS: All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval. RESULTS: Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs. CONCLUSIONS: ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Femenino , Humanos , Lactante , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Estudios de Cohortes , Darunavir/uso terapéutico , Leche Humana , Madres , Estudios Prospectivos , Raltegravir Potásico/uso terapéutico , Rilpivirina/uso terapéutico , Ritonavir/uso terapéutico , SuizaRESUMEN
BACKGROUND: Whether integrase strand transfer inhibitors (INSTIs) can decrease HIV-1 DNA levels more rapidly than boosted PIs during primary HIV-1 infection (PHI) is unknown. We hypothesized that once-daily dolutegravir/tenofovir/emtricitabine could reduce the viral reservoir through rapid viral replication control further than once-daily darunavir/cobicistat/tenofovir/emtricitabine. METHODS: The OPTIPRIM2-ANRS 169 study was a randomized (1:1), open-label, multicentre trial in adults with ≤5 or ≤3 HIV antibodies detected, respectively, by western blot or immunoblot in the last 10â days. The primary endpoint was total HIV-1 DNA levels in PBMCs at Week 48 (W48) adjusted for baseline levels. The main secondary endpoint was HIV-1 RNA level decrease. RESULTS: Between April 2017 and August 2018, 101 patients were included from 31 hospitals. Most patients were men (93%), the median age was 36â years and 17% were Fiebig stage ≤3. The median (IQR) plasma HIV-1 RNA and DNA levels were, respectively, 5.8 (5.0-6.6) and 3.87 (3.52-4.15)â log10 copies/million PBMCs. The median (IQR) decreases in HIV-1 DNA levels at W48 were -1.48 (-1.74 to -1.06) and -1.39 (-1.55 to -0.98)â log10 copies/million PBMCs in the dolutegravir and darunavir/cobicistat groups, respectively (Pâ=â0.52). Plasma HIV-1 RNA levels were <50â copies/mL in 24% versus 0% of patients in the dolutegravir and darunavir/cobicistat groups at W4, 55% versus 2% at W8, 67% versus 17% at W12, and 94% versus 90% at W48, respectively. CONCLUSIONS: Dolutegravir-based and darunavir-based regimens initiated during PHI strongly and similarly decreased the blood reservoir size. Considering the rapid viral suppression during a period of high HIV-1 transmission risk, dolutegravir-based regimens are a major first-line option.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas/uso terapéutico , ARN/uso terapéutico , Tenofovir/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: Dolutegravir is a widespread integrase strand-transfer inhibitor (INSTI) recommended for treatment of primary HIV infection (PHI). PHI is a high-risk stage for sexual transmission because of the high viral load in semen. Yet dolutegravir concentrations in semen are lower than in blood during chronic treatment. OBJECTIVES: To compare the kinetics of HIV-RNA and total HIV-DNA in the genital compartment in subjects receiving either tenofovir/emtricitabine/dolutegravir or tenofovir/emtricitabine/darunavir/cobicistat as a first-line combined ART (cART) at the time of PHI. PATIENTS AND METHODS: Eighteen subjects receiving tenofovir/emtricitabine/dolutegravir and 19 receiving tenofovir/emtricitabine/darunavir/cobicistat enrolled in the ANRS169 OPTIPRIM-2 trial participated in the genital substudy. RESULTS: Between week (W) 0 and W2 HIV-RNA in seminal plasma (SP) decreased by 1 log10 copies/mL. Undetectable SP HIV-RNA was achieved in similar proportions between the two regimens at each timepoint. Overall, eight patients still presented detectable HIV-RNA or HIV-DNA in semen at W48; 15.4% and 28.6% presented detectable HIV-RNA and 9.1% and 14.3% presented detectable HIV-DNA in dolutegravir- and darunavir-based cART groups, respectively, with no significant difference. CONCLUSIONS: For the first time, to the best of our knowledge, we showed that a dolutegravir-based regimen initiated as soon as PHI reduces HIV-RNA and HIV-DNA with no difference compared with a control group receiving a darunavir-based regimen. Although the viral purge in semen seems longer after treatment in PHI than CHI, due to high viral loads, early dolutegravir-based treatment initiation permits a major decay of both viral particles and infected cells in semen, efficiently reducing the high risk of transmission during PHI.
Asunto(s)
Infecciones por VIH , VIH-1 , ADN , Darunavir/uso terapéutico , Genitales , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , ARN ViralRESUMEN
The DUALIS study demonstrated efficacy and safety of switching to dolutegravir plus ritonavir-boosted darunavir (DRV/r) (2DR) as compared to standard-of-care-therapy with two nucleoside reverse transcriptase inhibitors + DRV/r (3DR) in pretreated people living with HIV (PLWH), 48 weeks after switching. This DUALIS sub-study investigates health-related-quality-of-life (HrQoL) in this study-population. The Hospital Anxiety and Depression Scale (HADS) and the Medical Outcome Survey-HIV (MOS-HIV) were used assessing anxiety and depression symptoms, respectively HrQoL. Data were collected at baseline, 4, 24, and 48 weeks after randomization. Outcome scores were dichotomized and used as criteria in longitudinal models identifying differential developments. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as main measures of effects. ORs<1 indicate better results for HADS, and worse for MOS-HIV scores in the 2DR compared to 3DR group. In total, 263 subjects were randomized and treated (2DR n=131, 3DR n=132; median age 48 years). Significant different progressions could only be found for HADS-Depression scores (OR=.87, 95% CI: .78, .98, p=.02). While HADS-Depression scores decreased in the 2DR group, they increased in 3DR group. This sub-study showed no disadvantages regarding HrQoL in PLWH after switching to DTG+DRV/r. Considering lifelong requirements for antiretroviral medication, close attention to HrQL is required.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Darunavir/farmacología , Darunavir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Persona de Mediana Edad , Oxazinas , Piperazinas , Piridonas , Calidad de Vida , Ritonavir/farmacología , Ritonavir/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: Studies which examine quality of life (QOL) provide important insights that are needed to understand the impacts of HIV/AIDS anti-retroviral treatment (ART), comorbid conditions and other factors on the daily activities of people living with HIV/AIDS (PLH). This study aimed to determine the inter-relationships between clinical factors, behavioural, socio-demographic variables and QOL among PLH. METHODS: The secondary analysis used data collected from 293 people living with HIV/AIDS (PLH) receiving second-line ART in Johannesburg in a clinical trial which evaluated the non-inferiority of ritonavir-boosted darunavir (DRV/r 400/100 mg) compared to ritonavir-boosted lopinavir (LPV/r) over a 48 week-period. Physical functioning, cognitive and mental QOL were measured using the Aids Clinical Trial Group questionnaire. Exploratory factor analyses were used to examine the structure, the relationships between and the construct validity of QOL items. Structural equation models which tested the a priori-hypothesised inter-relationships between QOL and other variables were estimated and goodness of fit of the models to the data was assessed. RESULTS: Patients on darunavir presented with lower pill burden. Older patients and women were more likely to report lower QOL scores. Pill burden mediated the effects of age, sex and treatment regimen on physical functioning QOL and adverse effects; the effects of age, sex, treatment regimen and adverse effects on cognitive QOL; and the effects of sex on mental QOL. CONCLUSION: QOL among PLH is associated with socio-demographic and clinical factors. Therefore, QOL could be enhanced by considering PLH characteristics, clinical factors such as regimen side-effects profile, management of comorbid conditions and mitigating risks such as potential adverse drug-to-drug interactions among patients on ART.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Darunavir/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Lopinavir/uso terapéutico , Calidad de Vida , Ritonavir/uso terapéutico , SudáfricaRESUMEN
HIV protease (HIVPR) is a key target in AIDS therapeutics. All ten FDA-approved drugs that compete with substrates in binding to this dimeric enzyme's active site have become ineffective due to the emergence of drug resistant mutants. Blocking the dimerization interface of HIVPR is thus being explored as an alternate strategy. The latest drug, darunavir (DRV), which exhibited a high genetic barrier to viral resistance, is said to have a dual mode of action - (i) binding to the dimeric active site, and (ii) preventing the dimerization by binding to the HIVPR monomer. Despite several reports on DRV complexation with dimeric HIVPR, the mode and mechanism of the binding of DRV to the HIVPR monomer are poorly understood. In this study, we utilized all-atomic MD simulations and umbrella sampling techniques to identify the best possible binding mode of DRV to the monomeric HIVPR and its mechanism of association. The results suggest that DRV binds between the active site and the flap of the monomer, and the flap plays a crucial role in directing the drug to bind and driving the other protein domains to undergo induced fit changes for stronger complexation. The obtained binding mode of DRV was validated by comparing with various mutational data from clinical isolates to reported in vitro mutations. The identified binding pose was also able to successfully reproduce the experimental Ki value in the picomolar range. The residue-level information extracted from this study could accelerate the structure-based drug designing approaches targeting HIVPR dimerization.
Asunto(s)
Infecciones por VIH , Inhibidores de la Proteasa del VIH , Darunavir/farmacología , Darunavir/uso terapéutico , Dimerización , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , MutaciónRESUMEN
BACKGROUND: Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. METHODS: Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient's characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multivariate analyses. RESULTS: The analysis included 725 patients. At 48 weeks, the combination of two or more IPTCrS (darunavir/cobicistat with rilpivirine and/or dolutegravir) was associated with higher decreases in Cr-eGFR [adjusted median difference (±SD) -3.5 ± 1.6 (95% CI -6.6 to -0.3), P = 0.047], and a decrease up to or higher than 15 mL/min/1.73 m2 was more frequent [adjusted OR 3.233 (95% CI 1.343-7.782), P = 0.009], with respect to darunavir/cobicistat alone. The Cr-eGFR changes between darunavir/cobicistat and darunavir/cobicistat with rilpivirine and/or dolutegravir showed more significant decreases in patients taking two or more IPTCrS at 12, 24 and 48 weeks. (ClinicalTrials.gov: NCT03042390). CONCLUSIONS: Concomitant use of darunavir/cobicistat plus IPTCrS dolutegravir, rilpivirine, or both produced an additive effect in the expected Cr-eGFR decrease.