RÉSUMÉ
INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.
Sujet(s)
Agents antiVIH , Infections à VIH , Pyridones , Rilpivirine , Humains , Rilpivirine/usage thérapeutique , Rilpivirine/administration et posologie , Femelle , Mâle , Adulte , Infections à VIH/traitement médicamenteux , Adulte d'âge moyen , Europe , Agents antiVIH/usage thérapeutique , Agents antiVIH/administration et posologie , Pyridones/usage thérapeutique , Pyridones/administration et posologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Enquêtes et questionnaires , PipérazinedionesRÉSUMÉ
We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.
Sujet(s)
Résistance virale aux médicaments , Infections à VIH , Inhibiteurs de l'intégrase du VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Composés hétérocycliques 3 noyaux , Composés hétérocycliques avec 4 noyaux ou plus , Oxazines , Pipérazines , Pyridones , Humains , Pyridones/usage thérapeutique , Composés hétérocycliques 3 noyaux/usage thérapeutique , Oxazines/usage thérapeutique , Pipérazines/usage thérapeutique , Infections à VIH/traitement médicamenteux , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Inhibiteurs de l'intégrase du VIH/usage thérapeutique , Inhibiteurs de l'intégrase du VIH/pharmacologie , Composés hétérocycliques avec 4 noyaux ou plus/usage thérapeutique , Pyridazines/usage thérapeutique , Pyridazines/pharmacologie , Échec thérapeutique , Amides/usage thérapeutique , Agents antiVIH/usage thérapeutique , Agents antiVIH/pharmacologie , PipérazinedionesRÉSUMÉ
INTRODUCTION: Long-acting injectable antiretroviral treatment (LAI-ART) has emerged as a novel alternative to the burden of daily oral pills. The bi-monthly intramuscular injectable containing cabotegravir and rilpivirine holds the promise of improving adherence to ART. The perspectives of potential users of LAI-ART, the majority of whom reside in Eastern and Southern Africa, are still largely unexplored. We set out to understand the experiences of people with HIV (PWH) who received LAI-ART at Fort Portal Regional Referral Hospital in mid-Western Uganda for at least 12 months. METHODS: This qualitative study, conducted between July and August 2023, was nested within a larger study. We conducted four focus groups with 32 (out of 69) PWH who received intramuscular injections of cabotegravir and rilpivirine. In-depth interviews were held with six health workers who delivered LAI-ART to PWH. Data were analyzed by thematic approach broadly modeled on the five domains of the Consolidated Framework for Implementation Research (CFIR). RESULTS: There was high acceptability of LAI-ART (30 /32 or 94%) participants requested to remain on LAI-ART even after the end of the 12-month trial. Adherence to ART was reportedly improved when compared to daily oral treatment. Participants credited LAI-ART with; superior viral load suppression, redemption from the daily psychological reminder of living with HIV, enhanced privacy in HIV care and treatment, reduced HIV-related stigma associated with taking oral pills and that it absolved them from carrying bulky medication packages. Conversely, nine participants reported pain around the injection site and a transient fever soon after administering the injection as side effects of LAI-ART. Missed appointments for receiving the bi-monthly injection were common. Providers identified health system barriers to the prospective scale-up of LAI-ART which include the perceived high cost of LAI-ART, stringent cold chain requirements, physical space limitations, and workforce skills gaps in LAI-ART delivery as potential drawbacks. CONCLUSION: Overall, PWH strongly preferred LAI-ART and expressed a comparatively higher satisfaction with this treatment alternative. Health system barriers to potential scale-up are essential to consider if a broader population of PWH will benefit from this novel HIV treatment option in Uganda and other resource-limited settings. TRIAL REGISTRATION: Trial Registry Number PACTR ID PACTR202104874490818 (registered on 16/04/2021).
Sujet(s)
Agents antiVIH , Infections à VIH , Personnel de santé , Rilpivirine , Humains , Ouganda , Infections à VIH/traitement médicamenteux , Mâle , Femelle , Adulte , Rilpivirine/usage thérapeutique , Rilpivirine/administration et posologie , Personnel de santé/psychologie , Adulte d'âge moyen , Injections musculaires , Agents antiVIH/usage thérapeutique , Agents antiVIH/administration et posologie , Adhésion au traitement médicamenteux , Recherche qualitative , Pyridones/administration et posologie , Pyridones/usage thérapeutique , Groupes de discussion , Jeune adulte , PipérazinedionesRÉSUMÉ
ABSTRACT: Long-acting injectable cabotegravir (CAB-LA) was US Food and Drug Administration-approved in 2021. However, little is known about providers' CAB-LA knowledge, attitudes, challenges, and prescribing preferences for transgender women patients. Understanding this is critical to developing new pre-exposure prophylaxis (PrEP) interventions tailored to transgender women. We conducted 45-min, in-depth Zoom interviews (IDIs) with United States-based health care providers who prescribe PrEP to transgender women. IDIs focused on providers' CAB-LA knowledge/acceptability, willingness to prescribe CAB-LA to transgender women, potential challenges, and solutions to mitigate challenges. Providers ( N = 17) had a mean age of 43 years, and 35.4% ( n = 6) identified as people of color. Most ( n = 12) had basic knowledge of CAB-LA but wanted additional training. All participants found CAB-LA acceptable and were willing to prescribe. Most ( n = 11) anticipated minimal challenges to implementation. Others ( n = 4) reported potential issues, including logistical/scheduling concerns that impede CAB-LA integration and staffing concerns. Many providers expressed support for self-injection ( n = 13) and injections at "drop-in" clinics ( n = 8) to overcome challenges.
Sujet(s)
Agents antiVIH , Infections à VIH , Personnel de santé , Prophylaxie pré-exposition , Pyridones , Recherche qualitative , Personnes transgenres , Humains , Personnes transgenres/psychologie , Personnes transgenres/statistiques et données numériques , Femelle , Adulte , États-Unis , Mâle , Prophylaxie pré-exposition/méthodes , Infections à VIH/traitement médicamenteux , Infections à VIH/prévention et contrôle , Personnel de santé/psychologie , Agents antiVIH/administration et posologie , Agents antiVIH/usage thérapeutique , Pyridones/administration et posologie , Pyridones/usage thérapeutique , Adulte d'âge moyen , Connaissances, attitudes et pratiques en santé , Injections , Accessibilité des services de santé , Préparations à action retardée , Attitude du personnel soignant , Entretiens comme sujet , PipérazinedionesSujet(s)
Agents antiVIH , Infections à VIH , Pyridones , Rilpivirine , Échec thérapeutique , Humains , Infections à VIH/traitement médicamenteux , Pyridones/usage thérapeutique , Mâle , Agents antiVIH/usage thérapeutique , Rilpivirine/usage thérapeutique , Congénères de la testostérone , Résistance virale aux médicaments , Adulte d'âge moyen , PipérazinedionesRÉSUMÉ
INTRODUCTION: HIV treatment currently consists of daily oral antiretroviral therapy (ART). Cabotegravir + rilpivirine long-acting (CAB + RPV LA) is the first ART available in Spain administered every 2 months through intramuscular injection by a healthcare professional (HCP). The objective of this analysis was to assess potential healthcare resource use (HRU) and cost impact of implementing CAB + RPV LA vs. daily oral ART at National Health System (NHS) hospitals. METHODS: Online quantitative interviews and cost analysis were performed. Infectious disease specialists (IDS), hospital pharmacists (HP) and nurses were asked about their perception of potential differences in HRU between CAB + RPV LA vs. daily oral ART, among other concepts of interest. Spanish official tariffs were applied as unit costs to the HRU estimates (2022). RESULTS: 120 responders (n = 40 IDS, n = 40 HP, n = 40 nurses) estimated an average number of annual visits per patient by speciality (IDS, HP, and nurse, respectively) of 3.3 vs. 3.7; 4.4 vs. 6.2; 6.1 vs. 3.9, for CAB + RPV LA vs. daily oral ART, and 3.0 vs. 3.2; 4.8 vs. 5.8; 6.9 vs. 4.9, respectively when adjusting by corresponding specialist responses. Estimation by the total sample led to an annual total cost per patient of 2,076 vs. 2,473, being 2,032 vs. 2,237 after adjusting by corresponding HCP, for CAB + RPV LA vs. daily oral ART. CONCLUSIONS: These results suggest that the implementation of CAB + RPV LA in NHS hospitals would not incur in increased HRU-related costs compared to current daily oral ARTs, being potentially neutral or even cost-saving.
Sujet(s)
Agents antiVIH , Infections à VIH , Pyridones , Rilpivirine , Humains , Infections à VIH/traitement médicamenteux , Infections à VIH/économie , Rilpivirine/usage thérapeutique , Rilpivirine/économie , Rilpivirine/administration et posologie , Espagne , Agents antiVIH/usage thérapeutique , Agents antiVIH/économie , Agents antiVIH/administration et posologie , Pyridones/économie , Pyridones/usage thérapeutique , Pyridones/administration et posologie , Administration par voie orale , Injections musculaires , Coûts des soins de santé/statistiques et données numériques , Ressources en santé/économie , Ressources en santé/statistiques et données numériques , PipérazinedionesRÉSUMÉ
BACKGROUND: Cabotegravir + rilpivirine long-acting (CAB + RPV LA) dosed every 2 months (Q2M) is a complete regimen for the maintenance of HIV-1 virologic suppression. In this study, we report month 12 clinical outcomes in patient study participants (PSPs) in the CAB and RPV Implementation Study in European Locations (CARISEL) study. SETTING: CARISEL is a phase 3b implementation-effectiveness study. METHODS: CARISEL was designed as a 2-arm, unblinded study with centers randomized to either enhanced or standard implementation arms. For PSPs, this study is single arm, unblinded, and interventional; all PSPs switched from daily oral therapy to CAB + RPV LA dosed Q2M. The primary objective was to evaluate the perceived acceptability, appropriateness, and feasibility of CAB + RPV LA implementation for staff participants (presented separately). Clinical secondary endpoints assessed through month 12 included the proportion of PSPs with plasma HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive plasma HIV-1 RNA levels ≥200 copies/mL), adherence to injection visit windows, and safety and tolerability. RESULTS: Four hundred thirty PSPs were enrolled and treated; the mean age was 44 years (30% ≥50 years), 25% were women (sex at birth), and 22% were persons of color. At month 12, 87% (n = 373/430) of PSPs maintained HIV-1 RNA <50 copies/mL, with 0.7% (n = 3/430) having HIV-1 RNA ≥50 copies/mL. One PSP had CVF. The safety profile was consistent with previous findings. Overall, the results were similar between implementation arms. CONCLUSION: CAB + RPV LA Q2M was well tolerated and highly effective in maintaining virologic suppression with a low rate of virologic failure.
Sujet(s)
Agents antiVIH , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Pyridones , Rilpivirine , Humains , Rilpivirine/usage thérapeutique , Rilpivirine/administration et posologie , Infections à VIH/traitement médicamenteux , Femelle , Mâle , Pyridones/usage thérapeutique , Agents antiVIH/usage thérapeutique , Agents antiVIH/administration et posologie , Adulte , Adulte d'âge moyen , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Europe , Charge virale/effets des médicaments et des substances chimiques , Résultat thérapeutique , Association de médicaments , PipérazinedionesRÉSUMÉ
BACKGROUND AND OBJECTIVE: Recent studies have highlighted the key role of the ATP-binding cassette (ABC) transporters, including the P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and the multi-drug resistance protein 4 (MRP4) in limiting the brain distribution of several antiviral agents. In this study, we investigated whether the inhibition of these transporters increases the permeability of the blood-brain barrier (BBB) to ganciclovir. METHODS: A microdialysis and high-performance liquid chromatographic method was developed to monitor the concentrations of unbound ganciclovir in the brain interstitial fluid and plasma, with and without the administration of ABC transporter inhibitors. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,plasma), the area under the brain interstitial fluid concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,brain), and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) were calculated. RESULTS: The mean AUC0-t,plasma, AUC0-t,brain, and Kp,uu,brain in rats who received ganciclovir (30 mg/kg, intraperitoneal) alone were 1090 min·µg/mL, 150 min·µg/mL, and 14%, respectively. After the administration of tariquidar (inhibitor of P-gp), Ko143 (inhibitor of BCRP), or MK-571 (inhibitor of MRP4), the Kp,uu,brain of ganciclovir increased to 31 ± 2.1%, 26 ± 1.3%, and 32 ± 2.0%, respectively. CONCLUSIONS: The findings of this study suggest that ABC transporters P-gp, BCRP, and MRP4 mediate the efflux of ganciclovir at the BBB and that the inhibition of these transporters facilitates the penetration of the BBB by ganciclovir.
Sujet(s)
Antiviraux , Barrière hémato-encéphalique , Ganciclovir , Ganciclovir/pharmacocinétique , Animaux , Barrière hémato-encéphalique/métabolisme , Rats , Mâle , Antiviraux/pharmacocinétique , Antiviraux/pharmacologie , Transporteurs ABC/métabolisme , Transporteurs ABC/antagonistes et inhibiteurs , Rat Sprague-Dawley , Transport biologique , Microdialyse/méthodes , Chromatographie en phase liquide à haute performance/méthodes , Encéphale/métabolisme , Membre-2 de la sous-famille G des transporteurs à cassette liant l'ATP/métabolisme , Membre-2 de la sous-famille G des transporteurs à cassette liant l'ATP/antagonistes et inhibiteurs , Glycoprotéine P/métabolisme , Glycoprotéine P/antagonistes et inhibiteurs , Pipérazinediones/pharmacocinétiqueRÉSUMÉ
Fungal secondary metabolite (SM) biosynthetic gene clusters (BGCs) containing dimethylallyltryptophan synthases (DMATSs) produce structurally diverse prenylated indole alkaloids with wide-ranging activities that have vast potential as human therapeutics. To discover new natural products produced by DMATSs, we mined the Department of Energy Joint Genome Institute's MycoCosm database for DMATS-containing BGCs. We found a DMATS BGC in Aspergillus homomorphus CBS 101889, which also contains a nonribosomal peptide synthetase (NRPS). This BGC appeared to have a previously unreported combination of genes, which suggested the cluster might make novel SMs. We refactored this BGC with highly inducible promoters into the model fungus Aspergillus nidulans. The expression of this refactored BGC in A. nidulans resulted in the production of eight tryptophan-containing diketopiperazines, six of which are new to science. We have named them homomorphins A-F (2, 4-8). Perhaps even more intriguingly, to our knowledge, this is the first discovery of C4-prenylated tryptophan-containing diketopiperazines and their derivatives. In addition, the NRPS from this BGC is the first described that has the ability to promiscuously combine tryptophan with either of two different amino acids, in this case, l-valine or l-allo-isoleucine.
Sujet(s)
Aspergillus nidulans , Aspergillus , Pipérazinediones , Amino-acid ligases , Tryptophane , Tryptophane/métabolisme , Tryptophane/composition chimique , Pipérazinediones/composition chimique , Aspergillus nidulans/génétique , Aspergillus nidulans/métabolisme , Aspergillus/composition chimique , Amino-acid ligases/métabolisme , Amino-acid ligases/génétique , Structure moléculaire , Famille multigénique , Alcaloïdes indoliques/composition chimique , Alcaloïdes indoliques/métabolisme , Alkyl et aryl transferases/métabolisme , Alkyl et aryl transferases/génétiqueRÉSUMÉ
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (1) and E2 (2), were isolated from a Penicillium fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.e., MCC13, MKL-1, UISO, and WaGa) in the low micromolar range. The relative and absolute configurations of 1 and 2 were determined by combined approaches, including NOESY spectroscopy, DFT ECD and DP4 plus calculations, and Marfey's reaction. Literature research and the comparison of NMR and ECD data led to the structure revision of three previously reported natural analogues, notoamides K and P and asperversiamide L. The structurally unstable 1 and 2 underwent steady interconversion under neutral aqueous conditions. Investigation of the degradation of 2 in acidic methanol solutions led to the identification of a new methoxylated derivative (6) and two new ring-opened products (7 and 8) with the rearranged, elongated, 4-methylpent-3-ene side chain. The facile transformation of 2 to 7 and 8 was promoted by the intrinsic impurity (i.e., formaldehyde) of HPLC-grade methanol through the aza-Cope rearrangement.
Sujet(s)
Pipérazinediones , Penicillium , Penicillium/composition chimique , Pipérazinediones/pharmacologie , Pipérazinediones/composition chimique , Structure moléculaire , Humains , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/isolement et purification , Tests de criblage d'agents antitumorauxRÉSUMÉ
INTRODUCTION: Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long-acting (LA) regimen recommended for maintaining HIV-1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation-effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months. METHODS: Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm-S) or enhanced arm (Arm-E). Arm-S included video injection training and provider/patient toolkits. Additionally, Arm-E included skilled wrap-around team meetings, face-to-face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi-structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1-5 Likert scale ranging from 1 = "completely disagree" to 5 = "completely agree"). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed. RESULTS: Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation- and intervention-based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections. CONCLUSIONS: CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible. GOV NUMBER: NCT04399551.
Sujet(s)
Agents antiVIH , Infections à VIH , Pyridones , Rilpivirine , Humains , Rilpivirine/usage thérapeutique , Rilpivirine/administration et posologie , Infections à VIH/traitement médicamenteux , Europe , Agents antiVIH/usage thérapeutique , Agents antiVIH/administration et posologie , Pyridones/usage thérapeutique , Mâle , Femelle , Adulte , Adulte d'âge moyen , PipérazinedionesRÉSUMÉ
Since the development of an effective antiretroviral therapy (ART) in 1996, substantial progress has been made in terms of efficacy, safety and ease of use. While at the beginning of the ART era the foremost goal necessarily was patient survival, over time it has become increasingly possible to shift the focus towards aspects of patient's quality of life. The latest developments are the long-acting injection therapies (LAI), foregoing for the first time the necessity to take pills. The only available injection therapy so far comprises 2 intramuscular injections every 2 months, with 3 ml of Cabotegravir 600 mg and 3 ml of Rilpivirine 900 mg being injected, respectively. Through this, patient's needs that were hitherto precluded from consideration could be addressed. These needs are inextricably linked to the stigmata people living with HIV (PLWH) are still confronted with on a daily basis. LAI have the potential to relieve PLWH of some of the heavy psychological burdens associated with the continued stigmatization. However, as a new therapy, new challenges need to be considered the use of LAI.
Sujet(s)
Agents antiVIH , Préparations à action retardée , Infections à VIH , Humains , Infections à VIH/traitement médicamenteux , Injections musculaires , Agents antiVIH/administration et posologie , Agents antiVIH/usage thérapeutique , Agents antiVIH/effets indésirables , Rilpivirine/administration et posologie , Rilpivirine/usage thérapeutique , Pyridones/administration et posologie , Pyridones/usage thérapeutique , Pyridones/effets indésirables , Qualité de vie , PipérazinedionesRÉSUMÉ
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.
Sujet(s)
Agents antiVIH , Indice de masse corporelle , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Pyridones , Rilpivirine , Humains , Rilpivirine/pharmacocinétique , Rilpivirine/usage thérapeutique , Rilpivirine/administration et posologie , Rilpivirine/effets indésirables , Infections à VIH/traitement médicamenteux , Infections à VIH/virologie , Mâle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Femelle , Agents antiVIH/pharmacocinétique , Agents antiVIH/administration et posologie , Agents antiVIH/usage thérapeutique , Agents antiVIH/effets indésirables , Adulte , Adulte d'âge moyen , Pyridones/pharmacocinétique , Pyridones/administration et posologie , Pyridones/effets indésirables , Charge virale/effets des médicaments et des substances chimiques , ARN viral/sang , Résultat thérapeutique , Association de médicaments , PipérazinedionesRÉSUMÉ
A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.
Sujet(s)
Infections à VIH , Virus de l'hépatite B , Hépatite B , Activation virale , Humains , Infections à VIH/traitement médicamenteux , Infections à VIH/virologie , Virus de l'hépatite B/génétique , Virus de l'hépatite B/immunologie , Mâle , Hépatite B/virologie , Hépatite B/traitement médicamenteux , Pyridones/usage thérapeutique , Anticorps de l'hépatite B/sang , Anticorps de l'hépatite B/immunologie , Agents antiVIH/usage thérapeutique , Pyrimidines/usage thérapeutique , Adulte d'âge moyen , Antigènes de surface du virus de l'hépatite B/immunologie , Antigènes de surface du virus de l'hépatite B/sang , PipérazinedionesRÉSUMÉ
Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.
Sujet(s)
Agents antiVIH , Interactions médicamenteuses , Infections à VIH , Pyridones , Rilpivirine , Humains , Rilpivirine/pharmacocinétique , Rilpivirine/administration et posologie , Rilpivirine/pharmacologie , Pyridones/pharmacocinétique , Pyridones/pharmacologie , Pyridones/administration et posologie , Infections à VIH/traitement médicamenteux , Agents antiVIH/pharmacocinétique , Agents antiVIH/administration et posologie , Agents antiVIH/pharmacologie , Afrique subsaharienne , Préparations à action retardée , PipérazinedionesRÉSUMÉ
Background: In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany. Methods: Based on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation. Results: The bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was 11,940 (maintenance therapy with initiation) and 10,950 (maintenance therapy without initiation). Conclusion: To our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.
Sujet(s)
Agents antiVIH , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Humains , Allemagne , Infections à VIH/traitement médicamenteux , Agents antiVIH/usage thérapeutique , Agents antiVIH/économie , Rilpivirine/usage thérapeutique , Ordonnances médicamenteuses/statistiques et données numériques , Mâle , Adulte , Femelle , Pyridones , PipérazinedionesRÉSUMÉ
Peptide ligation chemistries have revolutionized the synthesis of proteins with site-specific modifications or proteomimetics through assembly of multiple peptide segments. In order to prepare polypeptide chains consisting of 100-150 amino acid residues or larger generally assembled from three or more peptide segments, iterative purification process that decreases the product yield is usually demanded. Accordingly, methodologies for one-pot peptide ligation that omit the purification steps of intermediate peptide segments have been vigorously developed so far to improve the efficiency of chemical protein synthesis. In this chapter, we first outline the concept and recent advances of one-pot peptide ligation strategies. Then, the practical guideline for the preparation of peptide segments for one-pot peptide ligation is described with an emphasis on diketopiperazine thioester synthesis. Finally, we disclose the explicit protocols for one-pot four segment ligation via repetitive deprotection of N-terminal thiazolidine by a 2-aminobenzamide type aldehyde scavenger.
Sujet(s)
Peptides , Thiazolidines , Thiazolidines/composition chimique , Peptides/composition chimique , Pipérazinediones/composition chimiqueRÉSUMÉ
Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.
Sujet(s)
Surveillance des médicaments , Composés hétérocycliques 3 noyaux , Pipérazines , Pyridones , Spectrométrie de masse en tandem , Humains , Spectrométrie de masse en tandem/méthodes , Chromatographie en phase liquide à haute performance/méthodes , Surveillance des médicaments/méthodes , Composés hétérocycliques 3 noyaux/analyse , Composés hétérocycliques 3 noyaux/pharmacocinétique , Composés hétérocycliques 3 noyaux/usage thérapeutique , Composés hétérocycliques 3 noyaux/sang , Reproductibilité des résultats , Pyridones/analyse , Pyridones/sang , Pipérazines/analyse , Pipérazines/sang , Limite de détection , Modèles linéaires , Femelle , Oxazines/composition chimique , Raltégravir de potassium/analyse , Raltégravir de potassium/usage thérapeutique , Triazoles/analyse , Triazoles/sang , Composés hétérocycliques avec 4 noyaux ou plus/analyse , Composés hétérocycliques avec 4 noyaux ou plus/pharmacocinétique , Composés hétérocycliques avec 4 noyaux ou plus/sang , Pyridazines/analyse , Pyridazines/pharmacocinétique , Antirétroviraux/analyse , Antirétroviraux/pharmacocinétique , Antirétroviraux/sang , Antirétroviraux/usage thérapeutique , Pyridines/analyse , Pyridines/sang , Pyridines/pharmacocinétique , Pyridines/usage thérapeutique , Col de l'utérus/composition chimique , Infections à VIH/traitement médicamenteux , Amides , PipérazinedionesRÉSUMÉ
Seven previously undescribed compounds, including four diketomorpholine alkaloids (1â4), one indole diketopiperazine alkaloid (9), one chromone (10), and one benzoic acid derivative (13), and nine known compounds (5-8, 11, 12, and 14-16) were isolated from two different fungal sources. Nine of these metabolites (1-9) were obtained from a seagrass-derived Aspergillus alabamensis SYSU-6778, while the others were obtained from a mixed culture of A. alabamensis SYSU-6778 and a co-isolated fungus A. fumigatiaffinis SYSU-6786. The chemical structures of the compounds were deduced via spectroscopic techniques (including HRESIMS, 1D and 2D NMR), chemical reactions, and ECD calculations. It is worth noting that compound 10 was identified as a defensive secondary metabolite of strain SYSU-6786, produced through the induction of compound 8 under co-culture conditions. Compounds 3 and 4 possessed a naturally rare isotryptophan core. Moreover, compounds 1 and 2 exhibited potent inhibitory activities against fish pathogenic bacterium Edwardsiella ictalurid, with minimum inhibitory concentration values of 10.0 µg/mL for both compounds.
Sujet(s)
Aspergillus , Tests de sensibilité microbienne , Aspergillus/composition chimique , Aspergillus/métabolisme , Structure moléculaire , Techniques de coculture , Métabolisme secondaire , Antibactériens/composition chimique , Antibactériens/pharmacologie , Antibactériens/isolement et purification , Antibactériens/biosynthèse , Antibactériens/métabolisme , Animaux , Alcaloïdes/composition chimique , Alcaloïdes/pharmacologie , Alcaloïdes/isolement et purification , Alcaloïdes/métabolisme , Pipérazinediones/composition chimique , Pipérazinediones/pharmacologie , Pipérazinediones/métabolisme , Pipérazinediones/isolement et purification , Relation structure-activité , Relation dose-effet des médicamentsRÉSUMÉ
Subjecting the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339 to cultivation profiling using an innovative miniaturized 24-well plate format (MATRIX) enabled access to new examples of the rare class of 2,6-diketopiperazines, noonazines A-C (1-3), along with the known analogue coelomycin (4), as well as a new azaphilone, noonaphilone A (5). Structures were assigned to 1-5 on the basis of a detailed spectroscopic analysis, and in the case of 1-2, an X-ray crystallographic analysis. Plausible biosynthetic pathways are proposed for 1-4, involving oxidative Schiff base coupling/dimerization of a putative Phe precursor. Of note, 2 incorporates a rare meta-Tyr motif, typically only reported in a limited array of Streptomyces metabolites. Similarly, a plausible biosynthetic pathway is proposed for 5, highlighting a single point for stereo-divergence that allows for the biosynthesis of alternate antipodes, for example, the 7R noonaphilone A (5) versus the 7S deflectin 1a (6).