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Background: The aim of the study was to evaluate the 12-month cumulative probability of treatment discontinuation (TD) in people with human immunodeficiency virus (HIV; PWH) and a long exposure to antiretroviral therapy (ART) switching to long-acting cabotegravir and rilpivirine (CAB/RPV). Methods: SCohoLART is a single-center, prospective, cohort study designed to collect both samples and clinical data from PWH with virological suppression who switched to bimonthly long-acting CAB/RPV. TD occurred at switch to another regimen for any reason including virological failure (VF); VF was defined as HIV RNA levels ≥50 copies/mL at 2 consecutive measurements or a single HIV RNA level ≥1000 copies/mL. Results were reported as median (interquartile range [IQR]) or frequency (percentage). Cumulative probabilities of TD were estimated using Kaplan-Meier curves. Results: We evaluated 514 participants; 467 (90.9%) were male, and their median age (IQR) was 49 (40-56) years. At the time of switching, the median time from HIV diagnosis and the median duration of ART were 14.0 (IQR, 8.8-20.5) and 11.4 (7.9-17.4) years, respectively; before starting CAB/RPV, the median number of antiretroviral regimens was 3 (2-4). During a median study follow-up (IQR) of 13.1 (9.1-15.5) months, 52 PWH (10.1%) experienced TD, including 4 (0.8%) for VF. The 12-month cumulative probability of TD was 11% (95% confidence interval, 8%-14%). The main cause of TD was injection site reaction (15 participants [28.8%]). Conclusions: The 1-year cumulative probability of TD with long-acting CAB/RPV was quite low in this cohort of people with a median exposure to ART of 10 years, in whom injection site reaction was the leading cause of TD. VFs were rare during study follow-up.

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BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.

Asunto(s)

Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Lactancia Materna , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Inyecciones Subcutáneas , Profilaxis Pre-Exposición/métodos , Método Simple Ciego , Sudáfrica

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Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of MAP delivery of micronized cabotegravir sodium (CAB Na) for HIV pre-exposure prophylaxis (PrEP). The refinement of microneedle design parameters, including needle length, shape, density, and arrangement, and the formulation properties, such as solubility, viscosity, polymer molecular weight, and stability, are crucial for improving penetration and release profiles. Additionally, a bilayer MAP optimization step was conducted by diluting the CAB Na polymeric mixture to localize the drug into the tips of the needles to enable rapid drug deposition into the skin following MAP application. Six MAP designs were analyzed and investigated with regard to delivery efficiency into the skin in ex vivo and in vivo studies. The improved MAP design and formulations were found to be robust and had more than 30% in vivo delivery efficiency, with plasma levels several-fold above the therapeutic concentration over a month. Repeated weekly dosing demonstrated the robustness of MAPs in delivering a consistent and sustained dose of CAB. In summary, CAB Na MAPs were able to deliver therapeutically relevant levels of drug.

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The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well-established and clinically proven drug delivery approach to improve the pharmacokinetics and pharmacodynamics of drugs. Specifically, PEGylation can improve the parent drug's solubility, extend its circulation time, and reduce its immunogenicity, with minimal undesirable properties. PEGylation technology has been applied to various therapeutic modalities including small molecules, aptamers, peptides, and proteins, leading to over 30 PEGylated drugs currently used in the clinic and many investigational PEGylated agents under clinical trials. Here, we summarize the diverse types of PEGylation strategies, the key advantages of PEGylated therapeutics over their parent drugs, and the broad applications and impacts of PEGylation in clinical settings. A particular focus has been given to the size, topology, and functionalities of PEG molecules utilized in clinically used PEGylated drugs, as well as those under clinical trials. An additional section has been dedicated to analyzing some representative PEGylated drugs that were discontinued at different stages of clinical studies. Finally, we critically discuss the current challenges faced in the development and clinical translation of PEGylated agents.

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In the long-term management of chronic diseases, adherence and persistence to prescribed medications are continuous challenges in order to obtain all the potential benefits of drug therapies. Suboptimal drug adherence and discontinuations of therapies remain the most frequent reasons why several diseases are poorly controlled in the population. One the main issue is that physicians are relatively limited in time and tools to detect patients with a poor adherence. The present review discusses present and future strategies that are now available or are being developed to detect and to support adherence in patients with chronic diseases and provides some simple clues to identify patients at high risk of discontinuation in the clinic.

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Cumplimiento de la Medicación , Humanos , Enfermedad Crónica

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INTRODUCTION: Combination antiretroviral therapy (cART) has dramatically reduced morbidity and mortality of HIV-1-infected patients. Integrase strand transfer inhibitors (INSTIs) play an important role as a key drug in cART. The second-generation INSTIs are very potent, but due to the emergence of highly resistant viruses and the demand for more conveniently usable drugs, the development of 'third-generation' INSTIs and mechanistically different inhibitors is actively being pursued. AREAS COVERED: This article reviews the patents (from 2018 to the present) for two classes of HIV-1 integrase inhibitors of INSTIs and integrase-LEDGF/p75 allosteric inhibitors (INLAIs). EXPERT OPINION: Since the approval of the second-generation INSTI dolutegravir, the design of new INSTIs has been mostly focused on its scaffold, carbamoylpyridone (CAP). This CAP scaffold is used not only for HIV-1 INSTIs but also for drug discoveries targeting other viral enzymes. With the approval of cabotegravir as a regimen of long-acting injection in combination with rilpivirine, there is a growing need for longer-acting agents. INLAIs have been intensely studied by many groups but have yet to reach the market. However, INLAIs have recently been reported to also function as a latency promoting agent (LPA), indicating further development possibilities.

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Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Humanos , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Patentes como Asunto , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Integrasas/farmacología , Integrasas/uso terapéutico , Integrasa de VIH/farmacología

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Objectives: Aminopeptidase N (APN) is an enzyme highly expressed in metastatic cancers and could be used in targeted cancer therapy. Our previous work showed the successful construction of CNGRC-carboxypeptidase G2 (CPG2) and CNGRC-CPG2-CNGRC fusion proteins. Our conjugates and prodrugs were effective in targeting high APN-expressing cancer cells. In the present study, we aim to produce long-acting fusion proteins to overcome 2 of the main drawbacks of antibody-directed enzyme prodrug therapy. Methods: N-terminal and N-, C-terminal fusion CPG2, CNGRC-CPG2, and CNGRC-CPG2-CNGRC, respectively, were PEGylated using polyethylene glycol (PEG) maleimide (40K). We examined the effect of PEGylation on the therapeutic efficacy of the new products. The resulting PEGylated fusion proteins were tested for their stability, ex vivo immunotoxicity, binding capacity to their target on high HT1080, and low A549 APN-expressing cells. The catalytic activity of the resulting PEGylated fusion CPG2 proteins was investigated. Pro-drug "ZD2767P" cytotoxic effect in association with PEG CPG2-CNGRC fusion proteins on cancer cells was studied. Results: Our work demonstrated that the properties of the PEGylated single-fused proteins were significantly improved over that of un-PEGylated fused CPG2, and its kinetic activity and APN-binding affinity were not negatively affected by the PEGylation. Significantly, The PEGylated single-fused CPG2 had lower immunogenicity than the un-PEGylated CPG2. Our results, however, were different in the case of the PEGylated double-fused CPG2. Although its stability in human serum under physiological conditions was not significantly affected, the kinetic activity and its binding affinity to their cellular marker (APN) were substantially reduced. When the study was performed with high and low APN-expressing cancer cell lines, using the prodrug ZD2767p, the PEGylated fusion CPG2 demonstrated cancer cell killing effects. Conclusion: We have successfully produced PEGylated-CNGRC-CPG2, which is bioactive and with lower immunogenicity in ligand-directed enzyme prodrug therapy for cancer treatment.

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Antineoplásicos/farmacología , Péptidos Cíclicos , Profármacos/farmacología , Proteínas Recombinantes de Fusión/farmacología , gamma-Glutamil Hidrolasa , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Ligandos , Terapia Molecular Dirigida , Péptidos Cíclicos/química , Polietilenglicoles , Profármacos/química , Proteínas Recombinantes de Fusión/química , Análisis Espectral , gamma-Glutamil Hidrolasa/química

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Poly (lactic-co-glycolic acid) (PLGA) has been used in many long-acting drug formulations which have been approved by the US Food and Drug Administration (FDA). However, generic counterparts for PLGA products have yet to gain FDA approval due to many complexities in formulation, characterization, and evaluation of test products. To address the challenges of generic development of PLGA-based products, the FDA has established an extensive research program to investigate novel methods and tools to aid both product development and regulatory review. The research focus have been: (1) analytical tools for characterization of PLGA polymers; (2) impacts of PLGA characteristics and manufacturing conditions on product performance; (3) in vitro drug release testing and in vitro-in vivo correlation of PLGA-based products, and (4) modeling tools to facilitate formulation design and bioequivalence study design of PLGA-based drugs. This article provides an overview of FDA's PLGA research program and highlights scientific accomplishments as well as regulatory outcomes that have resulted from successful research investigations.

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Aprobación de Drogas , Portadores de Fármacos/química , Medicamentos Genéricos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Liberación de Fármacos , Humanos , Microesferas , Modelos Animales , Equivalencia Terapéutica , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudencia

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INTRODUCTION: A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties of human serum albumin for broad tissue distribution, prolonged circulation, and ligand transport have been engineered into albumin-based drug designs to modulate the pharmacokinetics to increase efficacy and reduce the frequency of dose. AREAS COVERED: This review highlights albumin structural features, ligand binding, and molecular interactions key to albumin-drug designs and an overview of the repertoire of albumin-drugs and approaches, with focus on pharmacokinetics of marketed products and clinical trials. EXPERT OPINION: Comparison, and advantages as well as disadvantages of the endogenous albumin-binding versus recombinant albumin construct approach, and half-life extension and intracellular drug delivery applications. The section addresses current challenges and solutions to the different drug designs, and considerations needed to progress the field such as conjugation chemistries, drug loading, and animal models. The section highlights the need for a paradigm shift in the field from 'utilizing' to 'controlling' albumin transport with recombinant human albumin variants engineered for tuned affinity to albumin cellular receptors.

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Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Albúmina Sérica Humana/química , Animales , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Albúmina Sérica Humana/metabolismo , Distribución Tisular

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Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos

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Despite the world's combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world's most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.

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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Polímeros/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tenofovir/administración & dosificación , Fármacos Anti-VIH/farmacología , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Ácidos Fosfóricos/química , Polietileno/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Tenofovir/farmacología , Células Tumorales Cultivadas

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OBJECTIVE: The present study aimed to review the relapse rate in patients with schizophrenia treated with orally taken atypical agents (serotonin dopamine antagonists, SDAs) and depot preparation of conventional (typical) antipsychotics. METHODS: In this historical cohort study, mean relapse per month (MRM) index, duration between initiation of antipsychotic treatment and the first relapse episode, and the time gap between successive relapses were compared between 84 patients on SDAs-except clozapine (group 1) and 81 others on depot typical antipsychotics (group 2). RESULTS: The two groups were comparable regarding mean (±SD) MRM index [0.033 (±0.004) in group1 and 0.044 (±0.05) in group 2; p = 0.345]. Mean (±SD) duration of time between initiation of maintenance treatment and the first relapse was 15.5 (±13.67) months in group 1 and 16.40 (±15.31) months in group 2, (p = 0.876). Mean (±SD) duration of remission periods between successive relapses were 17.92 (±14.2) and 15.8 (±16.9) months for group 1 and group 2, respectively (Mann-Whitney test, (p = 0.048). CONCLUSION: Orally taken atypical antipsychotics were able to keep the duration of remission periods between successive relapses more prolonged compared to depot conventional preparations. This could be added to their other remarkable benefits especially if the patient is expected to experience multiple relapses. DECLARATION OF INTEREST: None.