Search Results (74)

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

In 2022, 20 million women globally were living with HIV, yet they remain underrepresented in clinical trials, including those for antiretroviral treatments (ART). This study assesses the safety and efficacy of the long-acting cabotegravir-rilpivirine (CAB-RPV) regimen in a cohort of 54 women living with HIV (WLWH) over 24 weeks. A retrospective cohort study from the Sardinian HIV Network and Sicilian HIV Cohort (SHiNe-SHiC) included WLWH who switched to CAB-RPV. Primary objectives were achieving and maintaining HIV RNA levels <50 copies/mL at 24 weeks. Secondary objectives included treatment safety, durability, and reasons for discontinuation. Data on demographics, viro-immunological markers, lipid profiles, and treatment interruptions were analyzed. Of 54 WLWH, 46 reached 24 weeks. The median age was 50 years. A total of 71.8% transitioned from dolutegravir (DTG) regimens. Virological suppression was 97.8% at baseline and 95.5% at 24 weeks. Significant increases in the CD4/CD8 ratio (p = 0.0076) and decreases in serum creatinine levels (p = 0.0109) were observed. Cholesterol, triglycerides, ALT, and AST levels remained unchanged. The CAB-RPV regimen demonstrated significant virological and immunological efficacy and safety in women living with HIV over 24 weeks. Notably, the improvement in the CD4/CD8 ratio and the increase in the percentage of women achieving target not detected (TND) status highlight the regimen’s effectiveness. These findings emphasize the importance of gender-focused research in HIV treatment and the need for equitable access to effective treatment options for women, which is crucial for global efforts to eliminate HIV. Full article

South Africa continues to experience a high HIV prevalence, necessitating innovative prevention strategies aligned with the UNAIDS 95-95-95 targets. Long-acting injectable pre-exposure prophylaxis (PrEP), such as cabotegravir (CAB-LA), offers a promising alternative to daily oral regimens. However, the perspectives of primary healthcare workers (PHCWs)—key implementers of this intervention—remain underexplored. This scoping review aims to systematically map existing literature on PHCWs’ knowledge, awareness, perceptions, barriers, facilitators, and implementation experiences related to injectable PrEP within the South African healthcare context. The review will follow the Arksey and O’Malley framework, enhanced by Levac et al., and will be reported following PRISMA-ScR guidelines. A comprehensive search will be conducted across PubMed, Scopus, CINAHL (EBSCOhost), Web of Science, and Google Scholar, without language or date restrictions. The search strategy will employ both controlled vocabulary (e.g., MeSH and CINAHL Subject Headings) and free-text terms. Studies meeting the inclusion criteria will be managed using EndNote X20 and appraised using the Mixed Methods Appraisal Tool (MMAT) 2018 version. Data will be synthesized thematically and presented narratively and in tabular form. By consolidating PHCWs’ perspectives, this review will identify implementation challenges, training needs, and systemic barriers, informing the development of context-specific strategies for PrEP rollout. The findings are expected to support the design of effective, culturally relevant educational interventions and guide policymakers in strengthening HIV prevention efforts in high-burden settings. Full article

Treatment as Prevention (TasP) and Pre-Exposure Prophylaxis (PrEP) are both widely recognized as essential biomedical tools to control HIV/AIDS. TasP calls for the immediate initiation of fully subsidized and supported antiretroviral therapy (ART) following HIV diagnosis. TasP effectively prevents progression to AIDS, and premature AIDS-related deaths among people living with HIV (PLWH), and simultaneously renders HIV non-transmissible, thus preventing onward HIV transmission. In addition, PrEP has proven effective against HIV transmission among high-risk individuals who are adherent to the regimen. PrEP traditionally consists of two antiretrovirals given orally as one pill daily: originally, tenofovir-DF plus emtricitabine (TDF-FTC), and later, tenofovir-AF (TAF) plus FTC (more recently, other options have become available, including long-acting parenteral formulations; however, these are still of limited availability). Over the last two decades, the province of British Columbia has rolled out TasP among all PLWH, and starting in 2018, PrEP was added as a strategy to reach individuals most at risk of acquiring HIV to further accelerate progress in addressing HIV/AIDS as a public health threat. Our “generalized TasP + focused PrEP” program proved to be synergistic (or multiplicative) as it relates to reducing the HIV effective reproduction number (${\mathrm{R}}_{\mathrm{e}}$). TasP lowers HIV incidence by reducing the pool of individuals able to transmit HIV, which is dependent on the extent of community plasma viral load (pVL) suppression. Meanwhile, PrEP reduces the number of potential new infections among those most susceptible to acquiring HIV in the community, independent of viral load suppression among PLWH. Our results strongly support widespread implementation of the combination of “generalized TasP + focused PrEP” strategy and underscore the importance of long-term monitoring of ${\mathrm{R}}_{\mathrm{e}}$ at a programmatic level to identify opportunities for optimizing TasP and PrEP programs. This approach aligns with the United Nations goal of “Ending HIV/AIDS as a pandemic by 2030”, both in Canada and globally. Full article

Blood transports nutrients and oxygen to the cells while removing the waste. It also possesses a hemostasis function to prevent excessive bleeding. However, abnormal clot formation (thrombosis) within healthy blood vessels can lead to life-threatening conditions like heart attacks, strokes, and pulmonary embolism. This review explores anticoagulants, their historical aspects, current clinical applications, and future trends. Anticoagulants play a critical role in preventing and treating thrombosis by interfering with different stages of blood clotting. The journey began with heparin, a rapidly acting injectable medication discovered in 1916. The introduction of warfarin in the 1950s revolutionized anticoagulation by offering long-term oral regimens. Today, anticoagulants are crucial for managing conditions like deep vein thrombosis and pulmonary embolism, especially in an aging population with a rising prevalence of thrombotic complications. Three main types of anticoagulants are used today: vitamin K antagonists (VKAs), injectable heparins, and direct oral anticoagulants (DOACs). Despite advancements, managing anticoagulant therapy remains complex due to individual patient variability, the need for regular monitoring, and the delicate balance between preventing thrombosis and bleeding risks. Emerging trends include the development of factor XIa inhibitors, which promise more targeted thrombosis prevention with potentially lower bleeding risks. This review highlights the ongoing innovation in anticoagulant development, the need for precise management, and potential future avenues like factor XIa inhibitors. Additionally, artificial intelligence holds promise for improving patient outcomes and addressing the complexities of thrombotic disease management by personalizing therapy and reducing bleeding risks. Full article

Hepatitis C virus (HCV) eradication is usually associated with dyslipidemia. Most studies in this field have focused on genotype-specific direct-acting antivirals (DAAs), with research on pangenotypic DAAs being limited. This study examined how two pangenotypic DAA regimens, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), affect lipid profiles and insulin resistance after viral eradication in chronic HCV patients. A total of 100 patients (57 with GLE/PIB and 43 with SOF/VEL) treated between September 2020 and January 2022 were included in the retrospective analysis. This study found a significant increase in LDL and TC levels after treatment (p < 0.001), but no significant changes in triglycerides, high-density lipoprotein, HbA1C, or the Homeostatic Model Assessment of Insulin Resistance. According to a logistic regression analysis, higher baseline LDL or TC and lower baseline glucose are predictors of the degree of increase in LDL or TC following a sustained virological response. Both pangenotypic DAA regimens significantly impact lipid profiles, particularly LDL and TC, but not insulin resistance. This study emphasizes the need for more research into the long-term metabolic effects of DAAs. Full article

Introduction: Dalbavancin (DAL) is a long-acting lipoglycopeptide active against Gram-positive bacteria, including multidrug-resistant isolates. A growing body of evidence supports its efficacy in various difficult-to-treat infections. DAL shows time-dependent bactericidal activity in vitro at free drug concentrations equal to 4×MIC values. However, the optimal dosing scheme for achieving the PK/PD target in multidose treatment has not been fully established. Methods: Pharmacokinetic analysis was based on a nonlinear mixed effects modelling approach performed in NONMEM v7.5/Pirana, while R was used for data management and graphical summaries. Final model parameters were used to simulate the plasma disposition of DAL by Monte Carlo simulations to determine the multidose DAL regimen associated with a 90% target attainment of 100% fT > 4×MIC. Results: A two-compartmental model with first-order elimination and allometric-scaled bodyweight best described DAL disposition in patients with CLcr > 30 mL/min. Monte Carlo simulations showed that two 1500 mg DAL doses 7 days apart granted an optimal PTA > 90% of 100% fT > 4×MIC up to 5, 4, and 3 weeks in patients weighting from 40–80 kg, 80–120 kg and 120–200 kg, respectively. An additional third 1500 mg dose at the above time points by weight bands may extend the optimal PTA up to 9, 7, and 6 weeks of total treatment. Conclusions: Two 1500 mg DAL doses administered 7 days apart could be a valuable starting strategy for patients of all weight classes with CLcr > 30 mL/min. In patients requiring long-term DAL treatment, the optimal timing of additional administrations should be guided by routine TDM or empirically through patients’ total body weight when TDM is unavailable. Full article

Aripiprazole as a long-acting injectable (LAI) is initiated in oral aripiprazole-stabilised patients and needs, after first injection, 14 days supplementation of oral aripiprazole (one-injection start, OIS). Recently, an alternative two-injection start (TIS) was advanced, involving two 400 mg injections with a single 20 mg oral supplementation of aripiprazole. We tested the two regimens in patients with schizophrenia (SCZ, n = 152, 90 men and 62 women) with (SUD⁺; n = 93) or without (SUD^–; n = 59) substance use disorders (SUDs), comparing OIS (n = 66) with TIS (n = 86) and SUD⁺ vs. SUD^–. For 26 patients, we measured weekly for one month, aripiprazole + dehydroaripiprazole (active moiety) levels. Patients were followed for three months after LAI with psychopathology and quality-of-life scales (BPRS, CGI-S, ACES, BIS-11, and WHOQOL). All groups improved in psychopathology with no differences between OSI and TIS and between SCZ–SUD⁺ and SCZ–SUD^–. The TIS group was associated with serum blood levels of the active moiety within the therapeutic window, while the OIS group showed peaks above the window, possibly exposing patients to toxicity. Treatments were well-tolerated. Here we showed no disadvantages for TIS vs. OIS and possibly increased safety. Shifting the initiation of aripiprazole LAIs to the TIS modality may be safe and pharmacokinetically advantageous. Full article

The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management. Full article

Background: TV-46000 (Uzedy, Teva), a long-acting subcutaneous antipsychotic, is an injectable formulation of risperidone and is approved by the FDA for the treatment of schizophrenia in adults. Its innovative copolymer-based drug delivery depot technology (licensed from MedinCell, Jacou, France) allows for plasma concentrations of the total active moiety of risperidone (TAM) to reach clinically relevant levels within 6–24 h and the maintenance of these therapeutic levels with monthly and bimonthly dosing regimens. Objective: As part of the development program for TV-46000, the effect of extrinsic factors of manipulation on the site of injection, and on the pharmacokinetic (PK) profile of TAM following TV-46000 administration was evaluated. Methods: Studies were conducted assessing the effect of heat and rubbing with male Gottingen minipigs and the effect of rubbing with male beagle dogs. A pilot clinical study in healthy volunteers was performed to evaluate the effect of rubbing. Results: These investigations showed that heating or rubbing of the TV-46000 sc injection site immediately post-injection had no clinically meaningful impact on safety and no burst or uncontrolled release was evident. Furthermore, no impact of injection site manipulation on TAM exposure was observed after depot formation (≥0.5 h post-injection). Conclusions: The observed similarity in findings between the animal and human studies supports the suitability of animal models for evaluation of the effect of extrinsic factors on injection sites and its translatability to clinical settings. Full article

Background/Objectives: Obesity is an established risk factor for several infective conditions, including Acute Bacterial Skin and Skin Structure Infections (ABSSSIs), with a rising trend in their incidence expected in this population. Although numerous antibiotics are available for the prevention and treatment of ABSSSIs, their characterization in obese patients is not a regulatory mandate, highlighting a knowledge gap in this field. Dalbavancin (DAL) is the first approved long-acting antibiotic for the treatment of ABSSSIs. The aim of the study was to describe the clinical effectiveness of DAL in the treatment of ABSSSI, with or without concomitant osteoarticular infections (OAIs), in obese patients compared with non-obese patients. Furthermore, we compared the effectiveness of DAL and intravenous standard of care (SOC) regimens in a subgroup of obese patients with ABSSSI. Results: Overall, 45 subjects treated with DAL (12 obese and 33 non-obese) and 8 obese subjects treated with SOC regimens (1:1 ratio) were included. Obese patients treated with DAL had a similar clinical resolution to non-obese patients. However, obese patients tended to have a better cure rate in ABSSSI than OAI. The subgroup of obese patients with ABSSSI had a high clinical resolution, which was comparable to that of SOC. DAL was overall highly tolerated in obese patients. Methods: Over a three-year period, hospitalized subjects with ABSSSI who were treated with DAL were included. Patients were further divided into two groups according to the presence/absence of obesity (BMI ≥ 30 kg/m²). Furthermore, obese patients treated with DAL were compared with obese patients treated with SOC (1:1 ratio). Conclusions: In our real-world study, DAL confirmed its high effectiveness in the treatment of ABSSSI, including in a difficult-to-treat population such as obese patients. Full article

Background: Antiretroviral triple therapy has considerably reduced morbidity and mortality in people living with HIV and is the standard-of-care treatment. However, it is lifelong and linked to long-term side effects and adherence problems. Methods: Here, we report long-term virological and immunological outcome in 12 virally suppressed people on short-cycle therapy with bictegravir/emtricitabine/tenofovir alafenamide administered five days a week (Monday to Friday). Results: All patients, after a long term follow-up, were virally suppressed Conclusions: In the wait for new long-acting antiretroviral drugs and new antiretroviral formulations, short-cycle therapy has proven to be a safe and effective alternative to the standard daily antiretroviral regimen for individuals living with HIV who are virologically suppressed. Full article

Background: Despite achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs), an unexpected increase in the occurrence rate of hepatocellular carcinoma (HCC) has been observed among HCV-treated patients. This study aims to assess the long-term follow-up of HCV patients treated with DAAs who achieved an SVR to investigate the potential for late-onset HCC. Methods: In this prospective multicenter study, we enrolled consecutive HCV patients treated with DAAs following Italian ministerial guidelines between 2015 and 2018. Exclusion criteria included active HCC on imaging, prior HCC treatment, HBV or HIV co-infection, or liver transplant recipients. Monthly follow-ups occurred during treatment, with subsequent assessments every 3 months for at least 48 months. Abdominal ultrasound (US) was performed within two weeks before starting antiviral therapy, supplemented by contrast-enhanced ultrasonography (CEUS), dynamic computed tomography (CT), or magnetic resonance imaging (MRI) to evaluate incidental liver lesions. Results: Of the 306 patients completing the 48-months follow-up post-treatment (median age 67 years, 55% male), all achieved an SVR. A sofosbuvir-based regimen was administered to 72.5% of patients, while 20% received ribavirin. During follow-up, late-onset HCC developed in 20 patients (cumulative incidence rate of 6.55%). The pattern of HCC occurrence varied (median diameter 24 mm). Multivariate and univariate analyses identified liver stiffness, diabetes, body mass index, and platelet levels before antiviral therapy as associated factors for late HCC occurrence. Conclusions: Our findings suggest that late HCC occurrence may persist despite achieving SVR. Therefore, comprehensive long-term follow-up, including clinical, laboratory, and expert ultrasonography evaluations, is crucial for all HCV patients treated with DAAs. Full article

Background: Limited evidence is available about sleep quality changes associated with the use of Cabotegravir (CAB), a new, long-acting (LA) antiretroviral (ARV) drug belonging to the class of Integrase Strand Transfer Inhibitors (INSTIs). Methods: Pittsburgh Sleep Quality Index (PSQI) was calculated in 53 people living with HIV (PLWH) under the care of the outpatient services of two Italian Infectious Diseases Centers in Apuliabefore (M0) and seven months after (M7) the switch to LA CAB. Global scores and relative subitems were compared using paired sample tests. The same analysis was repeated in subgroups of PLWH switching from INSTIs-, Dolutegravir-(DTG), and Bictegravir (BIC)-based regimens. Results: A significant reduction was reported in global mean (±StandardDeviation, SD) PSQI at M7 compared to M0 (4 (±3) vs. 3 (±2), p = 0.01), particularly in the areas of sleep latency and sleep disturbances. The improvement was also significant in PLWH already on INSTIs- (from median 3 to 2 points, p = 0.02) and DTG-based (from median 4 to 2, p = 0.01) ARV regimens, but not among those who switched from BIC-based regimens. Conclusions: PLWH reported improved sleep quality after switching from ARV treatment to LA CAB. Further studies are needed to give deeper insights into this phenomenon. Full article

Background: Up to 34% of patients with schizophrenia are resistant to several treatment trials. Lack of continuous and adequate treatment is associated with relapse, rehospitalization, a lower effect of antipsychotic therapy, and higher risk of side effects. Long-acting injectables antipsychotics (LAI APs) enhance compliance and improve clinical outcomes and quality of life in patients with schizophrenia, and thus it may be advisable to administer two LAI APs at the same time in cases of treatment-resistant schizophrenia. The purpose of this review is to summarize the available literature regarding the combined use of two LAI APs in patients with schizophrenia or other psychotic spectrum disorders. Methods: An extensive literature search for relevant articles regarding any combination of two long-acting injectable antipsychotics has been performed from inception up to 9 February 2024, on PubMed, Scopus and APA PsycInfo, according to the PRISMA statement. Only studies reporting combination of two LAI APs and its clinical outcome in patients with schizophrenia and related disorders were selected. Results: After the selection process, nine case reports, four case series and two observational retrospective studies were included in the final analysis. All patients treated with dual LAI APs reported a good response, and no new or unexpected adverse effects due to the combination of two LAIs were reported. Different drug combinations were used, and the most frequent association resulted in aripiprazole monohydrate + paliperidone palmitate once monthly (32 times). Conclusions: Our review highlights that the treatment regimen with two concurrent LAI APs is already widely used in clinical practice and is recognized as providing a promising, effective, and relatively safe therapeutic strategy for treating the schizophrenia spectrum disorders. Full article