Search Results (224)

Background/Objectives: Pinocembrin is a promising drug candidate for treating ischemic stroke. The interaction of pinocembrin with drug transporters and drug-metabolizing enzymes is not fully revealed. The present study aims to evaluate the interaction potential of pinocembrin with cytochrome P450 (CYP450: CYP2B6, CYP2C9, and CYP2C19) and drug transporters including organic anion transporters (OAT1 and OAT3), organic cation transporters (OCT1 and OCT2), multidrug and toxin extrusion (MATE1 and MATE2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Methods: The interactions of pinocembrin on drug transporters were determined in the Madin–Darby canine kidney (MDCK) cells overexpressing human (h)OAT1 or hOAT3 and in the Chinese hamster ovary (CHO-K1) cells overexpressing hOCT1, hOCT2, hMATE1, or hMATE2. The interactions of pinocembrin with BCRP and P-glycoprotein were determined in Caco-2 cells. The CYP450 enzyme inhibitory activity was assessed by a cell-free CYP450 screening assay. Results: Pinocembrin effectively inhibited the function of OAT1 and OAT3 with a half-inhibitory concentration (IC₅₀) and inhibitory constant (Ki) of ∼2 μM. In addition, it attenuated the toxicity of tenofovir, a substrate of hOAT1, in cells overexpressing hOAT1. Based on the kinetic study and molecular docking, pinocembrin inhibited OAT1 and OAT3 via a competitive inhibition. In contrast to hOAT1 and hOAT3, pinocembrin did not significantly inhibit the function of OCT1, OCT2, MATE1, MATE2, BCRP, and P-glycoprotein. In addition, pinocembrin potently inhibited the activity of CYP2C19, whereas it exhibited low inhibitory potency on CYP2B6 and CYP2C9. Conclusions: The present study reveals the potential drug interaction of pinocembrin on OAT1, OAT3, and CYP2C19. Co-administration with pinocembrin might affect OAT1-, OAT3-, and CYP2C19-mediated drug pharmacokinetic profiles. Full article

Achieving HBsAg seroclearance is a key goal in treating chronic hepatitis B virus (HBV) infection but remains difficult with nucleos(t)ide analogues (NAs). Tenofovir alafenamide fumarate (TAF), a recommended NA for managing chronic HBV infection (CHB), has uncertain effects on HBsAg levels and potential adverse events when used long-term after switching from entecavir (ETV). We retrospectively evaluated 77 CHB patients, including 47 who switched from ETV to TAF with a median follow-up of 40 months post-switch and a median of 60 months of HBsAg monitoring pre-switch. No significant change in HBsAg levels was observed in the overall cohort post-switch, consistent with the ETV continuation group. However, a significant decrease in HBsAg was noted in patients with HBsAg < 100 IU/mL at the time of switching. HBsAg loss occurred in three patients who switched to TAF. No adverse effects were observed, and TAF was well tolerated. The most significant factor associated with achieving HBsAg < 100 IU/mL was the Fib-4 index, a marker of liver fibrosis, at the time of switching. Switching from ETV to TAF is an effective strategy in CHB management, with hepatic inflammation potentially playing an essential role in achieving HBsAg decrease. Patients with increased Fib-4 index were significantly more likely to show decreased HBsAg. This finding suggests patients with mild to moderate fibrosis may respond better to TAF in terms of HBsAg reduction. Full article

Efavirenz (EFV) causes neuropsychiatric effects such as anxiety, depression, and suicidal thoughts in people with HIV (PWH). Depressive disorders have been associated with the Tryptophan hydroxylase type 2 (TPH2) gene. Objectives: This study determines the genotypes and allelic frequencies of three TPH2 single nucleotide polymorphisms (SNPs) in a Mexican cohort of HIV-1 treatment-naïve-patients and the severity of depressive symptoms at baseline and after a four-week clinical follow-up of antiretroviral treatment. Methods: In a pilot prospective study, eighty-one antiretroviral treatment-naïve patients were recruited from the Infectious Disease Hospital, National Medical Center “La Raza”, in Mexico City. Of these, 39 were treated using a set-dose combination regimen of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus EFV and 42 were treated with TDF/FTC plus atazanavir/ritonavir (ATV/r), and fifty-nine control volunteers. Genomic DNA was obtained from peripheral blood mononuclear cells. All DNA samples underwent qPCR utilizing TaqMan probes for the three TPH2 SNPs studied. All participants underwent evaluation utilizing the Beck Depression Inventory. Results: Of the three SNPs examined, none exhibited any notable differences in the distribution of the alleles between the groups; nevertheless, rs4570625 TT and rs1386493 GG presented a twofold and fivefold greater risk of severe depression in PWH, respectively, independently of the treatment. Among PWH, those treated with EFV experienced severe depression at a higher rate of 90.4% after four weeks, compared to 87.5% in those treated with ATV/r. Conclusions: High rates of severe depression were identified in PWH, who presented the rs4570625 TT and rs1386493 GG polymorphic variants. Depression increased after four weeks of treatment and was higher with EFV than ATV/r. It is crucial to emphasize the necessity of conducting psychiatric monitoring for every patient with HIV and administering prompt antidepressant treatment. Full article

Background: With advances in antiretroviral therapy for HIV treatment, newer drug combinations provide improved efficacy, safety, and compliance. This study evaluates switching to a regimen of doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) in a cohort of people living with HIV (PLWH). Methods: this Italian retrospective study included 426 PLWH who switched from rilpivirine (RPV)/TDF/emtricitabine (FTC) to DOR/3TC/TDF. The analysis focused on treatment effectiveness, safety, and metabolic and renal markers. Results: this study reports a treatment failure (defined as virological failure or discontinuation of the regimen) rate of 2.34% (95% confidence interval, 1.28–4.50%), with significant improvement in CD4 counts (+49.93 cells/µL, p < 0.001). Notably, the switch to DOR/3TC/TDF did not result in adverse metabolic effects or significant changes in renal function. Analysis of lipid profiles showed stabilization in the majority of PLWH. Conclusions: this study indicates that switching to a DOR/3TC/TDF from RPV/TDF/FTC is an effective and well-tolerated option for PLWH, with benefits in terms of maintaining viral suppression, CD4 count recovery, and metabolic health, without evidence of renal impairment. These results support the continued use of DOR/3TC/TDF as part of HIV treatment strategies and highlight the need for ongoing research to refine ART regimens for different populations. Full article

Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance are currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistant mutations in HIV-1 subtype C for their phenotypic resistance to ISL. Prevalent single and combinations of NRTI-resistant mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI-resistant mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, and K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, and M184V). Combinations of M184V with one or more additional NRTI-resistant mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens, but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens. Full article

Adverse complications like metabolic disorders, neurotoxicity, and low central nervous system (CNS) penetration are associated with the long-term use of tenofovir disoproxil fumarate (TDF). Therefore, some modifications are required to enhance neurological functions using silver nanoparticles (AgNPs). This study aimed to evaluate the neuroprotective impact of silver nanoparticles (AgNPs)-conjugated TDF as AgNPs-TDF on the hippocampal microanatomy and some neuro-biomarkers of diabetic rats. Forty-two male Sprague-Dawley rats, with an average weight of 250 ± 13 g, were divided into non-diabetic and diabetic groups. They were further divided into 3 groups each (n = 7): non-diabetic control (NC), non-diabetic + TDF (NTF), and non-diabetic + TDF + silver nanoparticles (NTS), as well as diabetic control (DC), diabetic + TDF (DTF), and diabetic + TDF + silver nanoparticles (DTS). The characterization of AgNPs-TDF was assessed, and the conjugates were administered to the diabetic rats, followed by behavioral testing and biochemical, immunohistochemical, and microanatomy analyses of the hippocampus. The results showed that the administration of AgNPs-TDF significantly reduced the blood glucose level, malondialdehyde (MDA), and inflammatory biomarker concentrations in DTS compared with the DTF and DC groups. Furthermore, AgNPs-TDF administration significantly increased the levels of tissue superoxide dismutase (SOD), reduced glutathione (GSH), and insulin-like growth factor-1 in DTS compared with the DTF and DC groups. In addition, the DTS group revealed a monomorphic pattern of dark-stained neuronal nuclei similar to the control group and showed neuroprotective effects on hippocampal microanatomy compared with the DTF group. This study shows that AgNPs-TDF restores various alterations in the hippocampus and improves cognitive functions in diabetic rats. Full article

This study investigates the electrospinning and rheological properties of polyethylene terephthalate (PET) and polyvinyl alcohol (PVA) with varying degrees of hydrolysis (DH) for molecularly imprinted polymer (MIP) incorporation. The morphology and properties of the electrospun nanofibers were evaluated, revealing that PVA nanofibers exhibited smoother and more uniform structures compared to PET fibers. The rheological behavior of the polymer solutions was also characterized, showing that PVA 99 DH solution exhibited shear-thinning behavior due to the unique structural properties of the polymer chains. The introduction of MIP and NIP additives had no significant impact on the rheological properties, except for PVA 99 MIP and NIP solutions, which showed deviations from Newtonian behavior. The electrospun MIP nanofibers showed a conductivity of 1054 µS/cm for PVA (87–90% DH) and a viscosity of 165.5 mPa·s, leading to optimal fiber formation, while displaying a good adsorption capacity of 0.36 mg for PVA-MIP to effectively target pharmaceuticals such as emtricitabine and tenofovir disoproxil, showing their potential for advanced water treatment applications. The results suggest that the electrospinning process and rheological properties of the polymer solutions are influenced by the molecular structure and interactions within the polymer matrix, which can be exploited to tailor the properties of MIPs for specific applications. 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

Body weight is impacted by several individual host and environmental factors. In a person living with HIV (PLWH), weight is also influenced by the disease stage. Wasting syndrome is derived from disease progression, and it can be reversed by the effective use of highly active antiretroviral therapy (HAART). Body weight alterations have been studied and compared in several clinical ART trials, and they differ according to antiviral regimens. The newer integrase strand transfer inhibitors (INSTIs), such as bictegravir and dolutegravir, especially when co-administered with tenofovir alafenamide fumarate (TAF), seem to lead to greater weight increases compared to regimens that include tenofovir disoproxil fumarate (TDF), which seem to have an attenuating effect on weight gain. Nevertheless, despite the established association between INSTI and TAF and the negative impact on weight, more recent data suggest a more cautious approach when HAART treatment decisions are taken. In this manuscript, we review weight changes among PLWH receiving HAART and the relevant underlying pathogenic mechanisms described in recent literature. We try to provide a more critical appraisal of the available data and to underline the challenges in assessing the role of HAART in weight changes in both ART initiation and setting switching. Full article

Background/Objectives: Out of 39.9 million adults living with HIV in 2022, 20 million were women. Despite bearing a significant burden, women remain underrepresented in clinical trials, including those for antiretroviral treatments (ART). This study evaluates the safety and efficacy of the bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) regimen in a real-life cohort of 99 women with HIV (females with HIV, FWH) over 48 and 96 weeks. Methods: A retrospective cohort study utilized data from the Sardinian HIV Network and Sicilian HIV Cohort (SHiNe-SHiC) research group. The study included FWH, who started B/F/TAF as a treatment switch. The primary objectives were achieving and maintaining an HIV RNA level of <50 copies/mL at 48 and 96 weeks. Secondary objectives included treatment safety, durability, and reasons for discontinuation. Data on demographics, viro-immunological markers, lipid profiles, and treatment interruptions were extracted for analysis. Results: Among the 99 FWH, the median age was 51.9 years, and the median duration of HIV was 15.1 years. At baseline, 80.8% had undetectable HIV-RNA, which increased to 93.8% at 96 weeks. There was a statistically significant increase in CD4 cells/mL (48w p < 0.001, 96w p < 0.001) and CD4/CD8 ratio (48w p < 0.009, 96w p < 0.048), and reductions in total cholesterol (48w p < 0.003, 96w p < 0.006) and LDL (48w p < 0.004, 96w p < 0.009) levels at 48 and 96 weeks. Nine treatment interruptions were noted, with one due to adverse events. The regimen was well-tolerated overall. Conclusions: B/F/TAF demonstrated high efficacy and safety in this real-world cohort of FWH, highlighting the critical need for gender-focused research in HIV treatment. Ensuring equitable access to effective treatment options for women is imperative for the global health community’s efforts to eliminate HIV. Full article

Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug extensively used by people living with HIV. The TDF molecule is hydrolysed in vivo and liberates tenofovir, the active part of the molecule. Tenofovir is a very stable drug and the discharge of its residues into the environment can potentially lead to risk for aquatic species. This study evaluated the TDF biodegradation and removal by cultures of Microcystis novacekii with the bacteria Pseudomonas pseudoalcaligenes. Concentrations of TDF of 12.5, 25.0, and 50.0 mg/L were used in this study. The process occurred in two stages. In the first 72 h, TDF was de-esterified, forming the tenofovir monoester intermediate by abiotic and enzymatic processes associated in an extracellular medium. In a second step, the monoester was removed from the culture medium by intracellular processes. The tenofovir or other by-products of TDF were not observed in the test conditions. At the end of the experiment, 88.7 to 94.1% of TDF and its monoester derivative were removed from the culture medium over 16 days. This process showed higher efficiency of TDF removal at the concentration of 25 mg/L. Tenofovir isoproxil monoester has partial antiviral activity and has shown to be persistent, maintaining a residual concentration after 16 days in the culture medium, therefore indicating the need to continue research on methods for total removal of this product from the aquatic environment. Full article

Background: Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir for the treatment of chronic hepatitis B (CHB) that has shown a favourable renal safety profile while offering suppression of HBV DNA similar to tenofovir disoproxil fumarate (TDF). We aimed to study changes in markers of HBV replication and renal function in a real-world setting in European patients. Methods: In our prospective single-arm, non-interventional observational study, HBeAg-positive and HBeAg-negative patients with chronic HBV mono-infection receiving TAF as their first or following line treatment were enrolled. HBV DNA, HBsAg, markers of bone metabolism, and renal function were determined at baseline and every consecutive 3 months. Results: A total of 50 patients (70% male) were included. The mean duration of TAF treatment was 18 (3–36) months. In 20 patients with detectable HBV DNA at baseline, median serum levels of HBV DNA log₁₀ changed from 2.33 (0.766–6.47) to 1.04 IU/mL at the end of observation and became undetectable in 11 patients. Median HBsAg log₁₀ decreased from 3.37 (0.88–5.10) to 2.39 (1.52–4.19) IU/mL. During the entire observation period, the renal function parameters remained stable in patients with normal renal function and even in those with renal dysfunction. Mild adverse events were reported by 14 patients (28%). Conclusions: TAF was a safe and effective treatment, also in patients with decreased renal function. Full article

Introduction: Post-menopausal women living with Human Immunodeficiency Virus (WLHIV) face an increased risk of bone fractures due to the relationship between HIV-related factors and menopause. This narrative review aims to summarise the current knowledge about fracture risk among post-menopausal WLHIV in particular looking at hormonal changes, combined antiretroviral therapy (cART), lifestyle factors, and psychosocial implications. We also profiled a summary of the significant, recent studies of post-menopausal WLHIV residing in low-income countries (LIC). Methods: A thorough search of the literature was performed across PubMed, Medline, Scopus, and Google Scholar, focussing on studies published between 2000 and 2024. Inclusion criteria entailed original research, reviews, and meta-analyses addressing bone mineral density (BMD), fracture incidence, and related risk factors in post-menopausal WLHIV. Results: The review identified 223 relevant studies. Post-menopausal WLHIV exhibit significantly lower BMD and higher fracture rates compared to both HIV-negative post-menopausal women and pre-menopausal WLHIV. cART, particularly tenofovir disoproxil fumarate (TDF), contributes to reduced BMD. Menopausal status exacerbates this risk through decreased oestrogen levels, leading to increased bone resorption. Moreover, lifestyle choices such as smoking, alcohol consumption, and low physical activity are more prevalent in PWHIV, which further elevates fracture risk. Different psychosocial factors may make WLWHIV more vulnerable at this stage of their life, such as depression, isolation, stigma, and housing and nutritional issues. Women living in LICs face a variety of challenges in accessing HIV care. There are gaps in research related to the prevalence of osteoporosis and bone loss in post-menopausal WLHIV in LICs. Conclusion: Post-menopausal women living with HIV face a significantly higher risk of bone loss and fractures due to the combined effects of HIV and menopause. Antiretroviral therapy (particularly TDF), lifestyle factors, and psychosocial challenges exacerbate this risk. There is a need for careful selection of cART, hormone replacement therapy (HRT), and emerging treatments such as Abaloparatide. A holistic approach including lifestyle changes and psychosocial support is crucial to reduce fracture risk in WLHIV, especially in low-income countries. Full article

Introduction: Chronic hepatitis B (CHB) is a significant public health issue worldwide, especially in the Middle East region. Around 8% to 20% of patients with CHB develop cirrhosis, which may progress to hepatocellular carcinoma. The significant morbidity and mortality associated with CHB denote the importance of high-quality treatment. Methods: We searched the PubMed, Medline, and Cochrane databases from inception to January 2024 to identify relevant studies. Search terms were generated using established treatment guidelines for CHB. We also manually searched the bibliographies of relevant literature to obtain additional papers. Results: In this narrative review, we evaluated the seven currently licensed antiviral therapies for chronic Hepatitis B treatment, including nucleos(t)ide analogs (NAs) and pegylated interferon-alpha (PEG-IFNα). NAs can be divided into two categories: high barrier to resistance and low barrier to resistance. Tenofovir disoproxil fumarate, tenofovir alafenamide, and entecavir are NAs with a high barrier to resistance. Telbivudine has shown promise in providing high efficacy with low viral resistance rates; however, it is not recommended because of insufficient evidence and lack of cost-effectiveness. Lamivudine and adefovir dipivoxil, despite being efficacious, have a low barrier to resistance, the primary reason they are no longer recommended. PEG-IFNα has high efficacy and can be completed in 48 weeks. It is not associated with resistance; however, it has been reported to have several systemic adverse effects. Conclusions: Current first-line NA treatments in the Middle East include entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. These drugs are favored over other NAs because of their low rates of resistance. PEG-IFNα has superiority over NAs in inducing a more durable antiviral response and having a finite treatment duration. The main drawback of PEG-IFNα is an unfavorable safety profile. Full article

Human T-cell lymphotropic virus (HTLV) infection affects over ten million people worldwide, but there is no effective treatment so far. This review describes the virological, immunological, and clinical outcomes of antiretroviral therapy (ART) in people with HTLV infection. This systematic review followed PRISMA reporting guidelines and was registered in PROSPERO: CRD42022350076. The Newcastle–Ottawa Scale, adapted for cross-sectional studies, and Rob-2 were used to assess the methodological quality of these studies. Systematic searches were conducted in the Medline (PubMed), Scopus (Elsevier), Cochrane Library, and Web of Science (Clarivate Analytics) databases. We retrieved data from eight methodologically diverse articles on treatment of patients infected by HTLV-1 or HTLV-2 alone, or coinfected by HIV-1, who received Raltegravir, Tenofovir, Lamivudine, or Zidovudine. The proviral load decreased in three out of seven studies over 4 to 48 weeks of antiretroviral use. Cellular immune response (CD4, CD8, CD25, CD69, and CD71 cells) was evaluated in six studies. While no significant clinical improvement was observed, all studies reported clinical stability during treatment. Despite the demonstrated antiviral activity of ART, in vitro, clinical improvement was not proven. Most studies showed disease stability during ART use, suggesting potential clinical benefits. There is a need of larger, well-controlled trials to define the role of ART in the treatment of HTLV infection. Full article