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Objective International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the 2 regimens are lacking. Design In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to 31 March 2024 and extracted data from cohort studies and randomized controlled trials (RCTs) in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups. Results We included 31 studies with 2588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6–12 months (risk ratio: 0.10, 95% confidence interval [CI].07–.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval.16–7.61). Network meta-analysis showed equal efficacy of the 2 regimens in reducing MTCT (risk ratio: 1.09, 95% CI.15–7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking:.77 vs.72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens. Conclusions Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) dysfunction remains prevalent in people with HIV (PWH) despite effective antiretroviral therapy (ART). There is evidence that low-level HIV infection and ART drugs may contribute to CNS damage in the brain of PWH with suppressed viral loads. As cannabis is used at a higher rate in PWH compared to the general population, there is interest in understanding how HIV proteins and ART drugs interact with the endocannabinoid system (ECS) and inflammation in the CNS. Therefore, we investigated the effects of the HIV envelope protein gp120 and tenofovir alafenamide (TAF) on cannabinoid receptor 1 (CB1R), glial fibrillary acidic protein (GFAP), and IBA1 in the brain and on locomotor activity in mice. The gp120 transgenic (tg) mouse model was administered TAF daily for 30 days and then analyzed using the open field test before being euthanized, and their brains were analyzed for CB1R, GFAP, and IBA1 expression using immunohistochemical approaches. CB1R expression levels were significantly increased in CA1, CA2/3, and dentate gyrus of gp120tg mice compared to wt littermates; TAF reversed these effects. As expected, TAF showed a medium effect of enhancing GFAP in the frontal cortex of gp120tg mice in the frontal cortex. TAF had minimal effect on IBA1 signal. TAF showed medium to large effects on fine movements, rearing, total activity, total distance, and lateral activity in the open-field test. These findings suggest that TAF may reverse gp120-induced effects on CB1R expression and, unlike tenofovir disoproxil fumarate (TDF), may not affect gliosis in the brain.

In aviation, accurate wind prediction is crucial, especially during takeoff and landing at complex sites like Gran Canaria Airport. This study evaluated five Deep Learning models: Long Short-Term Memory (LSTM), Vanilla Recurrent Neural Network (vRNN), One-Dimensional Convolutional Neural Network (1dCNN), Convolutional Neural Network Long Short-Term Memory (CNN-LSTM), and Gated Recurrent Unit (GRU) for forecasting wind speed and direction. The LSTM model demonstrated the highest precision, particularly for extended forecasting periods, achieving a mean absolute error (MAE) of 1.23 m/s and a circular MAE (cMAE) of 15.80° for wind speed and direction, respectively, aligning with World Meteorological Organization standards for Terminal Aerodrome Forecasts (TAF). While the GRU and CNN-LSTM also showed promising results, and the 1dCNN excelled in wind direction forecasting over shorter intervals, the vRNN lagged in performance. Additionally, the autoregressive integrated moving average model underperformed relative to the DL models, underscoring the potential of DL, particularly LSTM, in enhancing TAF accuracy at airports with intricate wind patterns. This study not only confirms the superiority of DL over traditional methods but also highlights the promise of integrating artificial intelligence into TAF automation. [ABSTRACT FROM AUTHOR]

With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in humans after HIV-1. Like HIV-1, HTLV-1 overwhelmingly persists in a host via a reservoir of latently infected CD4+ T cells. Although most patients are asymptomatic, HTLV-1-associated pathologies are often debilitating and include adult T-cell leukaemia/lymphoma (ATLL), which presents in mature adulthood and is associated with poor prognosis with short overall survival despite treatment. Curiously, the strongest indicator for the development of ATLL is the acquisition of HTLV-1 through breastfeeding. There are no therapeutic or preventative regimens for HTLV-1. However, antiretrovirals (ARVs), which target the essential retrovirus enzymes, have been developed for and transformed HIV therapy. As the architectures of retroviral enzyme active sites are highly conserved, some HIV-specific compounds are active against HTLV-1. Here, we expand on our work, which showed that integrase strand transfer inhibitors (INSTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs) block HTLV-1 transmission in cell culture. Specifically, we find that dolutegravir, the INSTI currently recommended as the basis of all new combination antiretroviral therapy prescriptions, and the latest prodrug formula of the NRTI tenofovir, tenofovir alafenamide, also potently inhibit HTLV-1 infection. Our results, if replicated in a clinical setting, could see transmission rates of HTLV-1 and future caseloads of HTLV-1-associated pathologies like ATLL dramatically cut via the simple repurposing of already widely available HIV pills in HTLV-1 endemic areas. Considering our findings with the old medical saying "it is better to prevent than cure", we highly recommend the inclusion of INSTIs and tenofovir prodrugs in upcoming HTLV-1 clinical trials as potential prophylactics. [ABSTRACT FROM AUTHOR]

Terminal Aerodrome Forecasts (TAFs) are essential components of aviation meteorology, providing critical information for flight safety and operational decision-making. This study conducts a comprehensive analysis of TAF for European airports during the years 2022 and 2023, leveraging Python functions accessible via a dedicated GitHub repository. The complexity inherent in TAF, characterized by diverse change groups, header formats, and regional variations, presents challenges for accurate interpretation. The analysis focuses on key parameters within TAF, including the count of corrected messages and the frequency and types of change groups. The count of corrected messages serves as a metric for evaluating the quality of service provided, while the examination of change group utilization reveals distinct patterns and tendencies specific to each airport. The findings underscore the significance of regional regulations, meteorologist decision-making, and adherence to International Civil Aviation Organization (ICAO) standards in shaping TAF. The GitHub repository and associated Python functions presented in this study provide valuable resources for meteorologists, researchers, and aviation personnel to conduct in-depth analyses and derive insights from TAF. Ultimately, this study identifies local differences and inconsistencies in the publication of TAF, laying the groundwork for enhancing their consistency and uniformity. [ABSTRACT FROM AUTHOR]

The understanding of the mechanisms that regulate gene expression to establish differentiation programs and determine cell lineages, is one of the major challenges in Developmental Biology. Besides the participation of tissue‐specific transcription factors and epigenetic processes, the role of general transcription factors has been ignored. Only in recent years, there have been scarce studies that address this issue. Here, we review the studies on the biological activity of some TATA‐box binding protein (TBP)‐associated factors (TAFs) during the proliferation of stem/progenitor cells and their involvement in cell differentiation. Particularly, the accumulated evidence suggests that TAF4, TAF4b, TAF7L, TAF8, TAF9, and TAF10, among others, participate in nervous system development, adipogenesis, myogenesis, and epidermal differentiation; while TAF1, TAF7, TAF15 may be involved in the regulation of stem cell proliferative abilities and cell cycle progression. On the other hand, evidence suggests that TBP variants such as TBPL1 and TBPL2 might be regulating some developmental processes such as germ cell maturation and differentiation, myogenesis, or ventral specification during development. Our analysis shows that it is necessary to study in greater depth the biological function of these factors and its participation in the assembly of specific transcription complexes that contribute to the differential gene expression that gives rise to the great diversity of cell types existing in an organism. The understanding of TAFs' regulation might lead to the development of new therapies for patients which suffer from mutations, alterations, and dysregulation of these essential elements of the transcriptional machinery. [ABSTRACT FROM AUTHOR]

Terminal Aerodrome Forecasts (TAFs) are essential components of aviation meteorology, providing critical information for flight safety and operational decision-making. This study conducts a comprehensive analysis of TAF for European airports during the years 2022 and 2023, leveraging Python functions accessible via a dedicated GitHub repository. The complexity inherent in TAF, characterized by diverse change groups, header formats, and regional variations, presents challenges for accurate interpretation. The analysis focuses on key parameters within TAF, including the count of corrected messages and the frequency and types of change groups. The count of corrected messages serves as a metric for evaluating the quality of service provided, while the examination of change group utilization reveals distinct patterns and tendencies specific to each airport. The findings underscore the significance of regional regulations, meteorologist decision-making, and adherence to International Civil Aviation Organization (ICAO) standards in shaping TAF. The GitHub repository and associated Python functions presented in this study provide valuable resources for meteorologists, researchers, and aviation personnel to conduct in-depth analyses and derive insights from TAF. Ultimately, this study identifies local differences and inconsistencies in the publication of TAF, laying the groundwork for enhancing their consistency and uniformity.

BackgroundTenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV.MethodsIMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5-9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant.ResultsTwenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF.ConclusionTAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Aviation forecasters, recognized for their consistent professionalism and rigorous training, typically exhibit unwavering focus on their responsibilities. Despite this, acknowledging the human element, this research explores the potential impact of external social and psychological influences on their forecasting accuracy. Utilizing standard Terminal Aerodrome Forecasts (TAF) and Meteorological Aerodrome Reports (METAR) observations, the study assesses forecast quality, emphasizing significant events like the COVID-19 pandemic, Nordic storm, tornado, and ice hockey world cup finals. Instances of decreased forecast accuracy during these events prompt an investigation into the role of social and psychological factors. This paper introduces a novel approach, employing variance from the long-term average, to gauge the influence of social and psychological factors on professional performance. Beyond highlighting the daily impacts of the social environment on highly routinized and professional activities, the study underscores an often-overlooked prospect. It posits that professional and technical assessment metrics can robustly indicate the severity of social and natural events. The research thus contributes to a deeper understanding of the intricate interplay between meteorological expertise and external influences, emphasizing the potential for utilizing professional performance metrics as indicators of broader societal events.

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 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.

Background Lockdown due to the coronavirus disease 2019 (COVID-19) pandemic led to increases in weight in part of the population. Weight gain leads to hepatic steatosis (HS). Antiretroviral treatment could also influence HS in people with human immunodeficiency virus (PWH). The impact of lockdown on HS in PWH is unknown. The aim of this study was to analyze the changes in HS, as measured by the controlled attenuation parameter (CAP), during the COVID-19 pandemic in PWH. Methods This was a cohort study that included PWH who attended a tertiary care center in southern Spain from January 2018 to December 2021. The CAP was evaluated by transient elastography. Only those who had a valid CAP before and after March 2020 were included. HS was defined as CAP ≥248 dB/m. Results Six hundred eighty PWH were attended and 488 (71.8%) were included. Two hundred and fourteen (43.9%) had HS at baseline and 239 (49%) at the end of the follow-up (P =.036). The median change in CAP among PWH taking tenofovir alafenamide (TAF) was 8.5 (interquartile range [IQR], −24 to 46.3) dB/m versus −4 (IQR, −35 to 27) dB/m among PWH receiving TAF-free regimens (P =.003). After multivariate analysis, adjusted by sex and age, weight gain (adjusted odds ratio [AOR], 1.09 [95% confidence interval {CI}, 1.05–1.14]; P <.001), TAF therapy (AOR, 1.59 [95% CI, 1.07–2.35]; P =.021), plasma triglycerides (AOR, 1.01 [95% CI, 1–1.01]; P <.001), and fasting blood glucose (AOR, 1.01 [95% CI, 1–1.02]; P =.027) were associated with HS at the end of follow-up. Conclusions The frequency of HS increased during the COVID-19 pandemic among PWH. TAF is associated with HS development, regardless of metabolic factors. [ABSTRACT FROM AUTHOR]

Abstract Background Pediatric HIV infection cause retardation in height and weight. However, effective antiretroviral therapy (ART) result in desirable weight gain. Concerns have emerged regarding excessive weight gain related to the integrase inhibitor dolutegravir in adults but knowledge about the circumstances in children/adolescents is limited. We studied if dolutegravir containing ART or switch to dolutegravir affected body mass index (BMI) and described height development in the Stockholm pediatric/adolescent HIV cohort. Methods A retrospective cohort study of height, weight and BMI in relation to ART in 94 children/adolescents living with HIV. Results At last documented visit 60/94 children/adolescents were on dolutegravir, 50 had switched from a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Height standard deviation score (SDS) increased between first and last visit from mean height SDS -0.88 (16 had SDS

With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in humans after HIV-1. Like HIV-1, HTLV-1 overwhelmingly persists in a host via a reservoir of latently infected CD4+ T cells. Although most patients are asymptomatic, HTLV-1-associated pathologies are often debilitating and include adult T-cell leukaemia/lymphoma (ATLL), which presents in mature adulthood and is associated with poor prognosis with short overall survival despite treatment. Curiously, the strongest indicator for the development of ATLL is the acquisition of HTLV-1 through breastfeeding. There are no therapeutic or preventative regimens for HTLV-1. However, antiretrovirals (ARVs), which target the essential retrovirus enzymes, have been developed for and transformed HIV therapy. As the architectures of retroviral enzyme active sites are highly conserved, some HIV-specific compounds are active against HTLV-1. Here, we expand on our work, which showed that integrase strand transfer inhibitors (INSTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs) block HTLV-1 transmission in cell culture. Specifically, we find that dolutegravir, the INSTI currently recommended as the basis of all new combination antiretroviral therapy prescriptions, and the latest prodrug formula of the NRTI tenofovir, tenofovir alafenamide, also potently inhibit HTLV-1 infection. Our results, if replicated in a clinical setting, could see transmission rates of HTLV-1 and future caseloads of HTLV-1-associated pathologies like ATLL dramatically cut via the simple repurposing of already widely available HIV pills in HTLV-1 endemic areas. Considering our findings with the old medical saying “it is better to prevent than cure”, we highly recommend the inclusion of INSTIs and tenofovir prodrugs in upcoming HTLV-1 clinical trials as potential prophylactics.

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Background We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. Methods Children aged 3–15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)–recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8–9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration–time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. Results Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. Conclusions In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. Clinical Trials Registration ISRCTN22964075. [ABSTRACT FROM AUTHOR]

Aviation forecasters, recognized for their consistent professionalism and rigorous training, typically exhibit unwavering focus on their responsibilities. Despite this, acknowledging the human element, this research explores the potential impact of external social and psychological influences on their forecasting accuracy. Utilizing standard Terminal Aerodrome Forecasts (TAF) and Meteorological Aerodrome Reports (METAR) observations, the study assesses forecast quality, emphasizing significant events like the COVID-19 pandemic, Nordic storm, tornado, and ice hockey world cup finals. Instances of decreased forecast accuracy during these events prompt an investigation into the role of social and psychological factors. This paper introduces a novel approach, employing variance from the long-term average, to gauge the influence of social and psychological factors on professional performance. Beyond highlighting the daily impacts of the social environment on highly routinized and professional activities, the study underscores an often-overlooked prospect. It posits that professional and technical assessment metrics can robustly indicate the severity of social and natural events. The research thus contributes to a deeper understanding of the intricate interplay between meteorological expertise and external influences, emphasizing the potential for utilizing professional performance metrics as indicators of broader societal events. [ABSTRACT FROM AUTHOR]

Tenofovir alafenamide (TAF) is a prodrug of the nucleoside reverse transcriptase (RT) inhibitor tenofovir (TFV). Compared to the earlier TFV prodrug, TFV disoproxil fumarate (TDF), TAF achieves more than fourfold‐higher intracellular levels of its active metabolite TFV diphosphate (TFV‐DP) in clinical studies, while achieving a significant reduction of TFV systemic exposure. Resistance to TFV has been well established, with the K65R mutation in RT as the signature mutation. Here we evaluated the in vitro activity of TAF and TDF in patient‐derived HIV‐1 isolates harboring the K65R mutation. Clinical isolates containing K65R were cloned into the pXXLAI construct (n = 42). In vitro phenotypic susceptibility of the constructs to TAF and TDF was evaluated in an MT‐2 cell HIV assay and in viral breakthrough assays modeling physiological concentrations of TAF and TDF. TAF and TDF susceptibility were highly correlated in K65R‐containing mutants, ranging from 2.7‐ to 3.0‐fold (K65R alone) and 1.2‐ to 27.6‐fold (K65R+ other RT mutations) relative to wild‐type. In viral breakthrough assays mimicking differences in physiological concentrations, TAF inhibited breakthrough of 40 of 42 clinical isolates, while the TDF equivalent only inhibited 32 of 42 isolates tested. TAF displayed a higher barrier to resistance than TDF in this panel of K65R‐containing clinical isolates. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: The timing and magnitude of antiretroviral therapy–associated weight change attributions are unclear. Setting: HIV Outpatient Study participants. Methods: We analyzed 2007–2018 records of virally suppressed (VS) persons without integrase inhibitor (INSTI) experience who switched to either INSTI-based or another non–INSTI-based ART, and remained VS. We analyzed BMI changes using linear mixed models, INSTI- and tenofovir alafenamide (TAF) contributions to BMI change by linear mixed models–estimated slopes, and BMI inflection points. Results: Among 736 participants (5316 person-years), 441 (60%) switched to INSTI-based ART; the remainder to non–INSTI-based ART. The mean follow-up was 7.15 years for INSTI recipients and 7.35 years for non-INSTI. Preswitch, INSTI and non-INSTI groups had similar median BMI (26.3 versus 25.9 kg/m2, P = 0.41). INSTI regimens included raltegravir (178), elvitegravir (112), and dolutegravir (143). Monthly BMI increases postswitch were greater with INSTI than non-INSTI (0.0525 versus 0.006, P < 0.001). A BMI inflection point occurred 8 months after switch among INSTI users; slopes were similar regardless of TAF use immediately postswitch. Among INSTI + TAF users, during 8 months postswitch, 87% of BMI slope change was associated with INSTI use, 13% with TAF use; after 8 months, estimated contributions were 27% and 73%, respectively. For non-INSTI+TAF, 84% of BMI gain was TAF-associated consistently postswitch. Persons switching from TDF to TAF had greater BMI increases than others (P < 0.001). Conclusion: Among VS persons who switched ART, INSTI and TAF use were independently associated with BMI increases. During 8 months postswitch, BMI changes were greatest and most associated with INSTI use; afterward, gradual BMI gain was largely TAF-associated. [ABSTRACT FROM AUTHOR]

Objective: Tenofovir alafenamide (TAF) achieves increased renal safety and improved alanine aminotransferase (ALT) normalization but increased lipid profile in hepatitis B virus (HBV)–monoinfected patients switched from tenofovir disoproxil fumarate (TDF). It is unclear whether HIV coinfection perturbs these biochemical changes. To this end, we assessed these parameters in HIV/HBV-coinfected patients switched from TDF to TAF. Design: Retrospective, multicenter, observational study. Methods: HIV/HBV-coinfected patients switched from TDF to TAF-based antiretroviral therapy (ART) at 6 Canadian Hepatitis B Network (CanHepB) academic sites were included. Changes in lipid profile, estimated glomerular filtration rate (eGFR), and ALT were evaluated using linear mixed effect model regression. Results: Eighty-two HIV/HBV-coinfected patients with a mean 103-week follow-up duration were identified. At time of TAF switch, 80 of 82 (98%) were HBV virally suppressed, 29 of 82 (35%) had elevated ALT levels, and 63 of 82 (77%) had eGFR of ≥60 mL/min per 1.73 m2. Twenty-six/Eighty-two (32%) had preexisting renal comorbidities. There were no changes in total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels 2 years after TAF switch. Those with elevated ALT levels achieved greater ALT normalization after TAF switch (−0.004 [−0.008 to 0.0] log10U/L/mo, P = 0.03). eGFR decline rate while on TDF (−0.66 [−0.23 to −1.08] mL/min/month, P < 0.005) was diminished after switching to TAF (−0.02 [−0.16 to 0.11] mL/min/mo, P = 0.7) and those with eGFR of <60 mL/min experienced increase in eGFR after TAF switch (0.45 [0.03–0.87] mL/min/mo, P = 0.04). Conclusions: Our study supports switching from TDF to TAF with positive influence on overall long-term biochemical profile in HIV/HBV-coinfected individuals. [ABSTRACT FROM AUTHOR]

Background: The introduction of tenofovir alafenamide (TAF) in antiretroviral therapy has deeply modified the choice of the backbone for different treatment regimens, allowing the prevention of the bone and renal toxicity that was related to the previous formulation of tenofovir disoproxil fumarate (TDF). At the same time, literature data show an onset of dyslipidemia after a switch from TDF to TAF. To better understand the possible role of TAF in dyslipidemia, antiretroviral-naïve HIV-infected patients were evaluated, comparing those treated with TAF/emtricitabine with those with abacavir/lamivudine. Methods: We enrolled 270 antiretroviral-naïve HIV-infected patients in an observational, retrospective, longitudinal, multicenter study; they started treatment from 2017 to 2019 and were followed up for at least 72 weeks. We divided patients into two groups, one treated with a TAF-based backbone in their antiretroviral regimens (TAF group) and one without TAF (NO TAF group), to evaluate possible differences in the dynamics of lipid profiles from baseline(T0) to week 24 (T24), 48 (T48) and 72 (T72). Results: No significant differences were observed at baseline between the 2 groups. In the TAF group we observed a significant development of hypercholesterolemia throughout the follow-up (p < 0.0001), not evident in the NO TAF group, that instead showed a significant increase in high-density lipoprotein (HDL). There were no significant differences between the two groups regarding triglycerides, low-density lipoprotein (LDL) and cardiovascular risk index (CRI). A cholesterol-lowering treatment with statin, finally, was prescribed in 6 patients in both groups during the study. At binary logistic regression analysis, no factor was independently associated with hypercholesterolemia, except for higher age at T0. Conclusions: This real-life study shows that in HIV-naïve patients, TAF was associated with hypercholesterolemia throughout the follow-up. The clinical significance of this hypercholesterolemia will have to be clarified in further studies. [ABSTRACT FROM AUTHOR]

My collaboration with Prof. Antonín Holý, that spans a period of 3–4 decades (1976–2012), led to the discovery of several acyclic nucleoside phosphonates (ANPs) which were clinically developed by Gilead Sciences: cidofovir, adefovir, and tenofovir. The latter was further converted to two orally bioavailable prodrug forms, TDF and TAF, and both TDF and TAF were further combined with other antiviral drugs, thus giving rise to a broad array of antiviral drug combinations for the treatment of HIV infections. TDF and TAF are both available for the treatment of hepatitis B virus (HBV) infections, and, in combination with emtricitabine, also applicable as Truvada® and Descovy®, respectively, for the prophylaxis of HIV infections. [ABSTRACT FROM AUTHOR]

The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19. [ABSTRACT FROM AUTHOR]

Se expone la continuación de la metodología para la verificación de los pronósticos de aeródromo (TAF) emitidos por la Oficina Principal de Vigilancia Meteorológica perteneciente al Instituto de Aeronáutica Civil de Cuba. Esta segunda parte está destinada a la verificación de los grupos de cambio y de probabilidad incluidos en los TAF, el cual evalúa la correcta utilización de dichos grupos, el comportamiento de las variables durante o después del cambio, según sea el caso, y las características individuales de cada grupo. Para ello se tomaron en cuenta los requisitos de la Organización de Aviación Civil Internacional establecidos en el Anexo para los servicios meteorológicos para la navegación aérea internacional, así como otros de índole nacional recogidos en los Manuales y Regulaciones Aeronáuticas Cubanas. El procedimiento aquí expuesto está implementado en el Sistema Automatizado para la Evaluación de los TAF (SAETAF), software que fue introducido oficialmente en la Oficina Principal de Vigilancia Meteorológica en Cuba desde noviembre de 2015. Asimismo, la metodología presentada bien pudiera utilizarse en la verificación de los TAF elaborados por Oficinas Meteorológicas de Aeródromo de otros países.

Nicola Squillace,1 Elena Ricci,2 Barbara Menzaghi,3 Giuseppe Vittorio De Socio,4 Simone Passerini,5 Canio Martinelli,6 Maria Sabrina Mameli,7 Paolo Maggi,8 Katia Falasca,9 Laura Cordier,5 Benedetto Maurizio Celesia,10 Elena Salomoni,11 Antonio Di Biagio,12 Giovanni Francesco Pellicanò,13 Paolo Bonfanti1 On behalf of the CISAI Study Group1Infectious Diseases Unit ASST-MONZA, San Gerardo Hospital-University of Milano-Bicocca, Monza, Italy; 2“ASIA” Foundation ONLUS, Milan, Italy; 3Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio, Italy; 4Department of Internal Medicine 2, Infectious Diseases Unit, “Santa Maria della Misericordia” General Hospital, Perugia, Italy; 5 1st Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy; 6Infectious Diseases Unit, Careggi Hospital, Florence, Italy; 7Unit of Infectious Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 8University of Campania “Luigi Vanvitelli”, Napoli, Italy; 9Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University “G. d’Annunzio” Chieti-Pescara, Chieti, Italy; 10Unit of Infectious Diseases, University of Catania, ARNAS Garibaldi, Catania, Italy; 11Infectious Diseases Unit, Santa Maria Annunziata Hospital, Usl centro, Florence, Italy; 12Infectious Diseases, San Martino Hospital Genoa, Genoa, Italy; 13Department of Human Pathology of the Adult and the Developmental Age “G. Barresi”, Unit of Infectious Diseases, University of Messina, Messina, ItalyCorrespondence: Nicola SquillaceInfectious Diseases Unit, Azienda Socio Sanitaria Territoriale di MONZA, San Gerardo Hospital-University of Milano-Bicocca, Via Pergolesi 33, Monza 20900, ItalyTel +390392339588Fax +390392339327Email nicolasquillace74@gmail.comObjective: We aimed to investigate the effect of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on the hepatic safety and metabolic profile.Methods: Consecutive HIV patients, enrolled in the Surveillance Cohort Long-term Toxicity Antiretrovirals/Antivirals (SCOLTA) project, switching from TDF to TAF were included. Changes from baseline (T0) to 6-month follow-up (T1) were evaluated using paired t-test and signed rank test.Results: A total of 190 patients switched from TDF to TAF and had one 6-month follow-up visit. They were 80% male, 74.2% at CDC stage A–B, 93.7% with undetectable HIV-viral load. Mean age was 46.7± 10.7 years, body mass index was 25.0± 3.9 kg/m2, median CD4 cell count was 634 cell/μL (interquartile range [IQR]=439– 900), aspartate aminotransferase (AST) was 23 (IQR=19– 30) IU/L, and alanine aminotransferase (ALT) was 24 (IQR=17– 34) IU/L. At T1, both AST (median=− 1, IQR=− 5– 2 IU/L, P=0.004) and ALT (median=− 2, IQR=− 7– 3 IU/L, P=0.0004) showed a significant decrease. Among 28 patients with ALT > 40 at baseline, reduction was significant both clinically (− 17, IQR=− 32–− 1) and statistically (P=0.0003). Total cholesterol levels (TC) increased (+13.4± 3.8 mg/dL, P=0.0006), as well as HDL-cholesterol (HDL-C) (+3.8± 1.2 mg/dL, P=0.02), LDL Cholesterol (LDL-C) (+7.6± 3.4, P=0.03) and glucose (+4.0± 1.8 mg/dL, P=0.02). D:A:D: and Framingham risk score did not change at 6 months after switch.Conclusion: A significant reduction of liver enzymes was observed after switching from TDF to TAF, especially in subjects with initial level of ALT > 40 IU/L. Glucose, TC, HDL-C, and LDL-C increased, with no effect on cardiovascular risk scores.Keywords: HIV, TDF, TAF, liver enzymes

Se expone la metodología para la verificación de los pronósticos meteorológicos de aeródromo (TAF) emitidos por la Oficina Principal de Vigilancia Meteorológica perteneciente al Instituto de Aeronáutica Civil de Cuba. Para ello se consideraron los requisitos de la Organización de Aviación Civil Internacional establecidos en el Anexo para los servicios meteorológicos para la navegación aérea internacional, además de otros de índole nacional recogidos en los Manuales y Regulaciones Aeronáuticas Cubanas. El proceso de verificación está conformado por tres etapas fundamentales. La primera etapa está referida a la comparación con límites y rangos establecidos en las Regulaciones Aeronáuticas Cubanas (IACC, 2013) mientras que la segunda está destinada a la verificación de precisión y confiabilidad de los pronósticos. La tercera y última fase será tratada en otra nota técnica. Las variables a verificar son: dirección y velocidad del viento, precipitación, cobertura nubosa y altura de la nube más baja. Estos resultados se complementan además con las tablas de contingencias y los análisis estadísticos de alto impacto para las operaciones aeronáuticas de ellas derivados, dentro de los cuales se encuentran las falsas alarmas, la probabilidad de detección de los mínimos de visibilidad, de tormentas y niebla entre otros parámetros. El procedimiento aquí expuesto está implementado en el Sistema Automatizado para la Evaluación de los TAF (SAETAF), software introducido oficialmente en la Oficina Principal de Vigilancia Meteorológica en Cuba desde noviembre de 2015. Asimismo, la metodología presentada bien pudiera utilizarse en la verificación de los TAF elaborados por Oficinas Meteorológicas de Aeródromo de otros países.

Objectives: To identify limitations of abortion data in national Medicaid claims files by comparing abortion counts in Medicaid claims data with state abortion estimates., Study Design: We used procedure (Current Procedural Terminology/Healthcare Common Procedure Coding System) and drug (National Drug Code) codes to identify abortion claims in 2009 and 2010 Medicaid Analytic eXtract (MAX) and 2020 Transformed Medicaid Statistical Information System Analytic File (TAF) data. We compared the number of abortions in MAX and TAF to the number of expected abortions covered by Medicaid overall and by state. Based on recent published research, we estimated expected Medicaid-covered abortions as 62% of total abortions in states using state funds to cover abortion services for Medicaid enrollees and 0.9% in states that follow Hyde restrictions., Results: MAX data identified 11% (38,668/345,480) of expected Medicaid-covered abortions in 2009 and 13% (44,528/330,801) of expected Medicaid-covered abortions in 2010. In 2020 TAF data, we found 25% (69,728/279,048) of the expected Medicaid-covered abortions. Among the 16 states that used state funds to cover abortions for Medicaid enrollees in 2020, the majority had <10% of expected Medicaid-covered abortions (n = 8). Three states had between 10% and 50% of expected abortions. Four states had between 51% and 75% of expected abortions. One state had insufficient data for reporting., Conclusions: Abortion claims in MAX/TAF are an undercount of abortions covered by Medicaid, and this undercount varies across states. Variation in reporting across states and across time likely introduces bias into research trying to use MAX/TAF abortion claims across states and time. Researchers should use extreme caution when using MAX/TAF for abortion-related research., Implications: Researchers should use caution when using the Medicaid Analytic eXtract and Transformed Medicaid Statistical Information System Analytic Files for abortion-related research questions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The introduction of tenofovir alafenamide (TAF) in antiretroviral therapy has deeply modified the choice of the backbone for different treatment regimens, allowing the prevention of the bone and renal toxicity that was related to the previous formulation of tenofovir disoproxil fumarate (TDF). At the same time, literature data show an onset of dyslipidemia after a switch from TDF to TAF. To better understand the possible role of TAF in dyslipidemia, antiretroviral-naïve HIV-infected patients were evaluated, comparing those treated with TAF/emtricitabine with those with abacavir/lamivudine. Methods: We enrolled 270 antiretroviral-naïve HIV-infected patients in an observational, retrospective, longitudinal, multicenter study; they started treatment from 2017 to 2019 and were followed up for at least 72 weeks. We divided patients into two groups, one treated with a TAF-based backbone in their antiretroviral regimens (TAF group) and one without TAF (NO TAF group), to evaluate possible differences in the dynamics of lipid profiles from baseline(T0) to week 24 (T24), 48 (T48) and 72 (T72). Results: No significant differences were observed at baseline between the 2 groups. In the TAF group we observed a significant development of hypercholesterolemia throughout the follow-up (p < 0.0001), not evident in the NO TAF group, that instead showed a significant increase in high-density lipoprotein (HDL). There were no significant differences between the two groups regarding triglycerides, low-density lipoprotein (LDL) and cardiovascular risk index (CRI). A cholesterol-lowering treatment with statin, finally, was prescribed in 6 patients in both groups during the study. At binary logistic regression analysis, no factor was independently associated with hypercholesterolemia, except for higher age at T0. Conclusions: This real-life study shows that in HIV-naïve patients, TAF was associated with hypercholesterolemia throughout the follow-up. The clinical significance of this hypercholesterolemia will have to be clarified in further studies.

Background: Proximal renal tubulopathy (PRT) is an infrequent complication of tenofovir disoproxil fumarate (TDF). It remains to be established whether tenofovir alafenamide (TAF) can be safely administered to individuals who experienced PRT on TDF. Methods: Individuals with a history of TDF-associated PRT and current estimated glomerular filtration rate (eGFR) over 30 mL/min/1.73 m² initiated TAF and were followed for 96 weeks. The primary outcome of interest was recurrent PRT. Secondary outcomes were changes in kidney biomarkers, bone biomarkers, and bone mineral density (BMD). Data were analyzed using multilevel mixed-effects linear regression models. The trial was registered under EudraCT 2016-003345-29. Results: All 31 participants [median age 55 (inter-quartile range 51, 60) years, 97% men, 87% White ethnicity] remained on TAF at week 96, and none developed glycosuria or recurrent PRT. Participants experienced small declines in eGFR-creatinine [-1.9 (95% confidence interval: -3.5 to -0.3) mL/min/1.73 m²/yr; P = 0.024], but not in eGFR-cystatin C [-0.9 (-2.1 to 0.4) mL/min/1.73 m²/yr; P = 0.16]. Ten (32%) and 5 (16%) participants experienced rapid (>5 mL/min/1.73 m²/yr) decline in eGFR-creatinine and eGFR-cystatin C. No significant change in other kidney biomarkers, bone turnover, or BMD was observed (P > 0.2). Conclusions: In individuals with a history of PRT on TDF, 96 weeks of TAF was not associated with recurrent PRT or adverse effects on renal tubular function, bone turnover, or BMD. These data suggest that TAF is a treatment option for this vulnerable population. [ABSTRACT FROM AUTHOR]

Previous studies have focused on the changes of tumour cells in immune escape, and less is known about the effect of tumour microenvironment (TME) on immune escape. Tumour-associated fibroblasts (TAF) is an important part of the TME and has special physiological and biochemical characteristics, but the specific mechanism has not been clarified. In order to investigate the effect of TAF on the expression of PD-L1 in gastric cancer cells, gastric cancer cell lines MNK45, SGC7901 were non-contact co-culturing with TAF 1, 3 and 7 d via transwell. PD-L1 mRNA and protein expression were detected using qRT-PCR and FCM. Then, 95 cases of gastric cancer tissues were selected and evaluated PD-L1 and TAF expressions by immunohistochemical examination. The results showed that the mRNA and protein expression of PD-L1 in the experiment group were significantly higher than that in the control group. PD-L1 expression was associated with massive lymphocyte infiltration, diffuse/mixed histology and intratumoral TAFs in gastric cancers. In conclusion, TAFs promoted the growth in gastric cancer cell lines by increased the PD-L1 expression.

Background: The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian participants infected with human immunodeficiency virus (HIV)-1 through 96 or 144 weeks. Objective: In Asian population requiring treatment, it is imperative to have data specific to this group, particularly as there is a general concern that Asians with lower body weight have increased risk of tenofovir disoproxil fumarate (TDF)-related renal dysfunction. Methods: Studies -104 and 111 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive participants, comparing E/C/F/TAF versus E/C/F/TDF. Study 109 was a randomized, open-label, 96-week study conducted in virologically suppressed, ART-experienced participants, who switched to E/C/F/TAF from ritonavir/cobicistat-boosted atazanavir ATV+(RTV or COBI) + F/TDF regimens, from non-nucleoside reverse transcriptase inhibitors (NNRTI) + F/TDF regimens, or from E/C/F/TDF. Study 112 was a single arm, open-label, 144-week study conducted in HIV suppressed, ART-experienced participants with mild-moderate renal impairment, who switched to E/C/F/TAF. Results: Asian participants in these studies had sustained efficacy safety and tolerability. In Study 104/111, Asian participants achieved 93% virologic suppression on TAF vs 88% on TDF at week 144. At baseline, there were numerically more Asians with median CD4 counts < 200 cells/uL and VL > 100,000 c/mL. In Study 109, 95% of Asians on TAF vs 86% on TDF maintained virologic suppression at week 96. Lastly, in Study 112, 91% maintained virologic suppression at week 144. There were no discontinuations due to renal AE, no cases of PRT or Fanconi syndrome in any of the studies.

Chronic hepatitis B virus (HBV) infection remains an important global health problem, and may be difficult to manage in clinical practice. Nucleos(t)ide analogues (NAs) with a high barrier to resistance (entecavir [ETV], tenofovir disoproxil fumarate [TDF] and tenofovir alafenamide [TAF]) are the most frequently used HBV treatments because of their long‐term effectiveness and tolerability. ETV may be less effective in patients with lamivudine‐resistant strains, and TDF is associated with impaired renal function and reductions in bone mineral density. TAF, a new tenofovir prodrug, has been developed to overcome the less favourable safety profile of TDF. TAF is more stable in plasma, and higher tenofovir levels are achieved within cells at lower doses than with TDF. Several registration and real‐life studies, performed up to week 144 of treatment, have shown that TAF is at least as effective as TDF, with higher rates of ALT normalization and significantly fewer kidney disturbances and changes in bone mineral density. No emergence of drug resistance has been found with TAF use. The main limitation to prescribing TAF is its price. The European Association for the Study of the Liver has suggested selecting TAF or ETV instead of TDF in patients >65 years old and in those with a risk of osteoporosis or renal abnormalities, and to prescribe TAF rather than ETV in patients previously exposed to NAs. [ABSTRACT FROM AUTHOR]

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy. Descovy is a newer product not yet indicated in individuals at risk of HIV-1 infection from receptive vaginal sex, because it still needs to be evaluated in this population. A topical dapivirine vaginal ring is currently under regulatory review, and a long-acting (LA) injectable cabotegravir product shows strong promise. Although demonstrably effective, daily oral PrEP presents adherence challenges for many users, particularly adolescent girls and young women, key target populations. This limitation has triggered development efforts in LA HIV prevention options. This article reviews efforts supported by the Bill & Melinda Gates Foundation, as well as similar work by other groups, to identify and develop optimal LA HIV prevention products. Specifically, this article is a summary review of a meeting convened by the foundation in early 2020 that focused on the development of LA products designed for extended delivery of tenofovir alafenamide (TAF) for HIV prevention. The review broadly serves as technical guidance for preclinical development of LA HIV prevention products. The meeting examined the technical feasibility of multiple delivery technologies, in vivo pharmacokinetics, and safety of subcutaneous (SC) delivery of TAF in animal models. Ultimately, the foundation concluded that there are technologies available for long-term delivery of TAF. However, because of potentially limited efficacy and possible toxicity issues with SC delivery, the foundation will not continue investing in the development of LA, SC delivery of TAF products for HIV prevention. [ABSTRACT FROM AUTHOR]

The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.

The three helical Histone Fold Motif (HFM) of core histone proteins provides an evolutionarily favored site for the protein–DNA interface. Despite significant variation in sequence, the HFM retains a distinctive structural fold that has diversified into several non-histone protein families. In this work, we explore the ancestry of non-histone HFM containing families in the plant kingdom. A sequence search algorithm was developed using iterative profile Hidden Markov Models to identify remote homologs of core-histone proteins. The resulting hits were functionally annotated, classified into families, and subjected to comprehensive phylogenetic analyses via Maximum likelihood and Bayesian methods. We have identified 4390 HFM containing proteins in the plant kingdom that are not histones, mostly existing as diverse transcription factor families, distributed widely within and across taxonomic groups. Patterns of homology suggest that core histone subunit H2A has evolved into newer families like NF-YC and DRAP1, whereas the H2B subunit of core histones shares a common ancestry with NF-YB and DR1 class of TFs. Core histone subunits H3 and H4 were found to have evolved into DPE and TAF proteins, respectively. Taken together these results provide insights into diversification events during the evolution of the HFM, including sub-functionalization and neo-functionalization of the HFM. [ABSTRACT FROM AUTHOR]

Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p -hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)- b -p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)- b -p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications. Unlabelled Image [ABSTRACT FROM AUTHOR]

Objective to observe the efficacy and safety in the clinic practice of Propofol Tenofavir Fumarate (TAF) as a treatment of Chronic Hepatitis B (CHB) Method A total of 180 Chronic-Hepatitis-B patients who had taken TDF antiviral therapy for 48 to 49 weeks were chosen between January 2018 and February 2020. They were further separated into two groups regarding to the following treatments：one continues TDF treatment while the other replaces with TAF. The comparison was made based on the clinic efficacy and renal safety from such two groups after a 48-week continuous medication. Results TAF group showed a statistical difference significantly better in HBV-DNA inhibition rate，ALT normalization rate，and HBeAg serum conversion with χ² = 10.250，P = 0.001 and χ² = 6.871，P = 0.009，and χ² = 3.881，P = 0.049 respectively. In terms of the safety，TAF group also demonstrates a difference significantly lower in the urinary α1 microglobulin abnormal rate with χ² = 13.703，P = 0.000. On the other hand，there was no significant difference in bloom β2 microglobulin among the groups owning to P values ≥ 0.05. Conclusion With the statistical comparison between TAF and TDF treatments in this clinic study，TAF is observed to have a stronger antiviral effectiveness，fewer side effects such as less induced harm to the renal function，and reduce the risks deriving from the liver cirrhosis and cancer. [ABSTRACT FROM AUTHOR]

MTG8 (RUNX1T1) is a fusion partner of AML1 (RUNX1) in the leukemic chromosome translocation t(8;21). The AML1‐MTG8 fusion gene encodes a chimeric transcription factor. One of the highly conserved domains of MTG8 is TAFH which possesses homology with human TAF4 [TATA‐box binding protein‐associated factor]. To obtain specific inhibitors of the AML1‐MTG8 fusion protein, we isolated RNA aptamers against the MTG8 TAFH domain using systematic evolution of ligands by exponential enrichment. All TAF aptamers contained guanine‐rich sequences. Analyses of a TAF aptamer by NMR, CD, and mutagenesis revealed that it forms a parallel G‐quadruplex structure in the presence of K+. Furthermore, the aptamer could bind to the AML1‐MTG8 fusion protein and dissociate the AML1‐MTG8/DNA complex, suggesting that it can inhibit the dominant negative effects of AML1‐MTG8 against normal AML1 function and serve as a potential therapeutic agent for leukemia. [ABSTRACT FROM AUTHOR]

To overcome safety limitations of tenofovir-disoproxil, EASL guidelines proposed switching chronic hepatitis B patients older than 60 years or with bone or renal disease to tenofovir-alafenamide or entecavir. To estimate the number of patients who would benefit from a treatment switch in a real-life setting. Consecutive hepatitis B patients receiving tenofovir-disoproxil before 31 December 2017 were enrolled in a cross-sectional study in two European hospitals. Clinical and virological data were recorded; renal function was assessed by estimated glomerular filtrate rate, serum phosphate and creatinine, proteinuria, and albuminuria; bone involvement by spine and femur DEXA scan. In total, 565 patients included: 62 (18–91) years, 75% males, 92% Caucasian, 92% HBeAg-negative, 40% cirrhotic. Fifty-five percent of patients fulfilled age criterion (>60 years). Older patients had higher rates of cirrhosis (51% vs 26%, p <0.001), cardiovascular disease, and renal impairment. Thirty-six percent of patients met renal criteria, more commonly NA-experienced individuals (35% vs 21%, p =0.001); 17% had bone disease. Overall, 66% of patients had at least one criterion (71% if NA-experienced), 8% all three criteria, 28% age and renal criteria. Approximately two-thirds of patients receiving long-term tenofovir-disoproxil are candidates for an entecavir or tenofovir-alafenamide switch according to EASL recommendations [ABSTRACT FROM AUTHOR]

Background An unexpected excess in weight gain has recently been reported in the course of dolutegravir (DTG) treatment. The aim of the present study was to investigate whether weight gain differs among different DTG-containing regimens. Methods Adult naïve and experienced people with HIV (PWH) initiating DTG-based antiretroviral therapy (ART) between July 2014 and December 2019 in the Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) prospective cohort were included. We used an adjusted general linear model to compare weight change among backbone groups and a Cox proportional hazard regression model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for weight increases >10% from baseline. Results A total of 713 participants, 25.3% women and 91% Caucasian, were included. Of these, 195 (27.4%) started DTG as their first ART regimen, whereas 518 (72.6%) were ART-experienced. DTG was associated with abacavir/lamivudine in 326 participants, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 148, boosted protease inhibitors in 60, rilpivirine in 45, lamivudine in 75, and tenofovir alafenamide (TAF)/FTC in 59. At 6 and 12 months, weight gain was highest among PWH on TDF/FTC+DTG and TAF/FTC+DTG. Baseline CD4 <200 cells/mm3 (HR, 1.84; 95% CI, 1.15 to 2.96), being ART-naïve (HR, 2.24; 95% CI, 1.24 to 4.18), and treatment with TDF/FTC+DTG (HR, 1.92; 95% CI, 1.23 to 2.98) or TAF/FTC+DTG (HR, 3.80; 95% CI, 1.75 to 8.23) were associated with weight gain >10% from baseline. Higher weight (HR, 0.97 by 1 kg; 95% CI, 0.96 to 0.99) and female gender (HR, 0.54; 95% CI, 0.33 to 0.88) were protective against weight gain. Conclusions Naïve PWH with lower CD4 counts and those on TAF/FTC or TDF/FTC backbones were at higher risk of weight increase in the course of DTG-based ART. [ABSTRACT FROM AUTHOR]

Management of chronic hepatitis B (CHB) is still considered a challenge in clinical practice. Patients must be carefully evaluated before starting therapy. This includes virology and laboratory assessments, an estimation of fibrosis by invasive and/or noninvasive methods, and an estimation of the risk of hepatocellular carcinoma (HCC). Nucleos(t)ide analogues (NAs) with a high barrier to resistance (tenofovir disoproxil fumarate [TDF], entecavir [ETV] and tenofovir alafenamide [TAF]) are the most frequently used treatments because of their good long‐term efficacy and tolerability. None of these options has been shown to be more effective than the other, but certain factors should be considered when selecting the best therapy for specific populations. Most patients achieve a virological and biochemical response to these agents, with a low rate of emerging resistance during long‐term treatment. However, the rate of hepatitis B surface antigen (HBsAg) loss is low and in most cases NAs therapy is lifelong. Safety concerns for long‐term NA use have become a priority in the management of CHB, in particular, the risk of impaired kidney function and bone marrow density loss described with TDF regimens. The risk of HCC is not completely eliminated by NAs. Thus, patients at higher risk should be identified and provided with appropriate surveillance. [ABSTRACT FROM AUTHOR]

At Bristol-Myers (BM) (1985–1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as (S)-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John’s first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (i), TDF and TAF for the treatment of hepatitis B (HBV) infections (ii), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections (iii).