Machine Learning-Based Assessment of Survival and Risk Factors in Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma for Optimized Patient Management.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with an incidence that is exponentially increasing. Hepatocellular carcinoma (HCC) is the most frequent primary tumor. There is an increasing relationship between these entities due to the potential risk of developing NAFLD-related HCC and the prevalence of NAFLD. There is limited evidence regarding prognostic factors at the diagnosis of HCC. This study compares the prognosis of HCC in patients with NAFLD against other etiologies. It also evaluates the prognostic factors at the diagnosis of these patients. For this purpose, a multicenter retrospective study was conducted involving a total of 191 patients. Out of the total, 29 presented NAFLD-related HCC. The extreme gradient boosting (XGB) method was employed to develop the reference predictive model. Patients with NAFLD-related HCC showed a worse prognosis compared to other potential etiologies of HCC. Among the variables with the worst prognosis, alcohol consumption in NAFLD patients had the greatest weight within the developed predictive model. In comparison with other studied methods, XGB obtained the highest values for the analyzed metrics. In conclusion, patients with NAFLD-related HCC and alcohol consumption, obesity, cirrhosis, and clinically significant portal hypertension (CSPH) exhibited a worse prognosis than other patients. XGB developed a highly efficient predictive model for the assessment of these patients.

HBsAg level defines different clinical phenotypes of HBeAg(-) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality.

Background: HBe-antigen(Ag)-negative chronic hepatitis B virus (HBV) infection is characterized by little liver fibrosis progression and vigorous HBV-multispecific CD8+ T-cell response. Aims: To assess whether HBsAg level could discriminate different HBeAg-negative chronic HBV infection subtypes with dissimilar quality of HBV-specific CD8+ T-cell response. Methods: We recruited 63 HBeAg-negative chronic HBV infection patients in which indirect markers of liver inflammation/fibrosis, portal pressure, viral load (VL), and HBV-specific CD8+ cell effector function were correlated with HBsAg level. Results: A positive linear trend between HBsAg level and APRI, liver stiffness (LS), liver transaminases, and HBV VL, and a negative correlation with platelet count were observed. Frequency of cases with HBV-specific CD8+ T-cell proliferation against at least two HBV epitopes was higher in HBsAg < 1,000 IU/ml group. CD8+ T-cell expansion after HBVpolymerase456-63-specific stimulation was impaired in HBsAg > 1,000 IU/ml group, while the response against HBVcore18-27 was preserved and response against envelope183-91 was nearly abolished, regardless of HBsAg level. Cases with preserved HBVpolymerase456-63 CD8+ cell response had lower LS/duration of infection and APRI/duration of infection rates. HBV-polymerase456-63-specific CD8+ T-cell proliferation intensity was negatively correlated with LS/years of infection ratio. Conclusion: HBsAg > 1,000 IU/ml HBeAg-negative chronic HBV infection group shows indirect data of higher degree of inflammation, liver stiffness, and fibrosis progression speed, which are related to an impaired HBV-polymerase-specific CD8+ T-cell response.

Application of Machine Learning Techniques to Assess Alpha-Fetoprotein at Diagnosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is associated with high mortality rates. Approximately 80% of cases occur in cirrhotic livers, posing a significant challenge for appropriate therapeutic management. Adequate screening programs in high-risk groups are essential for early-stage detection. The extent of extrahepatic tumor spread and hepatic functional reserve are recognized as two of the most influential prognostic factors. In this retrospective multicenter study, we utilized machine learning (ML) methods to analyze predictors of mortality at the time of diagnosis in a total of 208 patients. The eXtreme gradient boosting (XGB) method achieved the highest values in identifying key prognostic factors for HCC at diagnosis. The etiology of HCC was found to be the variable most strongly associated with a poorer prognosis. The widely used Barcelona Clinic Liver Cancer (BCLC) classification in our setting demonstrated superiority over the TNM classification. Although alpha-fetoprotein (AFP) remains the most commonly used biological marker, elevated levels did not correlate with reduced survival. Our findings suggest the need to explore new prognostic biomarkers for individualized management of these patients.

Prognostic Factors for Mortality in Hepatocellular Carcinoma at Diagnosis: Development of a Predictive Model Using Artificial Intelligence.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for 75% of primary liver tumors. Controlling risk factors associated with its development and implementing screenings in risk populations does not seem sufficient to improve the prognosis of these patients at diagnosis. The development of a predictive prognostic model for mortality at the diagnosis of HCC is proposed. METHODS: In this retrospective multicenter study, the analysis of data from 191 HCC patients was conducted using machine learning (ML) techniques to analyze the prognostic factors of mortality that are significant at the time of diagnosis. Clinical and analytical data of interest in patients with HCC were gathered. RESULTS: Meeting Milan criteria, Barcelona Clinic Liver Cancer (BCLC) classification and albumin levels were the variables with the greatest impact on the prognosis of HCC patients. The ML algorithm that achieved the best results was random forest (RF). CONCLUSIONS: The development of a predictive prognostic model at the diagnosis is a valuable tool for patients with HCC and for application in clinical practice. RF is useful and reliable in the analysis of prognostic factors in the diagnosis of HCC. The search for new prognostic factors is still necessary in patients with HCC.

Bictegravir/Emtricitabine/Tenofovir Alafenamide in a Multicentre Cohort: Real-Life Experience From Spain.

BACKGROUND: The evaluation of bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in clinical trials has shown high rates of virological suppression but information about its use in real-life settings is scarce. OBJECTIVE: To evaluate the effectiveness, safety, durability, and predictive variables of therapeutic failure of BIC/FTC/TAF in a real-life cohort. METHODS: This observational, retrospective, multicentered cohort study included treatment-naive (TN) and treatment-experienced (TE) adult patients living with HIV (PLWH) who started treatment with BIC/FTC/TAF from January 1, 2019, to January 31, 2022. Treatment effectiveness (based on intention-to-treat [ITT], modified ITT [mITT], and on-treatment [OT]), tolerability, and safety were evaluated in all patients who started BIC/FTC/TAF antiretroviral therapy. RESULTS: We included a total of 505 PLWH of whom 79 (16.6%) were TN and 426 (83.4%) were TE. Patients were followed up for a median (interquartile range [IQR]) of 19.6 (9.6-27.3) months, and 76% and 56% of PLWH reached month 6 and month 12 of treatment, respectively. Rates of TN PLWH with HIV-RNA <50 copies/mL in the OT, mITT, and ITT groups were 94%, 80%, and 62%, respectively, after 12 months of BIC/FTC/TAF treatment. Rates of TE PLWH with HIV-RNA <50 copies/mL were 91%, 88%, and 75% at month 12. The multivariate analysis revealed that neither age, sex, CD4 cell count <200 cells/µL, or viral load >100 000 copies/mL were associated with therapeutic failure. CONCLUSION AND RELEVANCE: Our real-life data showed that BIC/FTC/TAF is effective and safe for use in the treatment of both TN and TE patients in clinical practice.

IL-15 boosts activated HBV core-specific CD8+ progenitor cells via metabolic rebalancing in persistent HBV infection.

A rebalance between energy supply and demand in HBV-specific-CD8+ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8+ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.

Effectiveness, durability and safety of dolutegravir and lamivudine versus bictegravir, emtricitabine and tenofovir alafenamide in a real-world cohort of HIV-infected adults.

OBJECTIVE: Dolutegravir plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment. The aim of this study was to analyze the effectiveness, durability, and safety of 2-DR compared to bictegravir/emtricitabine/tenofovir alafenamide (3-DR). PATIENTS AND METHODS: This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) people living with HIV/AIDS (PLWH), who started 2-DR or 3-DR between 01 July 2018, and 31 January 2022. The primary endpoint was non-inferiority, at 24 and 48 weeks, of 2-DR vs 3-DR regarding the percentage of PLWH with viral load (VL)<50 and 200 copies/mL in TN (12% margin) and VL≥50 and 200 copies/mL in TE (4% margin). Durability of response and safety were also measured. RESULTS: 292 PLWH were included (39 TN and 253 TE). In TN PLWH, non-inferiority was not achieved at 24 weeks (17; 95% CI -17 to 51 p = 0.348). By week 48, all PLWH on 3-DR maintained VL<50 copies/mL compared to 70% of PLWH on 2-DR although without reaching statistical significance (-33; 95% CI -60 to -10 p = 0.289). Non-inferiority was not achieved in TE PLWH either at 24 (0.4; 95% CI -9 to 10 p = 1) or at 48 weeks (4.5; 95% CI -0.5 to 9 p = 0.132). In TN, the risk of treatment discontinuation was similar between groups (HR: 0.31, p = 0.07); similar rates were also found in TE (HR: 1.3, p = 0.38). TE PLWH on 2-DR showed a better safety profile compared to 3-DR (p = 0.017). CONCLUSION: Our results did not show non-inferiority in terms of virological effectiveness. Additionally, durability and safety of 2-DR were confirmed to be similar to 3-DR.

Cabotegravir and Rilpivirine Long-Acting Antiretroviral Therapy Administered Every 2 Months is Cost-Effective for the Treatment of HIV-1 in Spain.

INTRODUCTION: Current antiretroviral therapies (ARTs) have improved outcomes for people living with HIV. However, the requirement to adhere to lifelong daily oral dosing may be challenging for some people living with HIV, leading to suboptimal adherence and therefore reduced treatment effectiveness. Treatment with long-acting (LA) ART may improve adherence and health-related quality of life. The objective of this study was to evaluate the cost-effectiveness of cabotegravir + rilpivirine (CAB+RPV) LA administered every 2 months (Q2M) compared with current ART administered as daily oral single-tablet regimens (STRs) from a Spanish National Healthcare System perspective. METHODS: A hybrid decision-tree and Markov state-transition model was used with pooled data from three phase III/IIIb trials (FLAIR, ATLAS, and ATLAS-2M) over a lifetime horizon, with health states defined by viral load and CD4+ cell count. Direct costs (in €) were taken from Spanish public sources from 2021 and several deterministic and probabilistic analyses were carried out. An annual 3% discount rate was applied to both costs and utilities. RESULTS: Over the lifetime horizon, CAB+RPV LA Q2M was associated with an additional 0.27 quality-adjusted life years (QALYs) and slightly greater lifetime costs (€4003) versus daily oral ART, leading to an incremental cost-effectiveness ratio of €15,003/QALY, below the commonly accepted €30,000/QALY willingness-to-pay threshold in Spain. All scenario analyses showed consistent results, and the probabilistic sensitivity analysis showed cost-effectiveness compared with daily oral STRs in 62.4% of simulations, being dominant in 0.3%. CONCLUSION: From the Spanish National Health System perspective, CAB+RPV LA Q2M is a cost-effective alternative compared with the current options of daily oral STR regimens for HIV treatment. CLINICAL TRIALS REGISTRATION: ATLAS, NCT02951052; ATLAS-2M, NCT03299049; FLAIR, NCT02938520.

Over the past decades, treatments for HIV infection have improved outcomes for people living with HIV. However, most of the treatments available consist of daily oral administration, which may present challenges for some people. These challenges may lead to a less optimal intake of the medicines and, therefore, to a potential reduction of treatment effectiveness. A new long-acting treatment alternative for HIV with two drugs is now available: cabotegravir + rilpivirine long-acting is the first injectable treatment administered in the muscle every 2 months by a healthcare professional. Long-acting injectables may improve treatment administration and health-related quality of life of people living with HIV. This study estimated the cost-effectiveness of cabotegravir + rilpivirine long-acting in Spain compared with daily oral single-tablet treatment for HIV. An economic model using clinical data and Spanish inputs was used to estimate cost-effectiveness and health outcomes over a lifetime. Cabotegravir + rilpivirine long-acting compared with daily oral single-tablet treatment showed an increase in health-related quality of life, leading to a cost-effectiveness ratio of €15,003, below the Spanish willingness-to-pay threshold of €30,000. All different scenarios tested showed consistent results, with cabotegravir + rilpivirine long-acting being cost-effective in 62.4% of the simulations and less costly and more effective in 0.3%. This study demonstrated that, in Spain, cabotegravir + rilpivirine long-acting administered every 2 months is a cost-effective alternative to the current daily oral single-tablet treatment options for HIV.

Plitidepsin in adult patients with COVID-19 requiring hospital admission: A long-term follow-up analysis.

Introduction: The APLICOV-PC study assessed the safety and preliminary efficacy of plitidepsin in hospitalized adult patients with COVID-19. In this follow-up study (E-APLICOV), the incidence of post-COVID-19 morbidity was evaluated and any long-term complications were characterized. Methods: Between January 18 and March 16, 2022, 34 of the 45 adult patients who received therapy with plitidepsin in the APLICOV-PC study were enrolled in E-APLICOV (median time from plitidepsin first dose to E-APLICOV enrollment, 16.8 months [range, 15.2-19.5 months]). All patients were functionally autonomous with regard to daily living (Barthel index: 100) and had normal physical examinations. Results: From the APLICOV-PC date of discharge to the date of the extension visit, neither Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5) grade 3-4 complications nor QT prolongation or significant electrocardiogram (EKG) abnormalities were reported. Five (14.7%) patients had another COVID-19 episode after initial discharge from APLICOV-PC, and in 2 patients (5.9%), previously unreported chest X-ray findings were documented. Spirometry and lung-diffusion tests were normal in 29 (85.3%) and 27 (79.4%) patients, respectively, and 3 patients needed additional oxygen supplementation after initial hospital discharge. None of these patients required subsequent hospital readmission for disease-related complications. Discussion: In conclusion, plitidepsin has demonstrated a favorable long-term safety profile in adult patients hospitalized for COVID-19. With the constraints of a low sample size and a lack of control, the rate of post-COVID-19 complications after treatment with plitidepsin is in the low range of published reports. (ClinicalTrials.gov Identifier: NCT05121740; https://clinicaltrials.gov/ct2/show/NCT05121740).

Effects of frailty, geriatric syndromes, and comorbidity on mortality and quality of life in older adults with HIV.

BACKGROUND: To understand the effects of frailty, geriatric syndromes, and comorbidity on quality of life and mortality in older adults with HIV (OAWH). METHODS: Cross-sectional study of the FUNCFRAIL multicenter cohort. The setting was outpatient HIV-Clinic. OAWH, 50 year or over were included. We recorded sociodemographic data, HIV infection-related data, comorbidity, frailty, geriatric syndromes (depression, cognitive impairment, falls and malnutrition), quality of life (QOL) and the estimated risk of all-cause 5-year mortality by VACS Index. Association of frailty with geriatric syndromes and comorbidity was evaluated using the Cochran-Mantel-Haenszel test. RESULTS: Seven hundred ninety six patients were included. 24.7% were women, mean age was 58.2 (6.3). 14.7% were 65 or over. 517 (65%) patients had ≥3 comorbidities, ≥ 1 geriatric syndrome and/or frailty. There were significant differences in the estimated risk of mortality [(frailty 10.8%) vs. (≥ 3 comorbidities 8.2%) vs. (≥ 1 geriatric syndrome 8.2%) vs. (nothing 6.2%); p = 0.01] and in the prevalence of fair or poor QOL [(frailty 71.7%) vs. (≥ 3 comorbidities 52%) vs. (≥ 1 geriatric syndrome 58.4%) vs. (nothing 51%); p = 0.01]. Cognitive impairment was significantly associated to mortality (8.7% vs. 6.2%; p = 0.02) and depression to poor QOL [76.5% vs. 50%; p = 0.01]. CONCLUSIONS: Frailty, geriatric syndromes, and comorbidity had negative effects on mortality and QOL, but frailty had the greatest negative effect out of the three factors. Our results should be a wake-up call to standardize the screening for frailty and geriatric syndromes in OAWH in the clinical practice. TRIAL REGISTRATION: NCT03558438.

Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib for Patients at High Risk of Severe Coronavirus Disease 2019: The PANCOVID Randomized Clinical Trial.

BACKGROUND: This study was designed to evaluate if patients with high risk for severe coronavirus disease 2019 (COVID-19) would benefit from treatment with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) followed by baricitinib in case of hypoxemia and systemic inflammation. METHODS: PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥2 comorbidities or aged ≥60 years and was conducted between 10 October 2020 and 23 September 2021. In the first randomization, patients received TDF/FTC or no TDF/FTC. In the second randomization, patients with room air oxygen saturation <95% and at least 1 increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected. RESULTS: Of the 355 included participants, 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% confidence interval [CI], .52-5.91; P = .379); it was 0.42 (95% CI, .11-1.59; P = .201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI, .66-1.40; P = .774); it was 0.90 (95% CI, .61-1.33; P = .687) for those treated with baricitinib. CONCLUSIONS: Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials. CLINICAL TRIALS REGISTRATION: EudraCT: 2020-001156-18.

48-Week effectiveness and tolerability of dolutegravir (DTG) + lamivudine (3TC) in antiretroviral-naïve adults living with HIV: A multicenter real-life cohort.

BACKGROUND: The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, information in real-life cohorts is relatively scarce for first-line use. METHODS: A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL. RESULTS: 135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure [M = F]) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic. CONCLUSIONS: In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness.

Trasplante de microbiota fecal como tratamiento de la infección por Clostridioides difficile recidivante: a propósito de un caso / Fecal transplantation for the treatment of Clostridioides difficile recurrent infection

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Different profiles among older adults with HIV according to their chronological age and the year of HIV diagnosis: The FUNCFRAIL cohort study (GeSIDA 9817).

BACKGROUND: People in their fifties with HIV are considered older adults, but they appear not to be a homogeneous group. OBJECTIVE: To evaluate the differences among older adults with HIV according to their chronological age and the year of HIV diagnosis. METHODS: Cross-sectional study of the FUNCFRAIL cohort. Patients 50 or over with HIV were included and were stratified by both chronological age and the year of HIV diagnosis: before 1996 (long-term HIV survivors [LTHS]) and after 1996. We recorded sociodemographic data, HIV-related factors, comorbidities, frailty, physical function, other geriatric syndromes, and quality of life (QOL). RESULTS: We evaluated 801 patients. Of these, 24.7% were women, 47.0% were LTHS, and 14.7% were 65 or over. Of the 65 or over patients, 73% were diagnosed after 1996. Higher rates of comorbidities among LTHS were found, being the more prevalent: COPD, history of cancer, osteoarthritis, depression, and other psychiatric disorders while the more prevalent among the 65 or over patients were: hypertension, diabetes, dyslipidemia, cancer, and osteoarthritis. LTHS showed a significantly worse QOL. There were no differences by the year of HIV diagnosis regarding frailty and functional impairment (SPPB <10) but they were more than twice as prevalent in the 65 or over patients compared to the other chronological age groups. CONCLUSIONS: A LTHS and a 65 or over person are both "older adults with HIV," but their characteristics and requirements differ markedly. It is mandatory to design specific approaches focused on the real needs of the different profiles.

Model to predict on-treatment restoration of functional HBV-specific CD8+ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV)-specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off-treatment HBV control in e-antigen-negative chronic hepatitis B (CHBe(-)). AIM: To predict this response with variables involved in T-cell exhaustion for use as a treatment stopping tool. METHODS: In NUC-treated CHBe(-) patients, we considered a functional response in cases with HBV-specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off-treatment follow-up according to LRM likelihood. RESULTS: We developed an LRM that predicted the presence of a proliferative type I cytokine-secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off-treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. CONCLUSIONS: Short-term low-level antigen exposure and early long-term NUC treatment influence the restoration of a functional HBV-specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off-treatment HBV control and HBsAg decline and loss.

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Measuring Violence Against Women: A Global Index.

Violence against women (VaW) is a widespread crime and violation of the rights of women. It is present in every country without exception and crosses boundaries of culture, class, education, income, and race. Despite the magnitude of the literature and the abundance of publications on this problem, the field lacks a comprehensive and homogeneous way to measure and compare the extent of VaW across countries. Proper quantification of this problem is needed to develop preventive policies and strategies to reduce it. This article develops an index of VaW (VAWI) with global scope and multidimensional approach for 102 countries. It is an original index that calculates the total level of VaW by capturing information from the main VaW types (physical, sexual, psychological, and economic violence) in a single value between 0 and 1, where 0 denotes complete absence of violence and 1 the highest level of violence in a country. The proposed index is easy to compute and is comparable across countries. Our main results show that the nations with the highest levels of global VaW are Yemen, Senegal, Oman, Cameroon, and Uganda. The countries with the lowest levels are the Northern European Countries, Canada, and Malta. This VAWI makes a novel and important contribution to the study of gender issues. It can be used not only to monitor the statistics on VaW data within countries over time but also to make comparisons among countries. Further, it could be useful in designing new policy initiatives to reduce VaW.

Effectiveness, Durability, and Safety of Dolutegravir and Lamivudine Versus Dolutegravir, Lamivudine, and Abacavir in a Real-Life Cohort of HIV-Infected Adults.

BACKGROUND: Dolutegravir (DTG) plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment. OBJECTIVE: To analyze the effectiveness, durability, and safety of 2-DR compared with DTG plus abacavir/lamivudine (3-DR). METHODS: This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) patients who started 2-DR or 3-DR between July 1, 2018, and November 30, 2020. The primary end point was noninferiority, at 24 and 48 weeks, of 2-DR versus 3-DR regarding the percentage of patients with viral load (VL)≥50 and 200 copies/mL in TN (4% margin) and VL<50 and 200 copies/mL in TE (margin 12%). Durability of response, and safety were also measured. RESULTS: 242 patients were included (53 TN and 189 TE). Two TN patients on 2-DR had VL≥50 copies/mL and 1 had VL≥200 copies/mL at week 24. In TE patients on 2-DR, 90.2% achieved VL<200 copies/mL at week 24 (difference: 3.8%; 95% CI = -6.3% to 14%) and 91.8% at week 48 (difference: 0.06%; 95% CI = -9% to 10%), meeting noninferiority criteria. Among the 53 TN patients, only 1 VF was observed in 2-DR. In TN patients, the risk of treatment discontinuation was similar between groups (hazard ratio [HR] = 0.37; P = 0.15); similar rates were also found in TE patients (HR = 0.94; P = 0.85). TE patients on 2-DR showed a better safety profile compared with 3-DR patients (P<0.001). CONCLUSION AND RELEVANCE: Our results did not show noninferiority in terms of virological effectiveness. Nevertheless, all effectiveness measures support the use of 2-DR in a real-life cohort of TN and TE. Additionally, durability and safety of 2-DR were confirmed to be similar to that of 3-DR.