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A false-negative case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is defined as a person with suspected infection and an initial negative result by reverse transcription-polymerase chain reaction (RT-PCR) test, with a positive result on a subsequent test. False-negative cases have important implications for isolation and risk of transmission of infected people and for the management of coronavirus disease 2019 (COVID-19). We aimed to review and critically appraise evidence about the rate of RT-PCR false-negatives at initial testing for COVID-19. We searched MEDLINE, EMBASE, LILACS, as well as COVID-19 repositories, including the EPPI-Centre living systematic map of evidence about COVID-19 and the Coronavirus Open Access Project living evidence database. Two authors independently screened and selected studies according to the eligibility criteria and collected data from the included studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We calculated the proportion of false-negative test results using a multilevel mixed-effect logistic regression model. The certainty of the evidence about false-negative cases was rated using the GRADE approach for tests and strategies. All information in this article is current up to July 17, 2020. We included 34 studies enrolling 12,057 COVID-19 confirmed cases. All studies were affected by several risks of bias and applicability concerns. The pooled estimate of false-negative proportion was highly affected by unexplained heterogeneity (tau-squared = 1.39; 90% prediction interval from 0.02 to 0.54). The certainty of the evidence was judged as very low due to the risk of bias, indirectness, and inconsistency issues. There is substantial and largely unexplained heterogeneity in the proportion of false-negative RT-PCR results. The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability. Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection given that up to 54% of COVID-19 patients may have an initial false-negative RT-PCR (very low certainty of evidence). Protocol available on the OSF website: https://tinyurl.com/vvbgqya.

Background Opportunistic infections (OIs) are common causes of mortality among people living with HIV (PLHIV). We determined prevalence and 30-day mortality due to histoplasmosis, cryptococcosis, and TB in PLHIV with advanced HIV disease (AHD). Methods PLHIV 18 years and older, with a CD4 + T-cell count of less than 350 cells/mm3 newly diagnosed with HIV infection or re-engaged in care after being without ART for more than 90 days (Group A). The second group included symptomatic PLHIV regardless of ART status or CD4 + T-cell count (Group B); all followed for 30 days. Detection of Histoplasma Ag (HisAg) in urine was done by enzyme immunoassay (EIA), Cryptococcus antigen (CrAg) was detected in serum and cerebrospinal fluid (CSF) specimens by lateral flow assay (LFA), and lipoarabinomannan (LAM) detection in urine was by LFA (TB LAM) and in sputum by GeneXpert for diagnosis of Mycobacterium infections. Results From August 2021 to June 2022, 491 PLHIV were enrolled; 482 (98%) had a CD4 + T-cell result, and 381 patients (79%) were classified with AHD according to CD4 + T-cell count (< 200 CD4/mm 3 ). Frequency of an OI was 38% ( n  = 145/381). Antigen test positivity rate was 16% (72/467) for TB-LAM, 9% (43/464) for HisAg, and 11% (51/484) for CrAg. Twenty-one of 34 (62%) patients receiving CSF CrAg tests were positive, confirming meningitis. Significant differences in 30-day mortality were observed in patients with an OI (16%) vs. no OI (7%) ( p  = 0.002). Mortality was highest in patients with histoplasmosis (25%), co-infection (22%), cryptococcosis (18% overall; 19% for cryptococcal meningitis), and TB (10%). Conclusions TB and fungal OIs, including co-infection, were common in PLHIV in Paraguay and had high associated mortality. Laboratories and health facilities need access to CD4 + T-cell testing and rapid diagnostic assays.

Introduction Recent studies have indicated a high enduring burden of advanced HIV disease, but estimates across regions and settings are lacking. The aim of this study was to estimate the prevalence of advanced HIV disease since 2015 among those people with CD4 measured in healthcare settings, disaggregated by age group, level of healthcare and region. Methods We searched MedLine via Pubmed and Hinari for studies that reported the proportion of individuals with advanced HIV disease (defined as CD4 cell count <200 cells/mm3) in healthcare settings since 2015; this search was complemented by conference s and data from the International epidemiology Databases to Evaluate AIDS Consortium (IeDEA). We estimated pooled prevalence of advanced HIV disease using random‐effects models and performed subgroup and sensitivity analyses to explore heterogeneity. Results We obtained data from 117 cohorts, representing 1,814,362 individuals from 52 countries across all six World Health Organization regions. The majority of studies (n = 83) were conducted among adults and recorded CD4 cell count among treatment naïve individuals at antiretroviral therapy start (n = 86). Studies included data reported up to 2023. The proportion of individuals with advanced HIV disease was higher in inpatient settings (44.3%, 95% CI 39.1−49.6%) compared to outpatient settings (33.5%, 95% CI 31.5−35.4%). Prevalence was similar across age groups, time since HIV diagnosis and treatment status, and highest in West and Central Africa, South‐East Asia and the Eastern Mediterranean region. Discussion This review finds that at least a third of people presenting to healthcare settings have advanced HIV disease, with no evidence that this has changed in recent years. Screening for advanced HIV remains important to be able to direct appropriate preventive, diagnostic and therapeutic interventions to prevent progression to severe illness and death. Conclusions This review summarizes recent evidence of the continued high proportion of individuals who (re)present to care with advanced HIV disease. These findings underscore the urgent need to reinforce programme capacity to diagnose, prevent and treat advanced HIV disease as an essential pillar of the global AIDS response.

Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy. The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age ≥18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100 000 vs ≥100 000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than −12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444. Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI −2·2 to 11·8; p=0·171). Patients with baseline viral load of at least 100 000 copies per mL showed similar results (87·2% vs 77·9%, respectively; difference 9·3%, 95% CI −2·8 to 21·5; p=0·145). Toxicity-related or tolerability-related discontinuations were more common in the triple-therapy group (n=10 [4·9%]) than in the dual-therapy group (n=1 [0·4%]; difference 4·5%, 95% CI −8·1 to −0·9; p=0·011). 65 adverse events in the dual-therapy group and 88 in the triple-therapy group were possibly or probably drug related (p=0·007). Two serious adverse events occurred, both in the dual-therapy arm, one of which (a case of gastritis) was reported as possibly or probably related to drug treatment. Dual therapy with lopinavir and ritonavir plus lamivudine regimen warrants further clinical research and consideration as a potential therapeutic option for antiretroviral-therapy-naive patients. Fundación Huésped and AbbVie.

Human immunodeficiency virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4 + T cells and causes acquired immunodeficiency syndrome (AIDS) if left untreated. Although antiretroviral treatment efficiently suppresses viremia, markers of immune activation and inflammation remain higher in HIV-1-infected patients than in uninfected individuals. The hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a fundamental role in coordinating cellular metabolism and function. Here we show that HIV-1 infection induces HIF-1α activity and that this transcription factor upholds HIV-1 replication. Moreover, we demonstrate that HIF-1α plays a key role in HIV-1-associated inflammation by promoting the release of extracellular vesicles which, in turn, trigger the secretion of inflammatory mediators by noninfected bystander lymphocytes and macrophages. In summary, we identify that the coordinated actions of HIF-1α and extracellular vesicles promote viral replication and inflammation, thus contributing to HIV-1 pathogenesis. Chronic immune activation and inflammation are hallmarks of HIV-1 infection and a major cause of serious non-AIDS events in HIV-1-infected individuals on antiretroviral treatment (ART). Herein, we show that cytosolic double-stranded DNA (dsDNA) generated in infected CD4 + T cells during the HIV-1 replication cycle promotes the mitochondrial reactive oxygen species (ROS)-dependent stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), which in turn, enhances viral replication. Furthermore, we show that induction of HIF-1α promotes the release of extracellular vesicles (EVs). These EVs foster inflammation by inducing the secretion of gamma interferon by bystander CD4 + T cells and secretion of interleukin 6 (IL-6) and IL-1β by bystander macrophages through an HIF-1α-dependent pathway. Remarkably, EVs obtained from plasma samples from HIV-1-infected individuals also induced HIF-1α activity and inflammation. Overall, this study demonstrates that HIF-1α plays a crucial role in HIV-1 pathogenesis by promoting viral replication and the release of EVs that orchestrate lymphocyte- and macrophage-mediated inflammatory responses. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4 + T cells and causes acquired immunodeficiency syndrome (AIDS) if left untreated. Although antiretroviral treatment efficiently suppresses viremia, markers of immune activation and inflammation remain higher in HIV-1-infected patients than in uninfected individuals. The hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a fundamental role in coordinating cellular metabolism and function. Here we show that HIV-1 infection induces HIF-1α activity and that this transcription factor upholds HIV-1 replication. Moreover, we demonstrate that HIF-1α plays a key role in HIV-1-associated inflammation by promoting the release of extracellular vesicles which, in turn, trigger the secretion of inflammatory mediators by noninfected bystander lymphocytes and macrophages. In summary, we identify that the coordinated actions of HIF-1α and extracellular vesicles promote viral replication and inflammation, thus contributing to HIV-1 pathogenesis.

In Argentina, transgender women (TGW) have a high HIV prevalence (34%). However, this population shows lower levels of adherence, retention in HIV care and viral suppression than cisgender patients. The World Health Organization (WHO) recommends the transition to dolutegravir (DTG)-based regimens to reduce adverse events and improve adherence and retention. The purpose of this study was to determine retention, adherence and viral suppression in naïve TGW starting a DTG-based first-line antiretroviral treatment (ART) and to identify clinical and psychosocial factors associated with retention. We designed a prospective, open-label, single-arm trial among ART-naïve HIV positive TGW (Clinical Trial Number: NCT03033836). Participants were followed at weeks 4, 8, 12, 24, 36 and 48, in a trans-affirmative HIV care service that included peer navigators, between December, 2015 and May, 2019. Retention was defined as the proportion of TGW retained at week 48 and adherence was self-reported. Viral suppression at <50 copies/mL was evaluated using snapshot algorithm and as per protocol analysis. Of 75 TGW screened, 61 were enrolled. At baseline, median age was 28 y/o., HIV-1-RNA (pVL) 46,908 copies/mL and CD4+ T-cell count 383 cells/mm 3 . At week 48, 77% were retained and 72% had viral suppression (97% per protocol). The regimen was well tolerated and participants reported high adherence (about 95%). Eleven of the fourteen TGW who discontinued or were lost to follow-up had undetectable pVL at their last visit. Older age was associated with better retention. DTG-based treatment delivered by a trans-competent team in a trans-affirmative service was safe and well tolerated by TGW and associated with high retention, high adherence and high viral suppression at 48 weeks among those being retained.

As governments, funding agencies and research organisations worldwide seek to maximise both the financial and non-financial returns on investment in research, the way the research process is organised and funded is becoming increasingly under scrutiny. There are growing demands and aspirations to measure research impact (beyond academic publications), to understand how science works, and to optimise its societal and economic impact. In response, a multidisciplinary practice called research impact assessment is rapidly developing. Given that the practice is still in its formative stage, systematised recommendations or accepted standards for practitioners (such as funders and those responsible for managing research projects) across countries or disciplines to guide research impact assessment are not yet available. In this statement, we propose initial guidelines for a rigorous and effective process of research impact assessment applicable to all research disciplines and oriented towards practice. This statement systematises expert knowledge and practitioner experience from designing and delivering the International School on Research Impact Assessment (ISRIA). It brings together insights from over 450 experts and practitioners from 34 countries, who participated in the school during its 5-year run (from 2013 to 2017) and shares a set of core values from the school’s learning programme. These insights are distilled into ten-point guidelines, which relate to (1) context, (2) purpose, (3) stakeholders’ needs, (4) stakeholder engagement, (5) conceptual frameworks, (6) methods and data sources, (7) indicators and metrics, (8) ethics and conflicts of interest, (9) communication, and (10) community of practice. The guidelines can help practitioners improve and standardise the process of research impact assessment, but they are by no means exhaustive and require evaluation and continuous improvement. The prima facie effectiveness of the guidelines is based on the systematised expert and practitioner knowledge of the school’s faculty and participants derived from their practical experience and research evidence. The current knowledge base has gaps in terms of the geographical and scientific discipline as well as stakeholder coverage and representation. The guidelines can be further strengthened through evaluation and continuous improvement by the global research impact assessment community.

Background: Little is known about the preferences for antiretroviral therapy (ART) administration methods, such as oral daily pills or long-acting injectable (LAI) options, as well as preferences for pre-exposure prophylaxis (PrEP) administration methods among people without HIV in Latin America. Objectives: This study aimed to assess the preferences for ART administration methods among people with HIV and PrEP methods among those without HIV, as well as to examine the correlations and reasons for these preferences. Design: We conducted a cross-sectional web-based questionnaire between April and July 2021, using social media accounts of a HIV non-governmental organization. The questionnaire was open to all adults living in Argentina, irrespective of their sexual orientation or gender identity. Methods: The questionnaire included questions on substance use, depression, chronic treatment, previous experiences with injectable medication, and HIV status. Those with HIV answered questions about ART adherence and their preferences for ART methods, while those without HIV were asked about condom use, awareness of PrEP, and their preferences for PrEP methods. Results: Out of 1676 respondents, 804 had HIV, and 872 did not. Among those with HIV, 91.5% expressed a high preference for LAI-ART, with significantly higher preferences among participants with higher educational levels, cisgender gay, bisexual, and queer men, younger individuals, and those with prior injectable medication experience. Among those without HIV, 68% preferred LAI-PrEP, and this preference was positively associated with previous positive experiences with injectable medication. Conclusion: The strong preference for LAI-ART suggests the potential for improved adherence and well-being among people with HIV. Additionally, the preference for LAI-PrEP among those without HIV emphasizes the importance of considering this option for HIV prevention strategies. This study highlights the need to offer diverse methods for ART and prevention to accommodate different preferences and improve health care outcomes in Latin America.

The rapid diagnosis of opportunistic infections (OIs) is critical for improving the health outcomes of people living with HIV/AIDS (PLWHA). This study aimed to describe the feasibility of implementing a package for the rapid diagnosis of tuberculosis, histoplasmosis, and cryptococcosis in patients with advanced HIV/AIDS disease in Porto Alegre, Brazil. The research involved two focus groups with health professionals, four in-depth interviews with healthcare managers, and twelve interviews with PLWHA. The corpus was analyzed using Descending Hierarchical Classification (DHC). The study found that the rapid test diagnosis intervention was generally well-received by patients and health professionals, improving diagnosis and treatment outcomes. However, it also identified several areas for improvement, including the need for expanded psychosocial support and enhanced coordination between health services. The findings have important implications for the development and implementation of policies and programs aimed at enhancing the diagnosis and treatment of OIs among PLWHA with advanced diseases. Further research should explore social determinants of HIV/AIDS mortality to offer valuable insights into improving prevention and treatment strategies. By prioritizing patient-centered care and improving coordination between health services, policymakers and health professionals can improve the health outcomes of PLWHA with advanced disease in Porto Alegre and other similar settings.