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During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, scientists from different areas are looking for alternatives to fight it. SARS-CoV-2, the cause of the infectious respiratory disease COVID-19, is mainly transmitted through direct or indirect contact with infected respiratory droplets. The integrity of the virus structure is crucial for its viability to attack human cells. Quaternary ammonium salts are characterized by having antiviral capabilities which alter or destroy the structure of the viral capsid. In this work, polypropylene (PP)/(1-Hexadecyl) trimethyl-ammonium bromide (CTAB) composites have been prepared in order to create an antiviral material. The composites were melt processed and blown to produce thin films. The CTAB content on the antiviral effect was evaluated using antibodies and serum from infected patients with the SARS-CoV-2 virus. In addition, the mechanical and thermal properties of blown films were investigated, and CTAB release kinetics from the films was followed by UV-Vis. The results indicate that the virus tends to remain less on the polymer surface by increasing the amount of CTAB in the PP matrix. KEYWORDS composites, COVID-19, polypropylene, quaternary ammonium salts, SARS-CoV-2, 1 | INTRODUCTION The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the infectious respiratory disease COVID-19 has had a considerable negative impact on the whole world. Health [...]

Introduction: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV. Methods: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at [greater than or equal to]1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-blcells. Statistical significance was calculated using the Fisher's exact test. Results: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others. Conclusions: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk. Keywords: dapivirine; HIV-1 drug resistance; HIV-1 prevention; next-generation sequencing; non-nucleoside reverse transcriptase inhibitors (NNRTI); pre-exposure prophylaxis (PrEP), INTRODUCTION Women in Sub-Saharan Africa have a disproportionate risk of HIV infection [1], highlighting the pressing need for safe and effective prevention strategies that allow for agency and choice. Dapivirine [...]

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg.sup.-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg.sup.-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4.sup.+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4.sup.+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for [greater than or equal to]168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load. A single dose of a broadly neutralizing, HIV-specific antibody transiently reduces viral load in plasma, and in some individuals is associated with durable virus suppression in the absence of antiretroviral therapy., Author(s): Kathryn E. Stephenson [sup.1] [sup.2] [sup.3] , Boris Julg [sup.1] [sup.3] [sup.4] , C. Sabrina Tan [sup.1] [sup.2] , Rebecca Zash [sup.1] [sup.2] , Stephen R. Walsh [sup.1] , [...]

Introduction: Both daily and on-demand regimens have been proven effective for pre-exposure prophylaxis (PrEP) against HIV in men who have sex with men (MSM). We aimed to compare the two regimens on their coverage of condomless anal intercourse (CLAI) in MSM. Methods: A randomized, controlled, open-label, crossover trialwas conducted in a teaching hospitalin Hong Kong. Participants were sexually active HIV-negative MSM aged 18 years or above with normalrenalfunction and without chronic hepatitis B infection. Oraltenofovir disoproxilfumarate 300 mg/emtricitabine 200 mg (TDF/FTC) tablets were prescribed for PrEP. After a 2-week lead-in with daily TDF/FTC for treatment-na[up arrow]ve MSM for tolerance assessment, participants were randomly assigned in a 1:1 ratio with a block size of four to either daily-first or on-demand-first arm based on the IPERGAY study, for receiving PrEP for 16 weeks, then crossed-over to the alternative regimen for another 16 weeks. The primary outcome was the proportion of days with PrEP-covered CLAI by intention-to-treat analysis. The trial is registered with the CCRB Clinical Trials Registry, CUHK, CUHKCCRB00606, and is closed to accrual. Results: Between 25 August 2018 and 23 March 2019, 119 eligible participants were assigned to daily-first arm (n = 59) and on-demand-first arm (n = 60) with an 87% overallcompletion rate (n = 103). With 96% and 54% of days on PrEP during daily and on-demand periods, respectively, the proportion of days with PrEP-covered CLAI between two arms were not statistically different (92% vs. 92%, p = 0.93). About half (47%) were diagnosed with at least one episode of incident sexually transmitted infection. Mild and time-limited adverse events, including diarrhoea, headache, nausea and dizziness, were reported in 37 (31%) and 10 (8%) during the daily and on-demand periods, respectively. At the end of the study, a similar proportion favoured daily or on-demand regimen. Conclusions: High prevention-effective adherence, as reflected from the coverage of CLAI, was achievable by either daily or on-demand PrEP among MSM, albeit a higher number of tablets taken for daily PrEP. As both regimens were well accepted, a flexible approach adopting either or both regimens with possible switching is warranted in order to suit individual health needs. Keywords: Asia; clinicaltrials; crossover design; HIV prevention trials; men who have sex with men; PrEP, 1 | INTRODUCTION Pre-exposure prophylaxis (PrEP) with co-formulated tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is a proven form of biomedical HIV prevention. Following the demonstration of its effectiveness in iPrEx, [...]

Introduction: Many children living with HIV (CLWH) display impaired cognition. Although early combination antiretrovira therapy (ART) produces improved cognitive outcomes, more long-term outcome data are needed. After concluding the Children with HIV Early antiRetroviral (CHER) trial in 2011, we investigated cognitive performance, at seven and nine years of age. Participants had been randomized to deferred ART (ART-Def; n = 22); immediate time-limited ART for 40 weeks (ART40W; n = 30) and immediate time-limited ART for 96 weeks (ART-96W; n = 18). We also recruited HIV-exposed uninfected (CHEU; n = 28) and HIV-unexposed (CHU; n = 35) children. Methods: Data were collected between May 2012 and December 2017. Mixed-model repeated-measures ANOVAs assessed differences over time between CLWH (ART-40W, ART-96W and ART-Def) and CHIV- CHEU and CHU between ART-Early (ART-40W and ART-96W), ART-Def, CHEU and CHU; and between ART-40W, ART-96W, ART-Def, CHEU and CHU. Results: All comparisons found significant effects of Time for most outcome variables (better scores at nine than at seven years; ps < 0.05). The first ANOVAs found that for (a) motor dexterity, CLWH performed worse than CHIV- at seven years (p < 0.001) but improved to equivalence at nine years, (b) visual-spatial processing and problem solving, only CLWH (p < 0.04) showed significant performance improvement over time and (c) working memory and executive function, CLWH performed worse than CHIV- at both seven and nine years (p = 0.03 and 0.04). The second ANOVAs found that for (a) working memory, CHU performed better than ART-Early and CHEU (p < 0.01 and 0.17). Similarly, for motor dexterity, ART-Def performed worse than ART-96W, CHEU and CHU at seven years (p < 0.04, 0.20). Conclusions: Although neurocognitive developmental trajectories for treatment groups and controls were largely similar (i.e. performance improvements from 7 to 9), all ART-treated children, regardless of treatment arm, remain at risk for cognitive deficits over early school ages. Although the nature of these deficits may change as cognitive development proceeds, there are potential negative consequences for these children's future learning, reasoning and adaptive functioning. Keywords: antiretroviral therapy; The Children with HIV Early Antiretrovira Therapy (CHER) trial; HIV/AIDS; HIV-associated neurocognitive impairment; paediatric HIV; working memory, 1 | INTRODUCTION Despite treatment advances, many children living with HIV (CLWH) have impaired cognitive performance [1-3]. Early and severe HIV-related neurological manifestations such as encephalopathy, increase the risk of [...]

Despite dire warnings, a stockpile of ready compounds to fight viral pandemics was sorely lacking. Can drugmakers finally do the right thing? Despite dire warnings, a stockpile of ready compounds to fight viral pandemics was sorely lacking. Can drugmakers finally do the right thing?, Author(s): Elie Dolgin Author Affiliations: Illustration by David Parkins Cartoon showing scientists in a bare storeroom containing just a few scattered bottles of antiviral drugs. The race for antiviral drugs [...]

All coronaviruses known to have recently emerged as human pathogens probably originated in bats.sup.1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801--an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials--markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19. Human and bat coronaviruses replicate efficiently in immunodeficient mice implanted with human lung tissue, and treatment or prophylaxis using EIDD-2801 in this model suggests that this oral antiviral agent may be effective in preventing COVID-19., Author(s): Angela Wahl [sup.1] [sup.2] [sup.3] , Lisa E. Gralinski [sup.4] , Claire E. Johnson [sup.1] [sup.2] [sup.3] , Wenbo Yao [sup.1] [sup.2] [sup.3] , Martina Kovarova [sup.1] [sup.2] [sup.3] [...]

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes.sup.1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics. The use of lung and colonic organoid systems to assess the susceptibility of lung and gut cells to SARS-CoV-2 and to screen FDA-approved drugs that have antiviral activity against SARS-CoV-2 is demonstrated., Author(s): Yuling Han [sup.1] , Xiaohua Duan [sup.1] [sup.2] , Liuliu Yang [sup.1] , Benjamin E. Nilsson-Payant [sup.3] , Pengfei Wang [sup.4] , Fuyu Duan [sup.5] , Xuming Tang [sup.1] [...]

The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B virus (HBV) surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with current therapeutics. We applied a multiplex droplet digital PCR assay to demonstrate that iDNA is responsible for maintaining HBsAg quantities in some individuals. Using paired bulk liver tissue from 16 HIV/HBV-coinfected persons on nucleos(t)ide analog (NUC) therapy, we demonstrate that people with larger HBsAg declines between biopsies derive HBsAg from cccDNA, whereas people with stable HBsAg levels derive predominantly from iDNA. We applied our assay to individual hepatocytes in paired tissues from 3 people and demonstrated that the individual with significant HBsAg decline had a commensurate loss of infected cells with transcriptionally active cccDNA, while individuals without HBsAg decline had stable or increasing numbers of cells producing HBsAg from iDNA. We demonstrate that while NUC therapy may be effective at controlling cccDNA replication and transcription, innovative treatments are required to address iDNA transcription that sustains HBsAg production., Introduction For the nearly 300 million people chronically infected with hepatitis B virus (HBV), current treatments, which include pegylated interferon a (PEG-IFN-[alpha]) and nucleos(t)ide analogs (NUCs), uncommonly result in cure, [...]

Background Accurate routine HIV viral load testing is essential for assessing the efficacy of antiretroviral treatment (ART) regimens and the emergence of drug resistance. While the use of plasma specimens is the standard for viral load testing, its use is restricted by the limited ambient temperature stability of viral load biomarkers in whole blood and plasma during storage and transportation and the limited cold chain available between many health care facilities in resource-limited settings. Alternative specimen types and technologies, such as dried blood spots, may address these issues and increase access to viral load testing; however, their technical performance is unclear. To address this, we conducted a meta-analysis comparing viral load results from paired dried blood spot and plasma specimens analyzed with commonly used viral load testing technologies. Methods and findings Standard databases, conferences, and gray literature were searched in 2013 and 2018. Nearly all studies identified (60) were conducted between 2007 and 2018. Data from 40 of the 60 studies were included in the meta-analysis, which accounted for a total of 10,871 paired dried blood spot:plasma data points. We used random effects models to determine the bias, accuracy, precision, and misclassification for each viral load technology and to account for between-study variation. Dried blood spot specimens produced consistently higher mean viral loads across all technologies when compared to plasma specimens. However, when used to identify virological failure, each technology compared best to plasma at a threshold of 1,000 copies/ml, the present World Health Organization recommended virological failure threshold. Some heterogeneity existed between technologies; however, 5 technologies had a sensitivity greater than 95%. Furthermore, 5 technologies had a specificity greater than 85% yet 2 technologies had a specificity less than 60% using a treatment failure threshold of 1,000 copies/ml. The study's main limitation was the direct applicability of findings as nearly all studies to date used dried blood spot samples prepared in laboratories using precision pipetting that resulted in consistent input volumes. Conclusions This analysis provides evidence to support the implementation and scale-up of dried blood spot specimens for viral load testing using the same 1,000 copies/ml virological failure threshold as used with plasma specimens. This may support improved access to viral load testing in resource-limited settings lacking the required infrastructure and cold chain storage for testing with plasma specimens., Author(s): Lara Vojnov 1,*, Sergio Carmona 2, Clement Zeh 3, Jessica Markby 4, Debrah Boeras 3, Marta R. Prescott 1, Anthony L. H. Mayne 5, Souleymane Sawadogo 6, Christiane Adje-Toure [...]

: Introduction: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand‐alone protocols, platform trials, single arm studies, sample size and the effect that follow‐up time during gestation has on analysis interpretations; and observational studies. Discussion: Pregnancy PK should be studied during drug development, after dosing in non‐pregnant persons is established (unless non‐clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand‐alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand‐alone pregnancy trial protocols can include pre‐specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost‐prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias. Conclusions: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high‐priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer., INTRODUCTION Pregnancy and lactation data are lacking for more than 90% of Food and Drug Administration (FDA)‐approved drugs [1], and pregnant/breastfeeding women are routinely excluded from pre‐ and post‐licensure clinical [...]

: Introduction: To allow the continued participation of women enrolled in pre‐licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non‐clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre‐licensure trials. Discussion: Completing all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre‐licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non‐clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non‐clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non‐clinical findings and the overall benefit–risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre‐licensure trials to remain on study will depend on the totality of the evidence and benefit–risk considerations. Conclusions: We propose that industry completes non‐clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal., INTRODUCTION Pregnant women, or women of childbearing potential (WOCP) without adequate contraception, have been excluded from most pre‐licensure drug trials, primarily due to concerns regarding foetal safety. However, many new [...]

Proliferation of latently infected [CD4.sup.+] T cells with replication- competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating [CD4.sup.+] memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of [CD4.sup.+] TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir., Introduction The advent of antiretroviral therapy (ART) has dramatically improved the life expectancy of people with HIV (PWH) infection. However, current ART regimens act by blocking de novo infection of [...]