Effectiveness of ivermectin and atazanavir on time to resolution from COVID-19 symptoms: a prospective cohort

Objective: to evaluate the effectiveness of Ivermectin and Atazanavir compared to placebo in the time to resolution of symptoms and duration of illness due to COVID-19. Method: observational, prospective, longitudinal, descriptive and analytical cohort study with symptomatic outpatients, followed for 06 months in two Basic Health Units for COVID-19 care in Teresina-Piaui, Brazil, from November to April 2021 identified by 1:1:1 random sampling. Reverse transcription polymerase chain reaction (RT-PCR) tests were performed for laboratory confirmation of suspected infection with the new coronavirus and sociodemographic and clinical evaluation. Results: of the 87 randomized patients, 62.1% (n=54) were male, with a mean age of 35.1 years, had a partner (53.9%), low income (50.6%), eutrophic (40.7%) and without health comorbidities (78.2%). There was no difference between the median time to resolution of symptoms, which was 21 days (IQR, 8-30) in the atazanavir group, 30 days (IQR, 5-90) in the ivermectin group compared with 14 days (IQR, 9-21) in the control group. At day 180, there was resolution of symptoms in 100% in the placebo group, 93.9% in the atazanavir group, and 95% in the ivermectin group. The median duration of illness was 8 days in all study arms. Conclusion: Treatment with atazanavir (6 days) and ivermectin (3 days) did not reduce the time to symptom resolution or the duration of illness among outpatients with mild COVID-19 compared to the placebo group. The results do not support the use of ivermectin and atazanavir for the treatment of mild to moderate COVID-19.

Oral Microbiota in Children Who Started Antiretroviral Therapy at Young Ages

Background: Infancy is an important developmental period when the human microbiome is shaped. Given links between young age at antiretroviral treatment (ART) initiation and smaller persisting viral reservoirs, we hypothesized that earlier ART initiation may leave distinct microbial signatures in the oral cavity detectable in children living with HIV (CLWH). Method(s): Oral swab samples were collected from 477 CLWH and 123 children without HIV at two sites in Johannesburg, South Africa. CLWH had started ART < 2 years of age with 60% starting < 6 months of age. Most were wellcontrolled on ART at a median of 10 years of age when the swab was collected. Controls were age-matched and recruited from the same communities. Sequencing of the V4 amplicon of the 16S rRNA gene was done using established protocols. DADA2, decontam, and phyloseq were used for sequence inference, contaminant removal, and subsequent analyses. All p-values were adjusted for multiple testing using Benjamini-Hochberg false discovery rate method. Statistical analyses were performed with R. Result(s): CLWH had lower alpha diversity than uninfected children (Shannon index p< 0.0001). Genus-level abundances of Granulicatella, Streptococcus and Gemella were greater and Neisseria and Haemophilus were less abundant among CLWH compared to uninfected children. Associations were strongest among boys. There was no evidence of attenuation of associations with earlier ART initiation. In fact, decreased bacterial diversity and differences in taxa abundances in CLWH versus controls were consistent regardless of whether ART was started before or after 6 months of age. Shifts in genus-level taxa abundances relative to uninfected controls were most marked in children on regimens containing lopinavir/ritonavir;with few shifts seen if on regimens containing efavirenz. Conclusion(s): A distinct profile of less diverse oral bacterial taxa was observed in school-age CLWH on ART versus uninfected age-matched children suggesting persisting interference of HIV and its treatments on microbiota in the mouth. Any effects of earlier ART initiation were not detectable at this age. Studies of treated adults with HIV have observed similar shifts in taxa abundances. Oral microbiota have been linked to salivary cytokine levels with associations between Granulicatella and IL-8 and Neisseria and IL-6. Declines in Neisseria abundances in oral samples have been associated with more severe outcomes in influenza and COVID-19.

Suicidal Risk among People with Hiv after Lockdown Due to Covid-19 Pandemic

Background: People with HIV (PWH), are known to be at increased risk for mental disorders and suicidal risk (SR) when compared to general population. Despite the fact that suicide represents the 7th cause of death, routine assessment of SR among PWH is uncommon. The COVID19 pandemic caused a significant increase in mental disorders in the general population. Few studies have described the impact of the pandemic on SR in PWH. We aim to describe the trend in SR prevalence in PWH who attended our HIV clinic before (2018 and 2019), during (2020) and after (2021) the lock-down due to COVID19, as well as the factors associated. Method(s): PWH (adults) receiving care in a third level facility in Mexico City during 2018-2021 were included. Since 2018, a questionnaire based on the Columbia Severity Rating Scale, has been routinely applied to screen for SR in all HIV clinic visits. We described and compared the sociodemographic characteristics of those classified with SR vs those without SR. We estimated SR using the responses of patients assessed through the questionnaire, by calendar year. We evaluated the potential association of calendar year on the SR probability using a mixed effects logistic regression model, including sex, being undetectable, CD4count and efavirenz(EFV)-based ART use, at evaluation date;cumulative time in ART, year and route of HIV transmission as fixed effects. Result(s): During the study period, 2275 patients were included;93%(n=2130) were routinely evaluated for SR at least once. Fifty-nine (3%) had SR. Those with SR, compared with those without SR, were more frequently women (19%vs10%), 27% vs 28% used EFV, and had 2.17(SD:1.39) assessments/year vs 1.62 (SD:0.84). SR rates per 1000 patients among those who were evaluated, increased significantly from 0.03 in 2018, 0.26 in 2019, 3.14 in 2020 and 10.58 in 2021. Throughout the model, independently of other covariables, no significant changes in SR were observed during 2019 and 2020, compared to 2018: OR 1.21 (0.57-2.52), p=0.61 and OR 0.21 (0.05-1.00), p=0.06;but we found a significant increase in the SR in 2021;OR 3.71 (1.55-8.88), p=0.003. In this model, EFV use vs non-EFV use was not associated with SR: OR:0.78 (0.39-1.56), p=0.48. Conclusion(s): After an adjusted analysis, suicidal risk in PWH was significantly higher after the lock-down due to COVID19, independently of EFV use. These results should encourage HIV health providers to actively look for suicidal risk and incorporate specialized mental care.

Drug repurposing against COVID-19 by GWAS

This note is prepared by the authors of a recent publication on shared genetic architecture of drug response based on summary statistics from genome-wide association studies (GWAS) to propose a drug repurposing approach for the treatment of coronavirus COVID-19. The authors proposed that in silico studies may be preceded by analyzing shared genetic architecture of drug response based on existing GWAS.Copyright © 2020, Health Biotechnology and Biopharma.

48-WEEK OUTCOMES after PROGRAMMATIC TRANSITION to DOLUTEGRAVIR in UGANDA

Background: In 2018, Uganda began programmatically switching individuals with HIV-1 RNA <1,000 copies/mL on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART to a fixed-dose regimen of tenofovir/lamivudine/dolutegravir (TLD). Our objective was to estimate the population effectiveness of the TLD transition in public-sector clinics in Uganda. Methods: We conducted a prospective cohort study that enrolled adults ≥18 years who were switched from NNRTI-based first-line ART to TLD at public-sector clinics in Uganda. We observed participants at 3 study visits over 1 year. We obtained blood specimens at each visit and conducted HIV-1 RNA viral load (VL) testing using Cepheid Xpert assays. We fit multivariable logistic regression models to assess predictors of our composite outcome of interest of viral suppression (<50 copies/mL) with retention in care 1 year after switch to TLD. Results: We enrolled 500 participants with a median age of 47 years (IQR 40-53);41% were women. The most common regimen prior to switch was lamivudine/tenofovir/efavirenz (44%), and median duration on ART prior to switch was 8.8 years (IQR 5.7-12.2). Over 95% (n=475/499) were virally suppressed (<50 copies/mL) at the time of switch to TLD. The final visit for all participants occurred a median of 54 weeks (IQR 49-67) after enrollment, with some participants affected by delays due to COVID-19 mitigation measures. One participant self-elected to disenroll. Only 3% (n=13/499) of participants discontinued TLD due to side effects or clinician discretion. We observed 1% mortality (n=6/499), 2% (n=10/499) lost to follow-up, and 5% (n=23/499) with HIV-1 RNA ≥50 copies/mL at 1 year, with a median VL of 252 copies/mL (IQR 81-78,200 copies/mL). Overall, 92% (n=459/499) were virally suppressed and in care at 1 year. An HIV-1 RNA ≥50 copies/mL at the time of switch to TLD, male gender, and any self-reported ART adherence <90% were all significant negative predictors of the composite outcome of retention in care with a suppressed VL (Table). Conclusion: Rates of viral suppression with retention in care >90% after 1 year on TLD, as well as a 2% TLD discontinuation rate, affirm World Health Organization guidelines for the regional transition to TLD. Nonetheless, an 8% failure rate in HIV-endemic countries corresponds to a large population of individuals. Long-term surveillance of this population, strategies to combat imperfect adherence, and continued attention to treatment options after failure on TLD may be needed.

PREDICTORS of VIRAL SUPPRESSION FOLLOWING ENHANCED ADHERENCE COUNSELING: VISEND TRIAL

Background: The WHO recommends enhanced adherence counseling (EAC) before regimen switch for HIV-positive, antiretroviral therapy (ART)-treated individuals with non-suppressed viral loads (VL). However, there is a paucity of data, especially within a clinical trial setting, on the determinants of viral suppression (VS) following EAC among those failing ART. We thus evaluated predictors of VS among adults failing ART who had undergone EAC in the VISEND clinical trial. Methods: Our trial is a randomized 144 week open label non-inferiority study with adults failing (VL≧ 1000 copies/mL) ART of tenofovir disoproxil fumarate (TDF), lamivudine (3TC) plus efavirenz (EFV) or nevirapine (NVP), switched to 1) TDF,3TC,DTG or 2) tenofovir alafenamide (TAF), emtricitabine (FTC),DTG or 3) lopinavir/ritonavir (LPV/r) or atazanavir/r (ATV/r), zidovudine (ZDV),3TC. Viral loads and other biomarkers were collected at weeks 12, 24, 48, 72, 96 and 144. Adults with VL≧ 1000 copies/mL at each of these time points underwent EAC involving 3 sessions over a period of 3 months according to existing guidelines. We calculated proportions of individuals who achieved VS post EAC and analyzed factors (demographic and clinical) independently associated with VS post EAC. Using multivariable log regression models, associations were analyzed as crude risk ratios (CRR) and adjusted risk ratios (ARR). Results: The overall VS rates following EAC among individuals with virologic failure was 66%;broken down as follows: TAF,FTC,DTG (78%), TDF,3TC,DTG (71%), ZDV,3TC,ATV/r (62%), and ZDV,3TC,LPV/r (53%). Compared to adults with no formal education, those having primary (ARR 1.55 [1.32-1.81], P<0.001) or secondary level education (ARR 1.93 [1.65-2.27], P<0.001) were more likely to achieve VS. Those less likely to suppress post EAC were individuals on ART for > 5 years (ARR 0.75 [0.75-0.75], P<0.001), VL > 10,000 copies/mL at time of failure (0.48 [0.48-0.48], P<0.001), presence of comorbidities (ARR 0.77 [0.66-0.90], P=0.001) and those taking concomitant medications (ARR 0.67 [0.58-0.79], P<0.001). Having suffered from COVID-19 infection had no association with VS post EAC (ARR 0.59 [0.22-1.58], P=0.30). Consistent results are in Table 1. Conclusion: In the VISEND trial, EAC led to VS rates near the WHO target of 70% with disparities in outcomes according to gender, education, and other factors. There is a need to routinely incorporate EAC into clinical trials and practice before regimen switch in order to maximize outcomes.

The Role of Nanotechnology in Antiviral Regime: An Overview

Nanomedicine or nanotechnology exhibits outstanding features to challenge severe health issues including pathogenic viral infections, the most culpable invaders in the present situation. The perpetual mutational pattern in viruses topped with raising resistance to drug epitomizes the current situation as a trigger to explore nanotech platforms in antiviral therapies. Referring to novel physicochemical features of nanomaterials associated with effective drug delivery, it is viewed as an ideal strategy for treatment of viral infections. The coronavirus induced pathogenesis, including MERS, SARS and SARS-CoV-2 infections, has triggered alarming and highly dangerous precedents against existence of humans. Applications of nanotechnology can serve a new direction for disinfection or treatment of viruses. Presently, various types of nanomaterials, such as nanogels, nanospheres, nanocapsules, liposomes, nanoparticles and many others, that have been investigated in vivo and in vitro for successful drug delivery, vaccination, diagnostic assay and device development with anticipation to be translated in advanced clinical practices, need a collective relook. This paper intents to contribute insightful critique of current studies on the efficacy of nanoplatforms as drug transporter, diagnostic tool and vaccine candidate against pathogenic viruses counting the highly pathogenic and incurable "coronaviruses".

Severe acute respiratory syndrome coronavirus 2 infection in an Iranian HIV-positive patient: A case report

The recent coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has more sequels among patients with comorbidities and coinfections. There are limited data regarding HIV/AIDS associated-coronavirus disease 2019 infection. We present a case of SARS-CoV-2 infection in a 37-year-old HIVpositive female patient. The patient admitted due to dry cough, headache, fatigue and a mild fever (37.6 -C) as well as bilateral ground-glass opacification in computed tomography. Her samples were positive by real-time PCR. She recovered and discharged after 16 days of hospitalization with stable conditions. This article presents the clinical symptoms, diagnosis and treatment of the first case of SARS-CoV-2 infection in an Iranian HIV-positive patient.

Antiviral drugs suppress infection of 2019-nCoV spike pseudotyped virus by interacting with ACE2 protein.

The outbreak of coronavirus disease 2019 (COVID-19) has induced a large number of deaths worldwide. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for the 2019 novel coronavirus (2019-nCoV) to infect the host cells. Therefore, ACE2 may be an important target for the prevention and treatment of COVID-19. The aim of this study was to investigate the inhibition effect of valaciclovir hydrochloride (VACV), zidovudine (ZDV), saquinavir (SQV), and efavirenz (EFV) on 2019-nCoV infection. The results of molecule docking and surface plasmon resonance showed that VACV, ZDV, SQV, and EFV could bind to ACE2 protein, with the KD value of (4.33 ± 0.09) e-8 , (6.29 ± 1.12) e-6 , (2.37 ± 0.59) e-5 , and (4.85 ± 1.57) e-5 M, respectively. But only ZDV and EFV prevent the 2019-nCoV spike pseudotyped virus to enter ACE2-HEK293T cells with an EC50 value of 4.30 ± 1.46 and 3.92 ± 1.36 µM, respectively. ZDV and EFV also have a synergistic effect on preventing entry of virus into cells. In conclusion, ZDV and EFV suppress 2019-nCoV infection of ACE2-HEK293T cells by interacting with ACE2.

Multidomain drug delivery systems of ß-casein micelles for the local oral co-administration of antiretroviral combinations.

The antiretroviral (ARV) cocktailrevolved the treatment of the human immunodeficiency virus (HIV) infection. Drug combinations have been also tested to treat other infectious diseases, including the recentcoronavirus disease 2019 (COVID-19) outbreak. To simplify administration fixed-dose combinationshave been introduced, however, oral anti-HIV therapy still struggles with low oral bioavailability of many ARVs.This work investigated the co-encapsulation of two clinically relevant ARV combinations,tipranavir (TPV):efavirenz (EFV) anddarunavir (DRV):efavirenz (EFV):ritonavir (RTV),within the core of ß-casein (bCN) micelles. Encapsulation efficiency in both systems was ~100%. Cryo-transmission electron microscopy and dynamic light scattering of the ARV-loaded colloidaldispersions indicatefull preservation of the spherical morphology, and x-ray diffraction confirm that the encapsulated drugs are amorphous. To prolong the physicochemical stabilitythe formulations were freeze-driedwithout cryo/lyoprotectant, and successfully redispersed, with minor changes in morphology.Then, theARV-loaded micelles were encapsulated within microparticles of Eudragit® L100, which prevented enzymatic degradation and minimized drug release under gastric-like pH conditionsin vitro. At intestinal pH, the coating polymer dissolved and released the nanocarriers and content. Overall, our results confirm the promise of this flexible and modular technology platform for oral delivery of fixed dose combinations.

Virtual screening, molecular docking studies and DFT calculations of FDA approved compounds similar to the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed as the causative virus of COVID-19 disease, which is currently a worldwide pandemic. Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is one of the most potent chemical compounds proposed to treat COVID-19 infection. We, therefore, performed virtual screening on FDA approved drugs that are similar to the efavirenz moiety. Subsequently, the compounds were subjected to screening by analyzing their drug-likeness, such as Lipinski's rule of five and ADMET properties. Molecular docking study revealed that Met165, His41, His163, and Phe140 were important interacting residues for COVID-19 main protease receptor-ligand interaction. Five top-ranked compounds, podophyllotoxin, oxacillin, lovastatin, simvastatin, and gefitinib, were selected by virtual screening and docking studies. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO) and energy gap values was calculated using density functional theory (DFT). The results of the study showed that lovastatin and simvastatin might be considered as lead compounds for further development for COVID-19 main protease inhibitors.