ABSTRACT
The proceedings contain 22 papers. The topics discussed include: heard but not seen: experiences of telehealth by people living with HIV (PLHIV) in COVID times;clinical guidelines: their influence on HIV-related legal proceedings;examining HIV anxiety in gay men as an embodied response to the AIDS crisis;weight and lipid changes in phase 3 cabotegravir and rilpivirine long-acting trials;comparison of viral replication for the 2-drug regimen (2DR) of dolutegravir/lamivudine;lifetime cost of HIV management in Australia: a modelling study;Intentions for future use of PrEP following COVID-19 restrictions: results from the Flux Study of gay and bisexual men in Australia;associations between social capital and HIV risk-taking behaviors among men who have sex with men in Japan;HIV testing, treatment and viral suppression among men who have sex with men (MSM) in five countries: results of the Asia Pacific MSM Internet Survey;sustained higher levels of intracellular HIV-1 RNA transcript activity in viral blip patients;and lost in translation: preventing the meanings of sexual and reproductive health from being lost during the translation of national surveys.
ABSTRACT
Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Methods: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds. Results: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the pro-tein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His41 and Cys145) and other essential residues for activity (Glu166 and Gln189) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclusion: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafir-lukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.
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Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.
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Background: The mechanism of bone loss in antiretroviral-treated HIV-positive patients is poorly understood. Plasma bone turnover markers(BTMs) suggest uncoupling of bone resorption and formation by a treatment effect on bone cells. Switching away from TDF to TAF-containing regimens has been associated with bone mineral density(BMD) gains measured by dual-energy X-ray absorptiometry (DXA). One explanation is reversal of ongoing subclinical bone loss in the TDF to TAF switchers. Quantitative imaging with 18F-PET/CT allows assessment of regional bone formation at specific skeletal sites and can help differentiate if BMD changes are associated with increased bone formation or reduced bone loss. Methods: PETRAM, an open-label, randomised study conducted at a single UK site, enrolled non-osteoporotic virologically suppressed HIV-positive males, on >24 weeks rilpivirine/emtricitabine/TDF (RPV/FTC/TDF). They were randomised 1:1 to remain on RPV/FTC/TDF or switch to RPV/FTC/TAF. The protocol specified scanning by DXA (to measure BMD) and 18F-PET/CT at several regions of interest-with primary focus on the lumbar spine (LS) and total hip (TH)-at baseline, 24 weeks, and 48 weeks. However, the timing of scans was disrupted, and in some cases considerably delayed, by COVID-19. The primary analysis was therefore based on change between the baseline and final scans, adjusting for the interval between them. Regions of interest were drawn on the PET/CT images and the standardised uptake value (SUV) measured. A sample of 30 (15 per arm) was estimated to provide 90% power to detect a difference in change of 25% in SUV between the randomised groups. Results: 32 males, median age 51 years, 76% White ethnicity, median duration RPV/FTC/TDF of 49 months, BMI 25.5 kg/m2 were enrolled;27(16 TAF:11 TDF) were included in the final analysis. The interval between baseline and final scans ranged between 23-103 weeks (median 55 weeks). There was no significant difference in change in SUV(18F-PET/CT) at the LS or TH between the TAF and TDF arms (Table);there was a trend towards improved LS BMD, but not TH BMD, in the TAF arm. Conclusion: As measured by 18F-PET/CT, regional bone formation at the hip or LS in patients replacing TDF with TAF in their ART combination did not differ, and contrary to our hypothesis, switching to TAF vs. remaining on TDF over 23-103 weeks did not change BMD or SUV at these key skeletal sites. The improved LS BMD in those switching to TAF is consistent with findings from other TAF-switch studies.
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Long-acting (LA) formulations have been designed to improve the quality of life of people with HIV (PWH) by maintaining virologic suppression. However, clinical trials have shown that patient selection is crucial. In fact, the HIV-1 resistance genotype test and the Body Mass Index of individual patients assume a predominant role in guiding the choice. Our work aimed to estimate the patients eligible for the new LA therapy with cabotegravir (CAB) + rilpivirine (RPV). We selected, from the Antiviral Response Cohort Analysis (ARCA) database, all PWH who had at least one follow-up in the last 24 months. We excluded patients with HBsAg positivity, evidence of non-nucleoside reverse transcriptase inhibitor (except K103N) and integrase inhibitor mutations, and with a detectable HIV-RNA (>50 copies/mL). Overall, 4103 patients are currently on follow-up in the ARCA, but the eligible patients totaled 1641 (39.9%). Among them, 1163 (70.9%) were males and 1399 were Caucasian (85.3%), of which 1291 (92%) were Italian born. The median length of HIV infection was 10.2 years (IQR 6.3-16.3) with a median nadir of CD4 cells/count of 238 (106-366) cells/mm3 and a median last available CD4 cells/count of 706 (509-944) cells/mm3. The majority of PWH were treated with a three-drug regimen (n = 1116, 68%). Among the 525 (30.3%) patients treated with two-drug regimens, 325 (18.1%) were treated with lamivudine (3TC) and dolutegravir (DTG) and only 84 (5.1%) with RPV and DTG. In conclusion, according to our snapshot, roughly 39.9% of virologically suppressed patients may be suitable candidates for long-acting CAB+RPV therapy. Therefore, based on our findings, many different variables should be taken into consideration to tailor the antiretroviral treatment according to different individual characteristics.
ABSTRACT
BACKGROUND: COVID-19 disease caused by SARS-CoV-2 is lacking efficient medication although certain medications are used to relief its symptoms. OBJECTIVES: We tested an FDA-approved antiviral medication namely rilpivirine to find a drug against SARS-CoV-2. METHODS: The inhibition of rilpivirine against multiple SARS-CoV-2 therapeutic targets was studied using in silico method. The binding attraction of the protein-ligand complexes were calculated using molecular docking analysis. RESULTS: Docking rilpivirine with main protease (Mpro), papin like protease (PLpro), sprike protein (Spro), human angiotensin converting enzyme-2 (ACE2), and RNA dependent-RNA polymerase (RdRp) yielded binding energies of -8.07, -8.40, -7.55, -9.11, and -8.69 kcal/mol, respectively. The electrostatic interaction is the key force in stabilizing the RdRp-rilpivirine complex, while van der Waals interaction dominates in the ACE2 rilpivirine case. Our findings suggest that rilpivirine can inhibit SARS-CoV-2 replication by targeting not only ACE2, but also RdRp and other targets, and therefore, it can be used to invoke altered mechanisms at the pre-entry and post-entry phases. CONCLUSION: As a result of our in silico molecular docking study, we suggest that rilpivirine is a compound that could act as a powerful inhibitor against SARS-CoV-2 targets. Although in vitro and in vivo experiments are needed to verify this prediction we believe that this antiviral drug may be used in preclinical trials to fight against SARS coronavirus.