Efficacy and Durability of Dolutegravir- or Darunavir-Based Regimens in ART-Naïve AIDS- or Late-Presenting HIV-Infected Patients.

BACKGROUND: Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients. METHODS: Retrospective multicenter study including AIDS- or late-presenting (def. CD4 ≤ 200/µL) HIV-infected patients starting dolutegravir or ritonavir/cobicistat-boosted darunavir+2NRTIs. Patients were followed from the date of first-line therapy initiation (baseline, BL) to the discontinuation of darunavir or dolutegravir, or for a maximum of 36 months of follow-up. RESULTS: Overall 308 patients (79.2% males, median age 43 years, 40.3% AIDS-presenters, median CD4 66 cells/µL) were enrolled; 181 (58.8%) and 127 (41.2%) were treated with dolutegravir and darunavir, respectively. Incidence of treatment discontinuation (TD), virological failure (VF, defined as a single HIV-RNA > 1000 cp/mL or two consecutive HIV-RNA > 50 cp/mL after 6 months of therapy or after virological suppression had been achieved), treatment failure (the first of TD or VF), and optimal immunological recovery (defined as CD4 ≥ 500/µL + CD4 ≥ 30% + CD4/CD8 ≥ 1) were 21.9, 5.2, 25.6 and 1.4 per 100 person-years of follow-up, respectively, without significant differences between dolutegravir and darunavir (p > 0.05 for all outcomes). However, a higher estimated probability of TD for central nervous system (CNS) toxicity (at 36 months: 11.7% vs. 0%, p = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, p = 0.046). CONCLUSIONS: Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir.

Missed opportunities for pre-exposure prophylaxis (PrEP) and outcomes of people acquiring HIV with previous or recent PrEP use

Background: With NHS PrEP now available for those at risk, we aimed to identify missed opportunities for people newly diagnosed with HIV who attended sexual and reproductive health (SRH) services, and to determine the HIV outcomes associated with people acquiring HIV with previous or recent PrEP use. Method(s): A retrospective observational study reviewed all new HIV diagnoses from the last 2 years to see if they were eligible for PrEP and offered in SRH services. Data was collected using electronic medical records on HIV outcomes - virological suppression, resistance and antiretroviral choice. Result(s): There were 74 new HIV diagnoses. 41 people were eligible but only 10 were known to have accessed PrEP at our services. 21% were heterosexual and of black ethnicity - it was not possible to ascertain whether they were eligible for PrEP from the notes. Of the 10 people with recent PrEP use, 2 stopped due to side effects;headaches, vomiting, fatigue and renal toxicity concerns. For the remaining adherence concerns were reported - taking event based dosing (EBD) incorrectly and difficulty accessing services. 80% of people achieved virological suppression. 90% were put on a second generation integrase or protease inhibitor. No one developed nucleoside reverse transcriptase inhibitor (NRTI) resistance. 6 people eligible for PrEP had attended SRH services but not given PrEP. 2 attended during the IMPACT trial being full and referred to IwantPrEPnow. 2 attended during COVID where baseline bloods were done with follow up but subsequently tested positive. 2 people refused PrEP with 1 deeming themselves to be low risk. Conclusion(s): Our data highlights several missed opportunities for starting same-day PrEP which potentially may have prevented HIV acquisition. If PrEP is not issued on the day, adequate follow up must be ensured. Reassuringly those who acquired HIV with recent PrEP use have achieved good virological control without NRTI mutations. Counselling on potential side effects, EBD dosing and ongoing HIV risk are essential. Despite NHS PrEP available over 2 years, our data shows we are still failing to meet the demand of PrEP not only in men who have sex with men but also in other key at risk groups.

Epidemiological and Molecular Evolution of the Hiv-1 Crf94: Birth of Crf132

Background: In 2018 we reported the emergence of the new HIV-1 recombinant CRF94-02BF2 involved in a large transmission cluster of 49 French MSM mostly infected in 2016-2017. This CRF94 raised concerns of enhanced virulence. Prevention actions were undertaken in the area and population affected. This study reported the molecular and epidemiological evolution of this CRF94 until June 2022. Method(s): In 2021-2022, French sequence databases were screened for patients infected with HIV-1 subtype CRF94 or similar strain. HIV subtyping was confirmed by phylogenetic analysis of genes encoding both protease and reverse transcriptase (1070bps), and integrase (696bps) using IQ-Tree. Five whole genomes, related but distinct from CRF94, were obtained with the DeepChek assay Whole Genome kits. Recombination breakpoints were estimated using RDP4 and SimPlot. Mann-Whitney and LogRank tests were used for statistical analyses to compare patients' characteristics. Result(s): In June 2022, 49 new HIV-1 sequences were collected: 14 clustered with the 49 previous CRF94, 32 formed a new cluster next to but distinct from CRF94, and 3 strains could not be classified. Analysis of 5 whole genomes from the new cluster revealed a new recombinant, the CRF132-94B, mainly consisting of CRF94 which recombined with subtype B in the POL and accessory genes. Vif gene changed from the F2 to the B subtype. Both CRF94 and 132 clusters involved >95% of MSM, mostly infected < 1 year before diagnosis. However, there were differences: 97% were diagnosed in 2013-2019 for CRF94 vs 90% in 2020-2022 for CRF132. At time of diagnosis, 33% of patients infected with CRF94 knew the Prep vs 95% for CRF132. In the cluster CRF94, patients were older (34 vs 30 years, p=0.02), had higher viral loads (5.42 vs 4.42 log10 copies/Ml;p< 0.001), a lower CD4 cell counts (358 vs 508 /mm3, p=0.002). On treatment, the patients with the CRF94 reached viremia < 50 copies/Ml significantly later than those infected with CRF132 (p=0.0002). The prevention activities targeting the CRF94 cluster could explained the few patients infected with this strain after 2018. The CRF132 is mainly located in another Paris region area, but no specific transmission place has been identified. Conclusion(s): After 2019, the CRF94 spread seems greatly slowed down but the very close CRF132-94B has given birth to a new highly active cluster in 2020- 2022, despite the COVID social-distancing and a strong knowledge of the Prep. CRF132 appears to be less virulent perhaps due to the Vif gene change. Identified breakpoints positions of the new HIV-1 CRF132-94B. GenBank accession numbers of the five references : ON901787 to ON901791.

Mechanisms of CRISPR-mediated immunity and applications beyond editing

Mammals, bacteria, and archaea have domesticated transposases (e.g., RAG1 and Cas1) to form adaptive immune systems. Bacteria and archaea acquire resistance to viruses and plasmids by preferentially integrating fragments of foreign DNA at one end of a CRISPR locus. DNA motifs upstream of the CRISPR (i.e., leader) facilitate integration at the first CRISPR repeat. But how do these upstream DNA motifs act over large distances of 130 bp, or roughly 440 A, to regulate integration allosterically? Here, we determine the structure of a 560 KDa integration complex that explains how the CRISPR leader DNA recruits Cas (i.e., Cas1-2/3) and non-Cas proteins (i.e., IHF). Cas1-2/3 and IHF cooperate to fold the genome into a successive U-shaped bend and a loop. The genomic U-bend traps foreign DNA against the integrase, whereas the genomic loop positions the leader-repeat junction at the Cas1 active site. The foreign DNA and the CRISPR repeat wrap around opposite faces of Cas2, poised for a Cas1-catalyzed strand-transfer reaction. The post-integration structure suggests that strand-transfer releases tension in the DNA loop. Therefore Cas1-2/3 may harness protein-induced DNA tension to favor the completion of the isoenergetic integration reaction. Cas1-2/3 interacts extensively with the leader and repeat without making sequence-specific contacts, and we demonstrate that protein-mediated folding of DNA drives integration into diverse sequences. These results reveal Cas1-2/3 and IHF strain DNA to enhance integration allosterically and suggest a mechanism for the de novo generation of new CRISPRs. Further, to address an urgent need for inexpensive and rapid detection of viruses, we recently repurposed a CRISPR immune signaling pathway to detect SARS-CoV-2 in patient samples. A.S-F. is a postdoctoral fellow of the Life Science Research Foundation, supported by the Simons Foundation. A.S-F. is supported by the PDEP award from the Burroughs Wellcome Fund, and by the National Institutes of Health, United States grant 1K99GM147842. This work was also supported by NSF (1828765), NIH (U24 GM129539, R35GM134867).Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants.

AIDS (Acquired immunodeficiency syndrome) is one of the chronic and potentially life-threatening epidemics across the world. Hitherto, the non-existence of definitive drugs that could completely cure the Human immunodeficiency virus (HIV) implies an urgent necessity for the discovery of novel anti-HIV agents. Since integration is the most crucial stage in retroviral replication, hindering it can inhibit overall viral transmission. The 5 FDA-approved integrase inhibitors were computationally investigated, especially owing to the rising multiple mutations against their susceptibility. This comparative study will open new possibilities to guide the rational design of novel lead compounds for antiretroviral therapies (ARTs), more specifically the structure-based design of novel Integrase strand transfer inhibitors (INSTIs) that may possess a better resistance profile than present drugs. Further, we have discussed potent anti-HIV natural compounds and their interactions as an alternative approach, recommending the urgent need to tap into the rich vein of indigenous knowledge for reverse pharmacology. Moreover, herein, we discuss existing evidence that might change in the near future.

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With HIV-1: Week 48 Results From the Phase 3, Non-inferiority SALSA Randomized Trial.

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term non-inferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CAR). METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48; Snapshot, intention-to-treat-exposed population, 5% non-inferiority margin). RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n=246) or continue CAR (n=247). At Week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating non-inferiority (adjusted difference, -0.8%; 95% CI, -2.4%, 0.8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through Week 48 but comparable post-Week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers. CONCLUSIONS: Switching to DTG/3TC was non-inferior to continuing CAR for maintaining virologic suppression at Week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC.

Can plant-derived anti-HIV compounds be used in COVID-19 cases?

People living with HIV are more exposed to the adverse health effects of the worldwide COVID-19 pandemic. The pandemic's health and social repercussions may promote drug abuse and inadequate HIV management among this demographic. The coronavirus pandemic of 2019 (COVID-19) has caused unprecedented disruption worldwide in people's lives and health care. When the COVID-19 epidemic was identified, people with HIV faced significant obstacles and hurdles to achieving optimal care results. The viral spike protein (S-Protein) and the cognate host cell receptor angiotensin-converting enzyme 2 (ACE2) are both realistic and appropriate intervention targets. Calanolides A, Holy Basil, Kuwanon-L, and Patentiflorin have anti-HIV effects. Our computational biology study investigated that these compounds all had interaction binding scores related to S protein of coronavirus of -9.0 kcal /mol, -7.1 kcal /mol, -9.1 kcal /mol, and -10.3 kcal/mol/mol, respectively. A combination of plant-derived anti-HIV compounds like protease inhibitors and nucleoside analogs, which are commonly used to treat HIV infection, might be explored in clinical trials for the treatment of COVID-19.

Achievement of virologic suppression with HIV antiretroviral therapy in a patient also taking multiple daily cation supplement doses: A case report and review of the literature.

DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To describe a case report of antiretroviral regimen selection, with considerations for drug-supplement interactions, for a patient living with HIV with complicated nutrition needs. SUMMARY: A 56-year-old white female with a history of sleeve gastrectomy was initiated on coformulated bictegravir/emtricitabine/tenofovir alafenamide for treatment of HIV infection. Her baseline HIV viral load was 139,790 RNA copies/mL, and the baseline CD4 cell count was 544 cells/mm 3. The patient additionally had a nutritional supplement regimen of twice-daily calcium and twice-daily multivitamins with minerals following sleeve gastrectomy. Due to binding interactions between polyvalent cations and bictegravir and the potential impact on antiretroviral efficacy, construction of a daily medication schedule to avoid interactions between the antiretroviral regimen and the supplements while promoting optimal dosing of each supplement was necessary; however there is currently no guidance on twice-daily cation dosing with coadministered bictegravir and limited guidance on multivitamin coadministration in this context. A review of the available literature on bictegravir interactions and pharmacokinetic parameters was performed. A dose separation strategy was utilized to design a regimen that maximized separation of doses of supplements from doses of bictegravir/emtricitabine/tenofovir alafenamide while minimizing interaction potential. At follow-up 8 weeks after regimen initiation, the HIV viral load was undetectable (<40 copies/mL) and the CD4 cell count had increased to 821 cells/mm 3. CONCLUSION: Integrase strand transferase inhibitor interactions with polyvalent cations in nutritional supplements can be avoided or mitigated with attention to timing of each dose and optimizing separation strategies. This case report shows the potential for alleviating such interactions through optimal dose scheduling.

Perspectives of people living with HIV-1 on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings: results from the CUSTOMIZE hybrid III implementation-effectiveness study.

INTRODUCTION: The CUSTOMIZE hybrid III implementation-effectiveness study evaluated implementation of once-monthly long-acting (LA) cabotegravir + rilpivirine in diverse US healthcare settings. Here, we report patient participant perspectives after 12 months in CUSTOMIZE. METHODS: CUSTOMIZE was a phase IIIb, 12-month study conducted from July 2019 to October 2020 at eight diverse US HIV clinics that enrolled virologically suppressed people living with HIV-1 (PLHIV) on a stable oral regimen to receive monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. Participants were administered quantitative surveys before injections at months 1 (baseline), 4 and 12. A randomly selected subset of participants was interviewed at baseline and month 12. Data collection at month 12 was completed by October 2020 (during the COVID-19 pandemic). RESULTS: At baseline, 109 and 34 participants completed surveys and interviews, respectively; 87% were male; 35% were Black or African American. All participants who remained in the study at month 12 (n = 102) maintained HIV-1 RNA <50 copies/ml; two participants withdrew due to injection-related reasons. Mean total scores measuring acceptability and appropriateness of cabotegravir + rilpivirine LA were high at baseline (4.5-4.6 out of 5) and month 12 (4.7-4.9). At month 12, 74% of participants reported nothing interfered with receiving LA injections; injection pain or soreness was the most common concern (15%). Time spent in the clinic and coming to the clinic for monthly injections was very or extremely acceptable after 12 months for most participants (93% and 87%, respectively), with 64% reporting having spent ≤30 minutes in the clinic for injection visits. At month 12, 92% of participants preferred LA injections to daily oral tablets (3%); 97% plan to continue LA treatment going forward. In month 12 interviews, 24 (77%) of 31 participants reported the COVID-19 pandemic did not impact their ability to receive treatment. CONCLUSIONS: Once-monthly cabotegravir + rilpivirine LA was highly acceptable among PLHIV who were virologically suppressed on a stable antiretroviral regimen and interested in trying LA therapy, with few participants reporting challenges receiving LA injections. Implementation data from CUSTOMIZE suggest that monthly LA injections provide a convenient and appealing treatment option for PLHIV.

Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins.

The emergence and spread of new HIV-1 variants pose a challenge for the effectiveness of antiretrovirals (ARV) targeting Pol proteins. During viral evolution, non-synonymous mutations have fixed along the viral genome, leading to amino acid (aa) changes that can be variant-specific (V-markers). Those V-markers fixed in positions associated with drug resistance mutations (DRM), or R-markers, can impact drug susceptibility and resistance pathways. All available HIV-1 Pol sequences from ARV-naïve subjects were downloaded from the United States Los Alamos HIV Sequence Database, selecting 59,733 protease (PR), 6,437 retrotranscriptase (RT), and 6,059 integrase (IN) complete sequences ascribed to the four HIV-1 groups and group M subtypes and circulating recombinant forms (CRFs). Using a bioinformatics tool developed in our laboratory (EpiMolBio), we inferred the consensus sequences for each Pol protein and HIV-1 variant to analyze the aa conservation in Pol. We analyzed the Wu-Kabat protein variability coefficient (WK) in PR, RT, and IN group M to study the susceptibility of each site to evolutionary replacements. We identified as V-markers the variant-specific aa changes present in >75% of the sequences in variants with >5 available sequences, considering R-markers those V-markers that corresponded to DRM according to the IAS-USA2019 and Stanford-Database 9.0. The mean aa conservation of HIV-1 and group M consensus was 82.60%/93.11% in PR, 88.81%/94.07% in RT, and 90.98%/96.02% in IN. The median group M WK was 10 in PR, 4 in RT, and 5 in IN. The residues involved in binding or catalytic sites showed a variability <0.5%. We identified 106 V-markers: 31 in PR, 28 in RT, and 47 in IN, present in 11, 12, and 13 variants, respectively. Among them, eight (7.5%) were R-markers, present in five variants, being minor DRM with little potential effect on ARV susceptibility. We present a thorough analysis of Pol variability among all HIV-1 variants circulating to date. The relatively high aa conservation observed in Pol proteins across HIV-1 variants highlights their critical role in the viral cycle. However, further studies are needed to understand the V-markers' impact on the Pol proteins structure, viral cycle, or treatment strategies, and periodic variability surveillance studies are also required to understand PR, RT, and IN evolution.

HIV-1 DIAGNOSES in NORTH CAROLINA, 2018-21: INCIDENT INFECTIONS and DRUG RESISTANCE

Background: Knowing the true incidence of HIV-1 infections (recent infections) among people newly diagnosed is pivotal to monitoring the course of the epidemic. We have developed a Primer ID Next Gen Sequencing (PID-NGS) assay to identify recent infection by measuring within-host viral diversity over multiple regions of the HIV-1 genome. We implemented a state-wide project to identify recent infections and transmitted drug resistance mutations (DRMs) in diagnostic samples in near real time. Methods: Serum samples from individuals with newly HIV-1 diagnoses (diagnostic sample collected within 30 days of diagnosis) were sequenced. PID-NGS libraries were constructed covering the coding regions for protease, a portion of reverse transcriptase, integrase, and the env gene. The use of the PID-NGS strategy allows for significant error correction and also a definition of the sampling depth of the viral population. Recent infection was defined as within 9-month of infection. DRMs were summarized at detection sensitivities of 30%, 10% and 1% based on viral population sampling depth. Results: From Jan 2018 to Jun 2021, we successfully sequenced partial genomes from 743 individuals with new diagnoses. Year 2020 had the lowest number of new diagnoses (Fig 1a, red bar). Overall, 39.2% of samples were inferred to have represented infection within the previous 9 months. Percent of recent infection varied significantly over the years, increasing from 29.6% in late 2018 to 50.9% in early 2020, but decreasing significantly to 32.7% in 2021 (Fig 1a, blue lines). Individuals younger than 30 y/o were more likely to be identified with recent infection (p<0.01). NNRTI DRMs, especially K103N, were the most abundant DRMs. Fig 1b shows the trend of DRMs over the four years. We observed a trend of decrease in the overall NNRTI DRMs and an increase in the NRTI DRMs in the population. Further analysis suggests that the increase in NRTI DRMs were from TAMs and their revertants, while clinically important NRTI DRMs (K65R and M184) were low (<1%). Conclusion: We have demonstrated a state-wide, all-in-one platform to monitor HIV-1 recency and DRMs in new diagnoses. The number of new diagnoses decreased significantly in 2020 in concert with the COVID-19 pandemic which suggests a decrease in overall HIV testing. The decline in the percentage of recent infections in early 2021 signals a return to broader HIV-1 testing and diagnosis. The increase of other NRTI DRMs suggests ongoing evolution at these sites within the viral population.

HUMORAL and CELLULAR RESPONSE to mRNA SARS-CoV-2 VACCINATION in HIV-INFECTED CHILDREN

Background: There are still scant data on the immunogenicity of SARS-CoV-2 mRNA vaccination in PWH, and no experience in HIV-infected adolescents has been reported. Methods: A prospective ongoing observational study is being conducted in HIV-infected adolescents after the introduction of mRNA vaccination in Spain starting in August, 2021. Blood samples were drawn 3-8 weeks after the second dose of BNT162b2(Pfizer/BioNTech) and CoV-2 mRNA-1273(Moderna) vaccines in 15 HIV-infected adolescents and were compared to 19 matched healthy subjets. Humoral response was assesed by detection of SARS-CoV-2 antibodies by chemiluminescent microparticle immunoassay (CMIA,Alinity® Quant assay-Abbott) to detect IgG against S1 region of the spike protein of SARS-CoV-2 (≥50U/mL considered reactive). T-Cell response to SARS-CoV-2 was measured by an interferon-gamma released assay (IGRA,Euroimmun) of S1 peptide-stimulated T-cells in whole blood (≥200mlU/ml considered reactive). Results: Fifteen HIV-infected adolescents (11female) were included, after administration of mRNA vaccination (13 Pfizer, 2 Moderna). All but 1 were perinatally infected, 10 Caucasian, 3 Latino and 2 from Sub-saharan Africa. Median age was 16.2 years (IQR12.7-19.2) and 14.3 years (IQR12.7-19.2), in patients and controls(p>0.05). Four patients were on CDC-Class C or 3. Median baseline CD4+ count was 703 cells/ul (IQR 596-1098). All were on integrase inhibitors-based ART (13had undetectable viral load). The nadir CD4 was 446 cells/ul (IQR 596-1098). Median interval days since last vaccine dose in HIV-infected adolescents and controls were 33 days(IQR29-49) and 33.5 days(IQR27-45), respectively(p>0.05). All patients and controls had reactive humoral and celular responses. HIV-infected subjects had lower anti-Spike antibodies titers (median:11320U/mL, IQR6074-21518) than controls (median: 30342 AU/mL, IQR9222-38013) (p=0.001). No significant differences were observed in cellular immune responses in HIV-infected adolescents (median 1759mlU/ml, IQR:1613-1856) vs controls (median 1853mlU/ml, IQR1782-1873) (p=0.12). No correlation was observed between quantitative humoral and cellular responses Conclusion: HIV-infected adolescents with good immuno-virologic status show appropriate specific antibody levels and cellular immune responses against SARS-CoV-2 shortly after mRNA vaccination. Although they appear to mount a similar quantitative celular inmune response, the elicited antispike antibody levels was lower than that in healthy controls.

LINKAGE to CARE and TIME to VIRAL SUPPRESSION in PWH in SPAIN: 2004-2020

Background: For newly diagnosed persons with HIV (PWH), early initiation of ART is essential in reducing morbidity and mortality and decreasing the risk of transmitting HIV. We have previously reported the trends in linkage to HIV medical care within one month of HIV diagnosis (LC-1Mo) and viral suppression within three months of HIV diagnosis (VS-3Mo) among PWH in Spain from 2004 to 2018. We herein update this information up to 2020. Methods: Longitudinal study based on the Cohort of the Spanish AIDS Research Network (CoRIS). VS was defined as ever having an HIV-RNA <200 copies/mL. We used logistic regression to assess differences by sex, age, country of birth, transmission category, and baseline CD4+ cell count. Results: A total of 13,632 PWH were enrolled in CoRIS in the study period: males 85%, men having sex with men (MSM) 62%, median age 35 (IQR: 28-43) years. LC-1Mo increased from 41% (95% CI, 37%-45%) in 2004 to 83% (79%-87%) in 2020 (P trend <0.001) (Figure). Median CD4+ cell counts at ART initiation increased from < 250/mm3 in 2004-2005 to > 350/mm3 since 2012 (P for trend <0.001). The percentage of initial ART regimens based on integrase strand transfer inhibitors (InSTI) increased from 3% in 2004 to > 70% from 2016 onwards (P trend <0.001). VS-3Mo increased from 6% (4%-8%) in 2004 to 43% (40%-47%) in 2019 with a small decrease to 41% (36%-46%) in 2020 (P trend [for the entire period] <0.001) (Figure). The odds of achieving VS-3Mo was higher among females (aOR, 95% CI: 1.30, 1.12-1.51), among non-Spanish Europeans and Latin Americans compared to native-born Spaniards (1.26, 1.11-1.44 and 1.36, 1.21-1.52, respectively), and among those older than 50 years (1.20, 1.03-1.41). Opposite, the odds of achieving VS-3Mo was lower among IDU compared to MSM (0.53, 0.40-0.70) and those with CD4 counts between 200-500 cells/uL (0.78, 0.69-0.89) and CD4 counts >500 cells/uL (0.51, 0.44-0.60) compared to those with CD4 < 200 cells/uL. Conclusion: Indicators of care have improved among newly diagnosed PWH in Spain over the last 16 years. Elimination of CD4 cell count restrictions for ART initiation and increasing use of InSTI-based regimens was decisive for progress. A slight decrease in VS-3Mo in 2020 compared with 2019 was observed, perhaps because of the COVID-19 pandemic.

Increased viral load in a hospitalized patient on treatment with crushed bictegravir/emtricitabine/tenofovir alafenamide: A case report and review of the literature.

PURPOSE: To describe a case of increased viral load in a patient with HIV-1 infection receiving treatment with crushed bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF). SUMMARY: A 43-year-old man, newly diagnosed with HIV, was hospitalized due to failure to thrive, neurological changes, and hypotension. Before treatment, the HIV viral load (VL) was 769,704 copies/mL and the CD4+ T-cell count was 36 cells/µL. On hospital day (HD) 8, B/FTC/TAF by mouth daily was initiated. During the hospitalization, the patient's course was complicated by opportunistic infections, bilateral pneumothorax, seizure activity, and acute respiratory distress, requiring multiple intubations and extended time in the intensive care unit. A repeat VL measurement on HD 28 was 5,887 copies/mL after the patient had received 14 of 20 scheduled B/FTC/TAF doses. Because of a failed swallow study and continued nutritional deficits, a percutaneous endoscopic gastrostomy (PEG) tube was placed on HD 38 and continuous tube feeds via the PEG tube were initiated. Subsequently, the B/FTC/TAF order was modified to be crushed, mixed in 30 mL water, and administered daily via the PEG tube. A repeat VL measurement on HD 65 showed an increase to 8,047 copies/mL, despite receipt of 37 consecutive doses of B/FTC/TAF. B/FTC/TAF was discontinued and dolutegravir 50 mg twice daily, darunavir 800 mg plus ritonavir 100 mg (DRV/r), and tenofovir disoproxil fumarate/FTC 300 mg/200 mg were started due to virological increase, need for a viable option compatible with PEG tube delivery, and potential for integrase inhibitor resistance. At the time of regimen change (HD 67), a resistance panel showed minor mutations, E157Q and V118I. The regimen was streamlined with discontinuation of DRV/r on HD 92. The patient was discharged on HD 161. The PEG tube was removed 2 months after discharge, oral B/FTC/TAF was reinitiated, and the patient was virologically suppressed at 1 year after discharge. CONCLUSION: Controlled studies are needed to verify acceptable pharmacokinetic and pharmacodynamic metrics for crushed B/FTC/TAF given via tube, with and without tube feeds, before use in this manner.

Anti-HIV Integrase Inhibitors as New Candidates for the Treatment of COVID-19: A Narrative Literature Review

Background: The initial reports of a contagious novel Severe Acute Respiratory Syndrome- Coronavirus-2 (SARS-CoV-2) were proclaimed by Wuhan, Hubei province, China. This pathogen quickly became a health concern due to the World Health Organization's (WHO) alarm of its pandemic essence. Hence, there is an urgent need for efficacious and curative therapy against COVID-19. Objective: Theoretically, repurposing anti-viral drugs, specifically HIV treatments, could help meet the urgent need for treating COVID-19 due to the structural similarities of their critical enzyme substrates. Integrase inhibitors are a category of anti-HIV drugs that inhibit integrase strand transfer. In this review, we investigate the binding affinity and stability of raltegravir, dolutegravir, bictegravir, and elvitegravir in interactions with crucial enzymes of coronavirus. Methods: A literature search was conducted using scientific databases such as Web of Science, Medline (PubMed), Scopus, Google Scholar, and Embase from commencement to September 2020. The most relevant articles regarding the potential effects of integrase inhibitors against COVID-19 were gathered. Ultimately, ten original articles related to the searched terms were selected for this narrative review. Results: Apparently, in addition to the recent drugs prescribed to cure SARS-CoV-2, integrase inhibitors are promising drugs for repurposing in COVID-19 treatment. Several studies on raltegravir, dolutegravir, bictegravir and elvitegravir were conducted using virtual screening to guess either they are effective or not. Encouraging results were mostly reported for raltegravir and dolutegravir. Nevertheless, bictegravir and elvitegravir need more investigations. Conclusion: Further experimental and clinical studies of antiviral drugs are necessary to introduce appropriate treatment options for COVID-19.

Clinical Characteristics of Patients Living with HIV Hospitalized for COVID-19

Background. Limited data exists regarding the impact of coronavirus disease 2019 (COVID-19) on people living with human immunodeficiency virus (PLWH). The purpose of the study was to compare the clinical outcomes of patients hospitalized with COVID-19 and HIV versus those without HIV. Methods. This was a retrospective, cohort study of adult patients admitted with confirmed COVID-19 from March 1st to May 30th 2020 at an urban hospital in New York City. Data collected included demographics, past medical history, HIV status, baseline laboratory values, treatment and outcomes such as length of stay, mechanical ventilation, patient disposition at discharge, and in-hospital mortality. Fisher's exact test was used to compare categorical values and a t-test was used to compare continuous values. Results. Out of 983 patients, 6.9% were PLWH and 93.1% were HIV-negative. The average age in both groups was 61 vs. 62 years, respectively. There were more male patients in the PLWH than the non-HIV group (76.8% vs. 58.6%). Majority of PLWH were Black (49.3%). Forty-seven percent of PLWH were mechanically ventilated versus 33.3% of the non-HIV group. The most common comorbidity in both groups was hypertension (82.4% vs. 72.6%). When compared to HIV-negative patients, PLWH had a higher rate of kidney disease (72.1% vs. 53.6%, p=0.0086), chronic obstructive pulmonary disease (41.2% vs. 14.5%, p=0.0001), liver disease (45.6% vs. 11.5%, p=0.0001) and current smoking (14.3% vs. 5.8%, p=0.0103). In PLWH, 70.6% of patients were on an integrase-based regimen. Fifty-three percent of PLWH had a CD4 count of > 200 cells/mm3 and 35.3% had an undetectable viral load (< 20 copies/mL). Unadjusted hospital mortality was 51.4% in PLWH and 36.2% in the non-HIV cohort (p=0.0089). The average length of hospital stay was 9.1 days vs. 8.4 days in PLWH versus the non-HIV group (p=0.4493). More patients were discharged to a nursing home in the non-HIV group vs. PLWH (37.8% vs. 14.3%, p=0.0001). Conclusion. Hospitalized patients with COVID-19 and HIV had a higher in-hospital mortality compared to those without HIV during the first COVID wave in New York City.

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds.

In a search for natural compounds with anti-HIV-1 activity, we studied the effect of the ethanolic extract obtained from leaves, bark, and peels of Punica granatum L. for the inhibition of the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) and integrase (IN) LEDGF-dependent activities. The chemical analyses led to the detection of compounds belonging mainly to the phenolic and flavonoid chemical classes. Ellagic acid, flavones, and triterpenoid molecules were identified in leaves. The bark and peels were characterized by the presence of hydrolyzable tannins, such as punicalins and punicalagins, together with ellagic acid. Among the isolated compounds, the hydrolyzable tannins and ellagic acid showed a very high inhibition (IC50 values ranging from 0.12 to 1.4 µM and 0.065 to 0.09 µM of the RNase H and IN activities, respectively). Of the flavonoids, luteolin and apigenin were found to be able to inhibit RNase H and IN functions (IC50 values in the 3.7-22 µM range), whereas luteolin 7-O-glucoside showed selective activity for HIV-1 IN. In contrast, betulinic acid, ursolic acid, and oleanolic acid were selective for the HIV-1 RNase H activity. Our results strongly support the potential of non-edible P. granatum organs as a valuable source of anti-HIV-1 compounds.

Dolutegravir Plus Lamivudine Two-Drug Regimen: Safety, Efficacy and Diagnostic Considerations for Its Use in Real-Life Clinical Practice-A Refined Approach in the COVID-19 Era.

The diagnostic and therapeutic management of the Coronavirus Disease 2019 (COVID-19) pandemic in the HIV population brought some known criticalities (and opportunities) to the forefront, for both those who are facing their first therapeutic line today, and for those already well viro-suppressed. The clinical, socioeconomic, and psychological impact of the COVID-19 pandemic should not affect the long-term care of people living with HIV, which creates an urgent need to optimize the diagnostic and treatment approach to the first-line or switch regimens. The use of dolutegravir plus a lamivudine two-drug regimen is one of the most promising solutions to ease the management of HIV treatment in this difficult period. In this review, we report the most salient features related to the use of this regimen from real-life cohorts, meta-analyses, randomized clinical trials, and studies presented at international conferences up to March 2021. We focused on the diagnostic and clinical-management implications of its use in real life, and how these comply with the contingent historical situation. The issue of the timing and type of diagnostic procedures and the relevance of classical diagnostic tests (such as genotype for resistance detection) is also discussed. According to the currently available results, dolutegravir plus a lamivudine two-drug regimen represents an outstanding tool, whose expected advantages fulfill the current requirements for optimal daily care of our HIV patients.

A review: Mechanism of action of antiviral drugs.

Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the major pathogenic agents that cause number of serious diseases in humans, animals and plants. Viruses cause many diseases in humans, from self resolving diseases to acute fatal diseases. Developing strategies for the antiviral drugs are focused on two different approaches: Targeting the viruses themselves or the host cell factors. Antiviral drugs that directly target the viruses include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors, polymerase inhibitors, protease inhibitors, inhibitors of nucleoside and nucleotide reverse transcriptase and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and darunavir), viral DNA polymerase (acyclovir, tenofovir, valganciclovir and valacyclovir) and of integrase (raltegravir) are listed among the Top 200 Drugs by sales during 2010s. Still no effective antiviral drugs are available for many viral infections. Though, there are a couple of drugs for herpesviruses, many for influenza and some new antiviral drugs for treating hepatitis C infection and HIV. Action mechanism of antiviral drugs consists of its transformation to triphosphate following the viral DNA synthesis inhibition. An analysis of the action mechanism of known antiviral drugs concluded that they can increase the cell's resistance to a virus (interferons), suppress the virus adsorption in the cell or its diffusion into the cell and its deproteinisation process in the cell (amantadine) along with antimetabolites that causes the inhibition of nucleic acids synthesis. This review will address currently used antiviral drugs, mechanism of action and antiviral agents reported against COVID-19.