Classes Of Antiretroviral Drugs Research Articles

Population-based nanopore sequencing of the HIV-1 pangenome to identify drug resistance mutations.

HIV-1 drug resistance genotypic tests have primarily been performed by Sanger sequencing of gene segments encoding different drug target proteins. Since the number of targets has increased with the addition of a new class of antiretroviral drugs, a simple high-throughput system for assessing nucleotide sequences throughout the HIV-1 genome is required. Here, we developed a new solution using nanopore sequencing of viral pangenomes amplified by PCR. Benchmark tests using HIV-1 molecular clones demonstrated an accuracy of up to 99.9%. In addition, validation tests of our protocol in 106 clinical samples demonstrated high concordance of drug resistance and tropism genotypes (92.5% and 98.1%, respectively) between the nanopore sequencing-based results and archived clinical determinations made based on Sanger sequencing data. These results suggest that our new approach will be a powerful solution for the comprehensive survey of HIV-1 drug resistance mutations in clinical settings.

[Artículo traducido] Análisis de la interrupción de la terapia antirretroviral en personas que viven con VIH/sida durante el periodo 2010–2021

ObjectiveIn the context of the advancement of antiretroviral therapy and, as the characteristics of people living with HIV progress toward an aging population, understanding the causes of treatment interruption becomes crucial. The aim of the study was to determine the change in reasons for antiretroviral treatment discontinuation for 12 years. Secondarily, compare annual antiretroviral regimen discontinuation rate and factors associated. MethodsWe conducted an analysis using data from people living with HIV who were receiving antiretroviral therapy and discontinued it for any reason. The study included people with HIV infection who visited an outpatient hospital pharmacy clinic from January 2010 to December 2021. Two periods were differentiated for the analysis: 2010–2015 and 2016–2021. The reasons for antiretroviral treatment discontinuation followed classification described by Swiss cohort. In the context of this study, it is pertinent to note that the term ‘interruption’ will be consistently used in this article to refer to the act of switching or stopping antiretroviral treatment. To examine factors associated with antiretroviral therapy discontinuation, we utilized Kaplan–Meier methods and Cox proportional models. ResultsWe included 789 people living with HIV, predominantly male (81,5%). The main reason for discontinuation was clinical decision (50.2%) followed by adverse effects (37.9%). Focusing on clinical decision, we observed a trend change that went from antiretroviral treatment simplification regimen (56.1%) in the first part of the period analyzed to the therapeutic optimization (53.6%) in the second half. Furthermore, factors that were statistically significantly associated with antiretroviral treatment discontinuation were people with HIV ≥50 years (HR 1.60; 95%CI 1.25–2.04), post-discontinuation single-tablet regimen (HR 1.49; 95%CI 1.06–2.11) and antiretroviral drug classes. ConclusionsOver the 12 years there has been a change in the main cause of antiretroviral treatment discontinuation, currently therapeutic optimization being the main reason. Integrase inhibitors-based regimens and singletablet regimen strategies were less likely to be discontinued than others antiretroviral drug classes, allowing for better clinical management due to the efficacy profile, especially in people living with HIV ≥50 years with comorbidities.

Building a ML-based QSAR model for predicting the bioactivity of therapeutically active drug class with imidazole scaffold

Human immunodeficiency virus, a retrovirus, causes AIDS, a chronic immune system disease. HIV interferes with the ability of our body to combat disease and infection by weakening our immune system. An essential enzyme necessary for HIV replication is reverse transcriptase (RT). RT inhibitors (RTIs) are a class of antiretroviral drugs that target HIV's RT enzyme, blocking its ability to convert viral RNA into DNA. The RT-1 enzyme has been found to be inhibited by imidazole. It attaches to the RT-1 enzyme's active site and prevents it from performing its usual activity. As a result, viral replication is inhibited, which can eventually aid in slowing the course of HIV and other retroviral diseases. A computational tool allows researchers to simulate and analyze the drug's behaviour in a virtual environment, providing valuable insights into its pharmacological properties, efficacy, and safety. QSAR modelling uses machine learning methods to create predictive models from datasets of chemical substances and the accompanying biological activity. Here, a comparative analysis of the model performances by four different algorithms for the Imidazole scaffold are reported. The algorithms of Support Vector Regression (SVR), Random Forest Regression (RFR), Decision Tree Regression (DTR) and Hist Gradient Boosting Regression (HGBR) have given promising results with the R2 value of 0.905, 0.993, 0.688 and 0.921 respectively for the train sets and for the test set 0.843, 0.977, 0.567 and 0.880. The best performed RFR model have been validated using developed RFR codes for randomly selected compounds and it shows the error percentage of about 0.151% only. From the R2 values, it is observed that the RFR and HGBR models show a better fit with the variables compared to the other models thereby making them the potential models for predicting the activity of novel anti-viral compounds.

Heavily treatment-experienced persons living with HIV currently in care in Italy: characteristics, risk factors, and therapeutic options—the ICONA Foundation cohort study

ObjectivesHeavily treatment-experienced (HTE) people living with HIV (PLWH) pose unique challenges due to limited antiretroviral treatment (ART) options. Our study aimed to investigate the prevalence and features of HTE individuals followed up in the Italian Cohort Naïve Antiretrovirals (ICONA) cohort as of December 31, 2021. MethodsHTE were defined based on meeting specific conditions concerning their current ART and their ART history up to December 31, 2021. Descriptive statistics were performed by HTE status. Regression analyses explored factors associated with becoming HTE based on pre-ART patients' characteristics. Cluster dendrogram analysis provided insights into subgroups with inadequate responses based on clusters of differentiation (CD4) counts and viral load (VL) trajectories. ResultsAmong the 8758 PLWH actively followed in our cohort, 163 individuals (1.9%), mainly female, younger, Italian, and infected through heterosexual contact, met the HTE criteria. A lower CD4 count at ART initiation (odds ratio [OR] 1.60 per 100 cells/mmc lower CD4, 95% confidence interval [CI] 1.06-2.41, P = 0.03) and hepatitis C virus antibody positivity (OR 1.90, 95% CI 1.16-3.11, P = 0.01) were associated with higher HTE risk. Thirty PLWH exhibited ongoing immune-virological failure (18% of the HTE subgroup and 0.003% of the total population). Thirty PLWH exhibited ongoing immune-virological failure (i.e., with a current CD4 count <200 cells/mmc or VL>200 copies/mL). A cluster analysis identified 13 (43%) with a current CD4 count <200 cells/mmc. Also, notably, 19/30 (63%) had major acquired resistance-associated mutations to at least one antiretroviral drug class. ConclusionsHTE is rare in our cohort and tends to co-exist with major resistance mutations. A focused investigation into treatment history and immuno-virological response is warranted, particularly given the availability of new antiretroviral drugs.

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

Revolutionizing antiretroviral therapy for human immunodeficiency virus/AIDS: A computational approach using molecular docking, virtual screening, and 3D pharmacophore building to address therapeutic failure and propose highly effective candidates.

In the context of human immunodeficiency virus (HIV) treatment, the emergence of therapeutic failures with existing antiretroviral drugs presents a significant challenge. This study aims to employ advanced molecular modeling techniques to identify potential alternatives to current antiretroviral agents. The study focuses on three essential classes of antiretroviral drugs: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Computational analyses were performed on a database of 3,343,652 chemical molecules to evaluate their binding affinities, pharmacokinetic properties, and interactions with viral reverse transcriptase and protease enzymes. Molecular docking, virtual screening, and 3D pharmacophore modeling were utilized to identify promising candidates. Molecular docking revealed compounds with high binding energies and strong interactions at the active sites of target enzymes. Virtual screening narrowed down potential candidates with favorable pharmacological profiles. 3D pharmacophore modeling identified crucial structural features for effective binding. Overall, two molecules for class 1, 7 molecules for class 2, and 2 molecules for class 3 were selected. These compounds exhibited robust binding affinities, interactions with target enzymes, and improved pharmacokinetic properties, showing promise for more effective HIV treatments in cases of therapeutic failures. The combination of molecular docking, virtual screening, and 3D pharmacophore modeling yielded lead compounds that hold potential for addressing HIV therapeutic failures. Further experimental investigations are essential to validate the efficacy and safety of these compounds, with the ultimate goal of advancing toward clinical applications in HIV management.

Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).

Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase.

HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.

Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal.

Antiretroviral drugs have dramatically improved the prognosis of HIV-infected patients, with strikingly reduced morbidity and mortality. However, long-term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs). One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies. We compared the effects of two distinct HIV PIs: ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted darunavir (DRN/r), used in combination treatments for HIV infection. Upon ATV/r, but not DRN/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors. Furthermore, mice receiving sustained ATV/r treatment showed an increase in senescent cells and age-related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN/r) may improve the associated age-related complications.

Factors associated with HIV-1 resistance to integrase strand transfer inhibitors in Spain: Implications for dolutegravir-containing regimens.

Integrase strand transfer inhibitor (INSTI)-containing regimens in HIV-1-infected patients have experienced a global increase. Recently, WHO has emphasized the need to fast-track the transition to dolutegravir (DTG)-based antiretroviral (ARV) treatments. However, continued surveillance of INSTI resistance is recommended. In this study, clinical, epidemiological, and virological features associated with INSTI resistance diagnosed in Spain were analyzed. Samples collected between 2008 and 2021 from HIV-1-infected patients were analyzed in integrase, protease, and reverse transcriptase using Sanger population sequencing. ARV drug resistance was evaluated with the Stanford University HIVdb program. Among 2,696 patients, 174 (6.5%) had INSTI resistance, all of them to first-generation INSTIs, and 71 (2.6%) had also resistance to second-generation INSTIs. Of these, only 5 individuals were exposed to DTG as the only INSTI, in whom resistance development was associated with poor treatment adherence and/or resistance to other ARV classes. Of newly HIV-1-diagnosed individuals, 0.92% harbored INSTI-resistant viruses, with low prevalences maintained along time, and only one had low-level resistance to DTG. Persons who inject drugs, age over 39 years, resistance to other ARV classes, and longer time from diagnosis were associated with INSTI resistance (p < 0.001). Non-subtype B INSTI-resistant viruses lacked the Q148H + G140S resistance pathway and showed lower INSTI resistance levels than subtype B viruses. In conclusion, INSTI resistance is uncommon and associated with long-term infections, older age and additional resistance to other ARV drug classes, and is rare in newly diagnosed HIV-1 infections. Our results also support the preferential use of DTG-containing regimens in first-line treatments, although surveillance of INSTI resistance is encouraged.

Modelling of HIV viral load and 2-LTR dynamics during high active antiretroviral therapy in a heterogeneous environment

This paper is concerned with a diffusive HIV infection model with space-dependent parameters, different infection stages and different classes of antiretroviral drugs, in which the cells are assumed to be comparatively immobile and the viruses obey Fickian diffusion in a continuous bounded domain with a smooth boundary. The aim of this paper is twofold: first, to investigate the combined effect of spatial heterogeneity, viral diffusion and high active antiretroviral therapy on the long-term dynamics of the model; second, to evaluate the effect of treatment intensification with the integrase inhibitor raltegravir on the viral load and 2-LTR dynamics in patients with uninterrupted antiretroviral therapy in a spatially heterogeneous environment. Through mathematical analysis, the basic reproduction ratio is explicitly calculated and determined as a threshold to predict whether the infection is cleared up in the cases of spatial heterogeneity and homogeneity. Besides, the results of numerical simulations show that: (i) both spatial heterogeneity and viral diffusion affect the basic reproduction ratio and the time evolution of viral load at each location; (ii) protease inhibitors may be more effective in reducing viral load than reverse transcriptase inhibitors, although both have the same effect on the basic reproduction ratio; (iii) treatment intensification with raltegravir induces a very minor decrease in viral load and a minor increase in 2-LTR, which implies that ongoing viral replication may not be the source of the persistence of low-level viral load.

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium

Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease. RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing. 29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (<1%) were transgender, with a median age of 44·3 years (IQR 36·2-51·3) at baseline. As of Dec 31, 2019, 14 000 (47·7%) of 29 340 participants had been exposed to an INSTI. During a median follow-up of 6·16 years (IQR 3·87-7·52; 160 252 person-years), 748 (2·5%) individuals had a cardiovascular disease event (incidence rate of 4·67 events [95% CI 4·34-5·01] per 1000 person-years of follow-up). The crude cardiovascular disease incidence rate was 4·19 events (3·83-4·57) per 1000 person-years in those with no INSTI exposure, which increased to 8·46 events (6·58-10·71) per 1000 person-years in those with more than 0 months to 6 months of exposure, and gradually decreased with increasing length of exposure, until it decreased to similar levels of no exposure at more than 24 months of exposure (4·25 events [2·89-6·04] per 1000 person-years among those with >24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44-2·39]; >6 to 12 months of exposure: 1·19 [0·84-1·68]; >12 to 24 months of exposure: 1·46 [1·13-1·88]; >24 to 36 months of exposure: 0·89 [0·62-1·29]; and >36 months of exposure: 0·96 [0·69-1·33]; p<0·0001). Although the potential for unmeasured confounding and channelling bias cannot fully be excluded, INSTIs initiation was associated with an early onset, excess incidence of cardiovascular disease in the first 2 years of exposure, after accounting for known cardiovascular disease risk factors. These early findings call for analyses in other large studies, and the potential underlying mechanisms explored further. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands National Observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.

Backward bifurcation and stability analysis in a within-host HIV model with both virus-to-cell infection and cell-to-cell transmission, and anti-retroviral therapy

Researches have shown that in addition to direct virus-to-cell infection, viral particles can also be transferred from a productively-infected cell to an uninfected cell through the formation of virological synapses. In order to reduce the viral load in infected individuals, different classes of antiretroviral drugs have been developed, including reverse transcriptase inhibitor (RTI), integrase inhibitor (II), protease inhibitor (PI) and so on. In this paper, we incorporate the mitotic proliferation of target cells which is described by the logistic term, both virus-to-cell infection and cell-to-cell transmission, the intracellular delay and RTI-based therapy into an in-host HIV infection model. Through mathematical analysis, we find that the model undergoes a backward bifurcation when the turn-over rate coefficient of productively-infected cells is smaller than its mitotic proliferation rate coefficient. When the turn-over rate coefficient of productively-infected cells is greater than its mitotic proliferation rate coefficient, the existence of Hopf bifurcation at the chronic-infection equilibrium with and without the intracellular delay is established, respectively. Numerical simulations suggest that the dynamics of the model be sensitive to parameter values and initial conditions, which may be of great significance to control HIV infection. We also show numerical evidence to support the fact that the smaller the therapy efficacy, the higher the viral load in infected individuals.

High Rate of HIV-1 Drug Resistance in Antiretroviral Therapy-Failure Patients in Liaoning Province, China.

This study aimed to monitor the prevalence of HIV-1 drug resistance and risk factors associated with drug resistance in antiretroviral therapy (ART)-failure individuals in Liaoning Province, China. Plasma samples were collected from HIV-1-positive individuals who experienced ART failure in Liaoning Province between April 2018 and September 2019. Genotype resistance test was performed using an in-house assay on these collected samples. Factors associated with drug resistance were identified by logistic regression analysis. We collected a total of 468 ART-failure individuals, of which 256 were successfully included in the final study. Of these, the most predominant genotype was CRF01_AE, accounting for 77.73%. The resistance rate to any of the three classes of antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors [NNRTIs], nucleoside reverse transcriptase inhibitors [NRTIs], and protease inhibitors [PIs]) was 64.84%. Among 256 ART-failure patients, 62.89% showed drug resistance to NNRTIs, 50.39% to NRTIs, and 3.13% to PIs. G190S (31.25%) and Y181C (25.78%) mutations were the most common NNRTIs resistance mutations. K65R (29.69%), M184V (28.52%) were the most common NRTIs resistance mutations. Factors associated with drug resistance included current ART regimen and viral load. The high drug resistance rate among ART-failure individuals in Liaoning Province needs more attention. Corresponding strategies for the risk factors associated with HIV drug resistance can better control and prevent the prevalence of resistance.

Novel Naturally Occurring Dipeptides and Single-Stranded Oligonucleotide Act as Entry Inhibitors and Exhibit a Strong Synergistic Anti-HIV-1 Profile.

IntroductionThe availability of new classes of antiretroviral drugs is critical for treatment-experienced patients due to drug resistance to and unwanted side effects from current drugs. Our aim was therefore to evaluate the anti-HIV-1 activity of a new set of antivirals, dipeptides (WG-am or VQ-am) combined with a single-stranded oligonucleotide (ssON). The dipeptides were identified as naturally occurring and enriched in feces and systemic circulation in HIV-1-infected elite controllers and were proposed to act as entry inhibitors by binding to HIV-1 gp120. The ssON is DNA 35-mer, stabilized by phosphorothioate modifications, which acts on the endocytic step by binding to cell host receptors and inhibiting viruses through interference with binding to nucleolin.MethodsChou–Talalay’s Combination Index method for quantifying synergism was used to evaluate the drug combinations. Patient-derived chimeric viruses encoding the gp120 (env region) were produced by transient transfection and used to evaluate the antiviral profile of the combinations by drug susceptibility assays.ResultsWe found that the combination WG-am:ssON or VQ-am:ssON had low combination index values, suggesting strong antiviral synergism. Of the two combinations, WG-am:ssON (1 mM:1 μM) had high efficacy against all prototype or patient-derived HIV-1 isolates tested, independent of subtype including the HIV-1-A6 sub-subtype. In addition, the antiviral effect was independent of co-receptor usage in patient-derived strains.ConclusionWG-am and ssON alone significantly inhibited HIV-1 replication regardless of viral subtype and co-receptor usage, and the combination WG-am:ssON (1 mM:1 μM) was even more effective due to synergism.

Genetic diversity and drug resistance mutations of HIV-1 in Leningrad Region

Introduction. The spread of the human immunodeficiency virus type 1 (HIV-1) has become a global concern and has approached the pandemic status. St. Petersburg, a major transportation, tourist, cultural, industrial center, and a border city, is characterized by high migration of the population. The growing number of migrants can contribute to importation and spread of new genetic variants of the virus and trigger recombination processes in the virus population in St. Petersburg and the Leningrad Region.The aim is to characterize the present-day HIV-1 subtype-specific profile and drug-resistance mutations among patients with virological failure on antiretroviral therapy (ART) in the Leningrad Region.Materials and methods. The study performed in 2016–2018 was based on clinical material from HIV-infected individuals living in the Leningrad Region and having confirmed virological failure on ART. The genetic diversity and distribution of drug-resistance mutations of the HIV-1 isolates were assessed through analysis of nucleotide sequences of the virus pol gene fragment that included regions encoding protease and the reverse transcriptase region.Results. In the group (n = 138), most of the patients had sub-subtype A6 (97.4%) common in Russia, though a few patients had subtype B and a recombinant containing circulating recombinant form CRF_03AB and sub-subtype A1. The tests showed that 95.79% of patients had at least one significant drug-resistance mutation; in most cases (73%) the virus was resistant to 2 classes of antiretroviral drugs and in some cases (8%) — to 3 classes. A total of 105 different drug-resistance mutations were found at 35 positions of the virus genome.Conclusions. The high prevalence of HIV-1 drug-resistance mutations among ART patients with virological failure calls attention to surveillance of drug resistance of the virus both among ART-experienced patients and ARTnaïve individuals.

High Level of Pre-Treatment HIV-1 Drug Resistance and Its Association with HLA Class I-Mediated Restriction in the Pumwani Sex Worker Cohort.

Background: We analyzed the prevalence of pre-antiretroviral therapy (ART) drug resistance mutations (DRMs) in a Kenyan population. We also examined whether host HLA class I genes influence the development of pre-ART DRMs. Methods: The HIV-1 proviral DNAs were amplified from blood samples of 266 ART-naïve women from the Pumwani Sex Worker cohort of Nairobi, Kenya using a nested PCR method. The amplified HIV genomes were sequenced using next-generation sequencing technology. The prevalence of pre-ART DRMs was investigated. Correlation studies were performed between HLA class I alleles and HIV-1 DRMs. Results: Ninety-eight percent of participants had at least one DRM, while 38% had at least one WHO surveillance DRM. M184I was the most prevalent clinically important variant, seen in 37% of participants. The DRMs conferring resistance to one or more integrase strand transfer inhibitors were also found in up to 10% of participants. Eighteen potentially relevant (p < 0.05) positive correlations were found between HLA class 1 alleles and HIV drug-resistant variants. Conclusions: High levels of HIV drug resistance were found in all classes of antiretroviral drugs included in the current first-line ART regimens in Africa. The development of DRMs may be influenced by host HLA class I-restricted immunity.

Immunogenetic features of HIV-infection and allergy comorbidity

Today, the comorbidity of infection caused by the human immunodeficiency virus (HIV) is an important problem due to the complexity of the selection of the optimal antiretroviral therapy and the diagnosing of associated pathological conditions. The study of the comorbidity of HIV-infection and allergy is an important area of research. This article presents a literature review on different types of comorbidity. Special attention is paid to the development of allergic reactions to antiretroviral drugs. The presence of an allergic reaction in a patient can cause low adherence to therapy and subsequent development of HIV resistance to the treatment. The review provides information on the possible causes of the development of hypersensitivity in HIV-infected patients. The data on the development of hypersensitivity reactions in response to treatment with the main classes of antiretroviral drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors, synthesis inhibitors, protease inhibitors, integrase inhibitors, cysteine-cysteine chemokine receptor 5 inhibitors) are presented. The most common allergic reactions to these drug classes are itching and rash, as well as increasing hepatic transaminase levels and cough. The existing scientific data on allergic reactions to drugs prescribed for other concurrent conditions (tuberculosis, fungal diseases) is also considered. The examples of studies reflecting the relevance of using immunogenetic and molecular genetic approaches in the study of comorbidity of HIV-infection and allergy are given. The identification of immunogenetic markers of the development of the hypersensitivity to therapy will optimize the diagnostic and treatment algorithms, especially in complex comorbid conditions.

Time to initial highly active antiretroviral therapy discontinuation and its predictors among HIV patients in Felege Hiwot comprehensive specialized hospital: a retrospective cohort study

BackgroundAnti-retroviral therapy regimen discontinuations become a big challenge and cause diminishing the clinical and immunological benefit of treatment in Ethiopia. It reduces both the duration and the chance of viral control due to cross-resistance between different alternative drugs and overlapping toxicity between and within a class of antiretroviral drugs in Ethiopia. However, information’s on the time of initial regimen discontinuation and its predictors are not well studied.ObjectiveThis study aimed to assess the time to initial highly active antiretroviral therapy discontinuation and its predictors among HIV patients in Felege Hiwot comprehensive specialized hospital, North West Ethiopia.MethodInstitution-based retrospective cohort study was conducted among 418 HIV patients who started HAART from January 1, 2014, to December 31, 2019. Data were collected from the patient chart using a data extraction tool. The Kaplan–Meier curve was employed to compare survival rates. Multivariable Cox proportional hazard regression was applied to identify independent predictors of time to initial regimen discontinuation.ResultA total of 418 patients on anti-retroviral therapy were followed. Incidence of initial HAART discontinuation was 16.7/100 person year. The median survival time was 3.5 years. Predictors showed association for time to initial HAART discontinuation were taking > 1 ART pills/day (AHR = 4.1, 95% CI 3.0–6.5), baseline CD4 count < 100 cells/mm3 (AHR = 2.6, 95% CI 1.5–4.7), 100–199 cells/mm3 (AHR = 2.2, 95% CI 1.2–4.0), baseline WHO clinical stage IV (AHR = 2.68, 95% CI 1.6–4.3) and stage III (AHR = 2.6, 95% CI 1.4–4.3) and TB infection (AHR = 2.3, 95% CI 1.6–3.5).ConclusionMost of the discontinuation occurred after 1 year of initiation of HAART. Baseline WHO clinical stage, TB infection, baseline CD4 count, and taking > 1 ART pill/day were found predictors of initial HAART regimen discontinuation. Work on early detection of HIV before the disease is advanced and initiation of one ART regimen daily is vital for survival on the initial regimen.