Combinations Of Antiretroviral Drugs Research Articles

Human Immunodeficiency Virus - a Review of the clinical aspects and detection of the infection

Introduction: Currently, many people are infected with the human immunodeficiency virus (HIV). Transmission is primarily through sexual contact, with additional routes including mother-infant exposure to needles and needle sharing. Since the HIV/AIDS pandemic was first identified in 1981, more than 75 million people have been infected. Numerous new cases continue to be reported, and infection can become the starting point for the development of HIV. Clinical manifestations include acute retroviral syndrome, opportunistic infections, and dermatological, neuromuscular, and other complications. Despite advances in antiretroviral therapy (ART), challenges remain, including drug resistance, opportunistic infections, and persistent HIV reservoirs in some cell types. Early and accurate diagnosis is essential, and recommended testing protocols include fourth-generation serological tests and point-of-care (POC) testing. ART, which includes combinations of antiretroviral drugs, is the standard treatment, and ongoing research into gene therapy shows promise for the future. Purpose of the work: The aim of this study is to review and characterize the clinical aspects and detection of human immunodeficiency virus infection. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: HIV, human immunodeficiency virus, ART, HIV manifestation, HIV detection, HIV diagnosis, HIV treatment.

Global Progress in HIV Therapeutics: An In-Depth Analysis of Dispersible Fixed-Dose Antiretroviral Combination and Their Regulatory Pathways: A Review .

This review offers a detailed examination of recent advancements in human immunodeficiency virus (HIV) therapeutics, with a particular focus on dispersible fixed-dose combinations (FDCs) of antiretroviral drugs and their associated regulatory pathways. The paper highlights the global progress made in the development and implementation of these formulations, emphasizing their benefits in facilitating administration and enhanced patient adherence. Dispersible FDCs are especially beneficial for pediatric, geriatric, and bedridden patients, as they simplify dosing and improve medication compliance. The review explores the evolution of FDCs, assessing their clinical efficacy and safety profiles while also discussing the regulatory frameworks and approval processes employed by major health authorities across the globe, including the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and other key regulatory bodies. By analyzing these aspects, the review aims to illuminate the critical role that FDCs play in optimizing HIV treatment and their broader implications for public health. Antiretroviral therapy has significantly transformed HIV/AIDS management, leading to extended lifespan and a better enhanced well-being for patients. Fixed-dose combinations have simplified treatment regimens and improved adherence. However, the path to developing and approving antiretroviral FDC dispersible tablets is fraught with regulatory challenges. This review not only identifies these challenges but also proposes strategies to overcome them, with the goal of ensuring timely access to safe and effective medications for HIV/AIDS treatment. Through this analysis, the review contributes to understanding how regulatory practices can support the advancement of HIV therapies and enhance global health outcomes.

New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs.

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease.

HIV-related cognitive disorders in children in Kinshasa (Democratic Republic of Congo)

ObjectivesHIV-infected individuals are at increased risk of neurocognitive disorders compared with the general population. Studies suggest that, despite the combination of antiretroviral drugs, HIV infection causes immune activation leading to significant neural damage; however, there is little data on HIV-infected young people in our country.MethodologyThis is a comparative cross-sectional study conducted between November 2020 and March 2021 on two hundred and sixteen children aged 6–15 years, including 106 HIV-positive children and 108 healthy children. Cognitive performance was assessed using the Differential Ability Scale Second Edition (DAS-II).ResultsHIV-infected children showed lower cognitive scores than control children in the subtest group of verbal ability (82.1% vs. 43.5%); non-verbal ability (84.9% vs. 45.4%); spatial ability (79.2% vs. 21.3%) and generall conceptual ability (GCA) (88.7% vs. 43.5%). The children in the control group had significantly higher ability scores in the diagnostic tests and in school achievement, and the difference was statistically significant.ConclusionCognitive impairment remains a significant complication in HIV-positive children, as suggested by low cognitive scores in more than half of our participants. This is an unresolved issue with implications for survival, quality of life and daily functioning in these children. It is important that clinicians are able to identify and manage these cognitive deficits.

Metabolic Dysfunction-Associated Steatotic Liver Disease in People Living with HIV-Limitations on Antiretroviral Therapy Selection.

Chronic liver disease is one of the main causes of morbidity and mortality in people living with HIV (PLWH). The increasing life expectancy of PLWH, effective treatment for viral hepatitis, and Western dietary patterns as well as the adverse effects of antiretroviral therapy (ART) have rendered metabolic dysfunction-associated steatotic liver disease (MASLD) the most common chronic liver disease in PLWH. The risk factors for MASLD in PLWH include traditional MASLD risk factors and additional virus-specific factors, including the adverse effects of ART. The management of patients suffering from HIV and MASLD is often challenging. Apart from the conventional management of MASLD, there are also certain limitations concerning the use of ART in this patient population. In general, the appropriate combination of antiretroviral drugs should be chosen to achieve the triad of effective viral suppression, avoidance of mitochondrial dysfunction, and deterrence of worsening the patient's metabolic profile. In the current review, we discuss the epidemiology of MASLD in PLWH, the risk factors, and the disease pathogenesis, as well as the limitations in the use of ART in this patient population, while practical recommendations on how to overcome these limitations are also given.

Assessment of the toxicity of different antiretroviral drugs and their combinations on Sertoli and Leydig cells

The human immunodeficiency virus continues to pose a significant global public health challenge, affecting millions of individuals. The current treatment strategy has incorporated the utilization of combinations of antiretroviral drugs. The administration of these drugs is associated with many deleterious consequences on several physiological systems, notably the reproductive system. This study aimed to assess the toxic effects of abacavir sulfate, ritonavir, nevirapine, and zidovudine, as well as their combinations, on TM3 Leydig and TM4 Sertoli cells. The cell viability was gauged using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays. Reactive oxygen species (ROS) production was assessed via the 2’,7’-dichlorofluorescein diacetate (DCFDA) test, and DNA damage was determined using the comet assay. Results indicated cytotoxic effects at low drug concentrations, both individually and combined. The administration of drugs, individually and in combination, resulted in the production of ROS and caused damage to the DNA at the tested concentrations. In conclusion, the results of this study suggest that the administration of antiretroviral drugs can lead to testicular toxicity by promoting the generation of ROS and DNA damage. Furthermore, it should be noted that the toxicity of antiretroviral drug combinations was shown to be higher compared to that of individual drugs.

The interplay of poorly soluble drugs in dissolution from amorphous solid dispersions

In recent years, the application of fixed dose combinations of antiretroviral drugs in HIV therapy has been established. Despite numerous therapeutic benefits, this approach poses several challenges for the formulation development especially when poorly soluble drugs are considered. Amorphous solid dispersions (ASD) thereby have gained considerable interest in the pharmaceutical field, however, mainly including binary systems containing only one drug and a polymer. The co-formulation of two amorphous drugs can be accompanied by an immense increase in the complexity of the system as exemplarily reported for ritonavir and lopinavir embedded in a composite polymer matrix of PVPVA. The present study aims to present a new formulation approach to overcome the well-documented interaction during dissolution. Two different polymers, PVPVA and HPMCAS were used to produce ASDs for both drugs individually via hot-melt extrusion. The embedding of lopinavir in the slower dissolving polymer HPMCAS, while using PVPVA for ritonavir was found to significantly improve the overall dissolution performance compared to the individual use of PVPVA as well as to the commercial product Kaletra®. In addition, the use of different grades of HPMCAS demonstrated the possibility to further modify the dissolution profile. For a preliminary biorelevant assessment, the selected formulations were tested in a biphasic dissolution setup.

Biocompatible metal-organic frameworks as promising platforms to eradicate HIV reservoirs ex vivo in people living with HIV.

The HIV attacks the immune system provoking an infection that is considered a global health challenge. Despite antiretroviral treatments being effective in reducing the plasma viral load in the blood to undetectable levels in people living with HIV (PLWH), the disease is not cured and has become chronic. This happens because of the existence of anatomical and cellular viral reservoirs, mainly located in the lymph nodes and gastrointestinal tract, which are composed of infected CD4+ T cells with a resting memory phenotype and inaccessible to antiretroviral therapy. Herein, a new therapeutic strategy based on nanotechnology is presented. Different combinations of antiretroviral drugs (bictegravir/tenofovir/emtricitabine and nevirapine/tenofovir/emtricitabine) and toll-like receptor agonists were encapsulated into metal-organic frameworks (MOFs) PCN-224 and ZIF-8. The encapsulation efficiencies of all the drugs, as well as their release rate from the carriers, were measured. In vitro studies about the cell viability, the hemocompatibility, and the platelet aggregation of the MOFs were carried out. Epifluorescence microscopy assays confirmed the ability of ZIF-8 to target a carboxyfluorescein probe inside HeLa cell lines and PBMCs. These results pave the way for the use of these structures to eliminate latent HIV reservoirs from anatomical compartments through the activation of innate immune cells, and a higher efficacy of the triplet combinations of antiretroviral drugs.

Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV

BackgroundFixed-dose combinations of antiretroviral drugs are commonly used to treat HIV infection and therapeutic monitoring is not part of routine clinical practice. However, drug concentrations monitoring might have role in different clinical scenarios as well as for research purposes. This study aimed to develop and validate UHPLC-MS/MS procedures for measuring total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Material and methodsEquilibrium dialysis preceded sample preparation (based on protein precipitation) for measuring unbound antiretroviral concentrations. Chromatographic separations were achieved on an Acquity®-UPLC® HSS™-T3 column (50 mm × 2.1 mm; 1.8 µm) using a non-linear water/acetonitrile gradient containing 0.1 % formic acid at a 0.5 mL/min flow rate. Antiretrovirals were detected by tandem mass spectrometry in positive electrospray ionisation and multiple reaction monitoring modes. ResultsNo significant interferences or carry-over were observed. Imprecisions, absolute relative biases, normalised matrix effects and recoveries were ≤15.0 %, ≤11.1 %, (94.7–104.1)% and (96.7–105.5)%, respectively. Non-linear measuring intervals were observed between (25–10,000) µg/L for total/plasma dialysate concentrations and linearity schemes (1.00–100) µg/L for buffer dialysate concentrations. ConclusionsThe UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.

Cost-utility analysis of the fixed-dose combination of dolutegravir/abacavir/lamivudine as initial treatment of HIV+ patients in Spain

ObjectiveFixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients.The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtrici- tabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System. MethodThe ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/ EFV), and the fixed-dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or ral- tegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in € (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness. ResultsTreatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44€/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-1 005 117.13€/QALY). All the sensitivity analyses performed showed the consistency of these findings. ConclusionsWith the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ARTnaive HIV infected patients from the Spanish Health System perspective

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

АНАЛИЗ КЛИНИЧЕСКИХ СЛУЧАЕВ ОСТРОГО ПАНКРЕАТИТА НА ФОНЕ КОМОРБИДНЫХ ПАТОЛОГИЙ

The article collects and analyzes the available information on the pathogenesis, features of diagnosis and course of acute pancreatitis in patients with HIV and COVID-19 based on cited scientific papers. Patients with HIV/AIDS can be affected to a wide range of factors for the development of acute pancreatitis, such as opportunistic infections, neoplasms and metabolic changes due to the use of antiretroviral drugs. Morphological changes in the pancreas, including its endocrine, exocrine apparatus and interstitial tissue, as well as the ductal system, observed in about 20% of HIV-infected patients. Pathological and morphological changes in the pancreas during autopsy detected in 90% of cases. With the introduction of combined antiretroviral drugs, new metabolic disorders appeared, such as liver steatosis and lactic acidosis, which also have a toxic effect on the pancreas. COVID-19 can cause severe complications from the heart, lungs, brain, kidneys, blood vessels and other vital human systems and organs. Scientists associate the effect of the virus on pancreatic cells with the placement of ACE-2 receptors in the organ. The presence of ACE-2 in non-respiratory organs has a positive effect on the functioning of these tissues. As is known, COVID-19 infection was caused by the SARS-CoV-2 virus. This virus actively replicates using intracellular ARF-2 and then destroys the host cell when it enters the extracellular space [1]. Although COVID-19 refers to respiratory infections, doctors recognize that the disease is multisystem, in other words, it can affect any organ [2]. During the period of COVID-19 disease, the human excretory system ceases to cope with its functions due to oxygen starvation, blood detoxification does not occur. Against this background, multiple organ failure and numerous edemas of the tissues of internal organs develop. The organs of the endo- and exocrine systems suffer, including the organ of mixed secretion – the pancreas. The study of the impact of the new coronavirus infection is the most relevant nowadays, from that moment this infection is relatively young and poorly studied. By analyzing rare clinical cases, we can predict the consequences of the disease and anticipate late complications. The analysis was made on the basis of laboratory and morphological features. Comparison of pancreatitis in patients with HIV and COVID-19 has been conducted. As a result, the most relevant questions on this topic have been formed.

Impact of Concurrent Exposure of Diabetic Male Sprague Dawley Rats to Alcohol and Combination Antiretroviral Therapy (cART) on Reproductive Capacity

The prevalence of diabetic patients who abuse alcohol while on combination antiretroviral drug therapy (cART) therapy is rising in society. Little is known about the impact of this scenario on the testes and male reproductive viability, and therefore, these factors were evaluated. Thirty 10-week-old male Sprague Dawley rats were distributed into five groups of six rats each: control, diabetic only (DM), diabetic treated with alcohol (DM+A), diabetic treated with Atripla, fixed-dose cART (DM+cART), and diabetic treated with both alcohol and cART (DM+A+cART). After 90 days of treatment, rats were terminated, and blood and testes were harvested for immunoassay, histological, and immunohistochemistry analyses. Testicular perturbations of varying severity were recorded in all treated groups for most of the parameters. The DM+A treated group showed the most severe perturbations, followed sequentially by the treated groups DM+A+cART, DM, and DM+cART. Alterations in the testes and seminiferous tubule morphometry as well as the spermatogenic, Sertoli, and Leydig cells were found in all treated groups. Further, a significant decrease in Johnsen’s testicular scores, the appearance of seminiferous tubule lesions, changes in the basement membrane and capsule thickness, and a reduction in the testis connective tissue fibers were demonstrated in the treated groups. Additionally, reproductive hormone levels were altered, and the number and staining intensity of Sertoli and Leydig cells expressing androgen receptors reduced significantly in all treated animals. The study results reveal that the consumption of alcohol and/or the use of cART in diabetic individuals induces a derangement in circulating reproductive hormone levels and in the testicular structure and function, which consequently leads to a decline in the male reproductive capacity.

Interactions of alcohol and combination antiretroviral (cART) drug in diabetic male Sprague Dawley rats: Hippocampal perturbations and toxicosis.

Hippocampal pathology in diabetes is constantly investigated but the resultant health impact of the concomitant presence of alcohol and combined antiretroviral therapy (cART) in diabetes requires further studies to delineate toxicities inimical to hippocampal normal function. Forty-eight male Sprague Dawley rats were divided into eight groups (n=6): negative control (NC), alcohol (AL), cART (AV), alcohol-cART (AA), diabetic control (DB), diabetes-alcohol (DAL), diabetes-cART (DAV), and diabetes-alcohol-cART (DAA) exposure groups. Following diabetes induction and sub-chronic (90 days) treatment exposure, hippocampal homogenates were profiled for pro-inflammatory cytokines and oxidative stress (MDA and GPx) using immunoassay, while apoptotic genes (BAX, Bcl2, and Caspase-3), insulin receptor genes (INSR and IRS-1), and blood-brain barrier (BBB) junctional proteins (claudin-5, and occludin) gene expression were assessed using qPCR. Histomorphology of hippocampal neuronal number, nuclei area, and volume of dentate gyrus and neurogenesis were accessed using Giemsa stain, Ki67, and DCX histochemistry respectively. A central hippocampal effect that underpins all treatments is the reduction of DG neuronal number and antioxidant (GPx), highlighting the venerability of the hippocampal dentate gyrus neurons to diabetes, alcohol, cART, and their combinatorial interactions. Additionally, elevated BAX, Bcl2, and IRS1 mRNA levels in the DAL group, and their downregulation in AA, suggests IRS-1-regulated apoptosis due to differential modulating effects of alcohol treatment in diabetes (DAL) in contrast to alcohol with cART (AA). Although the interaction in AA therapy ameliorated the independent alcohol and cART effects on MDA levels, pro-inflammatory cytokines, and DCX, the interaction in AA exacerbated a deficiency in the expression of INSR, IRS-1 (insulin sensitivity), and BBB mRNA which are implicated in the pathogenies of diabetes. Furthermore, the diabetic comorbidity groups (DAV, DAL, and DAA) all share a central effect of elevated hippocampal oxidative stress, BAX, and Caspase-3 mRNA expression with the reduced number of hippocampal neurons, dentate gyrus volume, and neurogenesis, highlighting neurodegenerative and cognitive deficiency implication of these comorbidity treatments. Considering these findings, assessment of hippocampal well-being in patients with these comorbidities/treatment combinations is invaluable and caution is advised particularly in alcohol use with cART prophylaxis in diabetes.

Prevalence of Cytopenia and its Correlation with Immunosuppression in Naïve HIV-1 Infected Patients Initiating First-Line Antiretroviral Therapy: A Pilot Study.

Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency virus (HIV) infection. This study aimed to assess the prevalence of cytopenias and their correlation with the level of immunosuppression in treatment-naive HIV-infected participants after initiating highly active combined antiretroviral drug therapy (cART24). This prospective study focused on evaluating cytopenia in 44 treatment-naive HIV-infected patients who consented to initiate cART and were consecutively enrolled. The research was conducted at the Nasara HIV Treatment & Care Centre of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria, spanning from December 2016 to January 2018. Cytopenias, including anemia, leucopenia, lymphocytopenia, and thrombocytopenia, were defined and assessed according to World Health Organization guidelines. A combination of cross-sectional and longitudinal mixed-design two-step analysis was employed to validate our findings. The median time from enrollment to cART initiation was 7 days, following the universal test and treat protocol. The prevalence of cytopenia was 75% at the baseline before treatment and increased to 84% after cART24 administration. There were no statistically significant differences in the median values of immuno-hematological parameters between baseline and after cART24 initiation (P >0.05). In terms of longitudinal assessment, the prevalence of anemia, leucopenia, lymphopenia, and thrombocytopenia at baseline were 66%, 23%, 0%, and 11%, respectively, and after cART24, the rates were 66%, 29%, 5%, and 20%. Notably, the prevalence of cytopenia correlated with declining CD4+ T cell counts. Among instances of unicytopenia, 58% exhibited isolated anemia, 6% had lone leucopenia, and 6% had solitary thrombocytopenia. Additionally, 27% demonstrated bi-cytopenia, and 3% exhibited pancytopenia. Interestingly, none of the study participants presented with lymphopenia. The most common combination was anemia and thrombocytopenia. Both longitudinal and cross-sectional analytical findings were consistent. In treatment-naive HIV-infected individuals, the prevalence of cytopenias, particularly anemia and thrombocytopenia, was substantial and correlated with the degree of immunosuppression as indicated by CD4+ T cell counts. These cytopenias persisted despite initiation of cART24, highlighting the complexity of hematological manifestations in HIV infection. Our study underscores the significant hematopathological impact of HIV and antiretroviral therapy, highlighting the necessity for preventive strategies to mitigate these adverse effects.

A Stability Indicating Novel Analytical Method for the Determination of Lamivudine and Dolutegravir in Bulk and its Tablets Using Reverse Phase High-Performance Liquid Chromatography

Aim: A simple and sensitive analytical method was developed to simultaneously estimate lamivudine (LAM) and dolutegravir (DOL), anti-retroviral drug combination in bulk and dosage forms. Materials and Methods: Separation of analytes was done on a BEH Shield RP18 (2.1 mm × 100 mm × 1.7 mm, 5 μm Particle size) using sodium dihydrogen phosphate pH 4.9 adjusted with orthophosphoric acid: Methanol (60:40, %v/v) as mobile phase pumped at 1.0 ml/min. A photodiode array detector was used to find the detection wavelength at an isosbestic point of 292 nm while maintaining the column temperature at 30°C. With a total run period of 8 min, the mobile phase was utilized as a diluent. The International Council on Harmonization guidelines were followed in the method's validation. The method's capacity to indicate stability was confirmed by experiments on forced degradation. Results: LAM and DOL eluted at 2.88 and 3.83 min, respectively. Both the drugs exhibited excellent linearity between 105.00–315.00 and 17.50–52.50 μg/ml for LAM and DOL, respectively. The LOD and LOQ were found to be 4.51 and 15.03 μg/ml for LAM and 5.82 and 19.41 μg/ml for DOL, respectively, which are very minute concentrations. Conclusion: The method was therefore found to be quite sensitive. The proposed high-performance liquid chromatography technique was thereby sensitive, reproducible, accurate, and reliable for the measurement of LAM and DOL.

Can simplified antiretroviral drug combination therapies resist resistance?

Can simplified antiretroviral drug combination therapies resist resistance?

Practical aspects of human immunodeficiency virus multiresistance in modern clinical practice

The article presents an analysis of a special clinical case: a male patient with perinatal HIV infection and the development of HIV multi-resistance to antiretroviral drugs. Multiple corrections of treatment regimens were carried out based on the results of determining HIV resistance to the antiretroviral drugs used. The treatment regimen included antiretroviral drugs with fundamentally new mechanisms of action for HIV, not registered in the Russian Federation. However, to date, in the patient with more than twenty years of experience in antiretroviral therapy, it has not been possible to achieve immunological and virological efficacy of treatment. There continues to be a persistent decrease in the indicators of the immune status and an increase in the viral load of HIV in the blood, the appearance of clinical symptoms of opportunistic diseases indicating the progression of HIV infection and an unfavorable vital prognosis, despite the use of various combinations of antiretroviral drugs. This observation demonstrates the difficulties in choosing an effective antiretroviral therapy, taking into account the established sensitivity of HIV to antiretroviral drugs and the possibility of their progredient administration. It is certainly necessary to analyze all ART regimens with the results of HIV resistance to antiretroviral drugs using to improve the effectiveness of therapy is in each case.

Effect of drug-to-lipid ratio on nanodisc-based tenofovir drug delivery to the brain for HIV-1 infection.

BackgroundCombination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood–brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge.MethodsThis study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo.ResultThe nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models.ConclusionThe study provides potential applications of nanodiscs for HIV-1 therapy development.

Optimal control of combined antiretroviral therapies in an HIV infection model with cure rate and fusion effect

This paper mainly targets to deduce an optimal treatment strategy for combined antiretroviral drugs, which can maximize healthy CD4+ T cells level with minimum side effects and cost. For this purpose, we consider a within-host treatment model for the HIV infection with two controls incorporating full logistic proliferation of healthy CD4+ T cells, cure rate and fusion effect. These two controls represent the effects of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs), respectively. The model analysis begins with proving different basic properties like non-negativity, boundedness of the model solutions and calculation of the basic reproduction number of the model under consideration. Then, stability results are obtained for HIV infection-free equilibrium point and also, a critical efficacy for the combined therapies is calculated. After that, the optimal control problem is proposed and solved numerically using a forward–backward iterative method. Finally, we obtain an optimal treatment strategy that can maximize healthy CD4+ T cells count and control the viral load, and HIV-infected CD4+ T cells count to an undetectable level resulting in improved health conditions of infected individuals.