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Objectives. The main purpose of this work is to adapt the architecture of the REINVENT neural network to generate potential inhibitors of the HIV-1 envelope protein gp120 using in the learning process with reinforcement of molecular docking on GPUs.Methods. To modify the initial network model, molecular docking on GPUs implemented in the learning process with reinforcement was used, and an algorithm was developed that allows converting the representations of connections generated by the SMILES network into the PDBQT format necessary for docking. To accelerate the learning of the neural network in the modified version of the REINVENT model, the AutoDock-Vina-GPU-2.1 docking program was used, and to clarify the results of its work, the procedure for revaluing the affinity of compounds to the target using the RFScore-4 evaluation function was used.Results. Using a modified version of the REINVENT model, more than 60,000 compounds were obtained, of which about 52,000 molecules have a binding energy value to the HIV-1 gp120 protein comparable to the value calculated for the HIV-1 inhibitor NBD-14204, used in calculations as a positive control. Of the 52,000 compounds selected, about 34,000 molecules satisfy the restrictions imposed on a potential drug to ensure its bioavailability when taken orally.Conclusion. The results obtained allow us to demonstrate the effectiveness of an adapted neural network by the example of designing new potential inhibitors of the gp120 HIV-1 protein capable of blocking the CD4- binding site of the gp120 virus envelope protein and preventing its penetration into host cells.

Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. due to the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of drug absorption enhancers (DAEs) (also referred to as bioenhancers) into dosage forms, and exploration of nanocarriers such as liposomes as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Liposomes loaded with efavirenz or mefloquine in combination with drug absorption enhancers, as well as placebo dosage forms, were prepared using a thin-lipid film hydration technique and characterized for their particle size and zeta potentials, entrapment efficiency, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) using H-4-II-E liver cells in vitro. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1 mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26 mol/mol/mol) exhibited the best results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release, and permeability. DSPC:CHOL:DPPC liposomes released EFV-based formulations better than DPPC:CHOL liposomes for immediate release behaviour. DOPC:CHOL liposomes produced a controlled release and more drug was released in the presence of DAEs for both EFV (0.4-fold higher) and MQ-based (sevenfold higher) formulations in the first 2 h. However, these liposomes were less biocompatible (< 50% cell viability) with liver cells. DOPC:CHOL and DSPC:CHOL:DPPC liposomes could provide a useful nano-formulation platform, which could ensure drug loading, followed by sustained release of both anti-HIV and antimalaria drugs. [ABSTRACT FROM AUTHOR]

The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by in vitro studies since there are concerns related to interference with their active sites.

Lopinavir and ritonavir (LPV/r) are the primary anti-human immunodeficiency virus (HIV) drugs recommended by the World Health Organization for treating children aged 3 years and above who are infected with the HIV. These drugs are typically available in liquid formulations to aid in dosing for children who cannot swallow tablets. However, the strong bitter taste associated with these medications can be a significant obstacle to adherence, particularly in young children, and can jeopardize the effectiveness of the treatment. Studies have shown that poor palatability can affect the survival rate of HIV-infected children. Therefore, developing more child-friendly protease inhibitor formulations, particularly those with improved taste, is critical for children with HIV. The molecular mechanism by which lopinavir and ritonavir activate bitter taste receptors, TAS2Rs, is not yet clear. In this study, we utilized a calcium mobilization assay to characterize the activation of bitter taste receptors by lopinavir and ritonavir. We discovered that lopinavir activates TAS2R1 and TAS2R13, while ritonavir activates TAS2R1, TAS2R8, TAS2R13, and TAS2R14. The development of bitter taste blockers that target these receptors with a safe profile would be highly desirable in eliminating the unpleasant bitter taste of these anti-HIV drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) – islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) – Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance. [ABSTRACT FROM AUTHOR]

Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer.

OBJECTIVE: To investigate the application status and trend of anti-HIV drugs in outpatient department of this hospital, and analyze the application rationality. METHODS: Retrospective analysis method was performed to analyze the number, gender, age and frequency of visits of AIDS patients, patients with pre-exposure prevention and post-exposure blockade of HIV infection in outpatient department of the hospital from 2016 to 2020. According to the defined daily dose method recommended by WHO, defined daily dose system(DDDs), consumption sum of self-paid drugs, defined daily cost (DDC) and consumption sum ranking / DDDs ranking (B/ A) of all anti-HIV drugs in this hospital were analyzed and evaluated. RESULTS: From 2016 to 2019, the number of outpatients in this hospital for AIDS patients and patients with pre-exposure prevention and post-exposure blockade of HIV infection increased year by year, and decreased slightly in 2020. From 2016 to 2020, among the anti-HIV drugs in outpatient department of this hospital, the top five drugs ranked by DDDs were tenofovir, lamivudine, efavirenz, lopinavir, ritonavir and and zidomivir divudine, all of which were national free drugs, and the DDDs of tenofovir, lamivudine and efavirenz ranked the top three. The DDDs of self-paid drugs were relatively low, and the DDDs of some self-paid drugs increased in 2019, such as emtricitabine and tenofovir, and rilpivirine. The dosage and DDDs of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fumarate increased significantly in 2020. The DDC of self-paid drugs was higher, ranging from 40 yuan to 96 yuan, of which the DDC of rilpivirine was 40 yuan, and the DDC of dotiabalamib was 96 yuan; the B/ A of self-paid drugs were <1. CONCLUSIONS: The varieties of anti-HIV drugs in outpatient department of the hospital can basically meet the clinical needs, and the application of anti-HIV drugs is basically reasonable. [ABSTRACT FROM AUTHOR]

Introduction: Human immunodeficiency virus (HIV) test-treat-retain cascade analysis, is a model to identify gaps at every stage of service delivery, and formulate potential solutions to enhance coverage of these services, as we aimed to carry out in the present study. Material and methods: In order to detect problems, develop solutions, and further prioritize them at different stages of HIV cascade, Fishbone analysis model (WHO 2018) was used. At first, an Excel file including 15 sheets was constructed, each sheet for a significant demographic data of sub-group covering all key populations. Within each sheet, cascade diagram for diagnostic services, connection to services, treatment, and suppression of viral load was demonstrated. Excel file was sent to 28 key persons. Participants were instructed to identify problems in each stage and list all probable reasons for every specific problem. These reasons were classified into six groups based on Fishbone model, including: 1) policies/guidelines; 2) service/program management; 3) human resources; 4) supplies; 5) services delivery methods; and 6) patient/client-related factors. Subsequently, participants were instructed to propose their potential solutions to address these obstacles. Finally, four key informants prioritized the problems and suggested solutions. Results: Analysis of the most important solutions (with 10-12 scores) proposed by key persons of the five groups, including the increase of society awareness, addressing the stigma of HIV disease in mass media, collaboration between politics and health parties to enhance society knowledge, expanding the treatment and counseling centers and facilities across the country, healthcare workers training to provide valid and reliable guidance and information to people who live with HIV, and refer them to designated centers for care, counseling, and treatment as well as appropriate patient detection, mapping procedure, and gathering precise statistics, and finally, employment of professional caregivers in counseling and testing centers. Conclusions: Based on the identified gaps, innovative strategies to improve HIV testing and early case detection, particularly for key populations, are critical to reach the 90-90-90 target of the UNIAID. [ABSTRACT FROM AUTHOR]

Related substance is a test which quantitates impurities in formulation. This research paper presents a logical and scientific development & validation of analytical method for estimation of impurities of Lamivudine, Tenofovir disoproxil fumarate & Efavirenz in fixed dose tablet formulation. Estimation of impurities of Lamivudine, Tenofovir disoproxil fumarate & Efavirenz in fixed dose tablet formulation was conducted by RPHPLC. The separation was achieved under optimized chromatographic condition on an Inertsil ODS-3 150×4.6mm; 5μm column with mobile phase-A consist of 20mM acetate buffer pH-3.8±0.05: Methanol (95:5 %v/v) & mobile phase-B consist of 20mM acetate buffer pH-3.8±0.05: Methanol (5:95 %v/v) with gradient elution at a flow rate of 1.0 mL/min using 35°C column oven temperature with PDA detection at 260 nm. The method was validated as per ICH and USP guideline and the values were found to be within the limits. So, the proposed method was found to be simple, linear, accurate, precise, robust and specific. [ABSTRACT FROM AUTHOR]

Introducción: El Rategravir pertenece a los inhibidores de integrasas, quedando demostrado y aprobado por diversos ensayos clínicos como un potente antirretroviral seguro y eficaz para el tratamiento de pacientes infectados con el virus de inmunodeficiencia humana (VIH), con buena tolerancia y baja toxicidad, incluyéndose en el esquema de tercera línea o rescate y se inicia cuando los esquemas de primera y segunda línea han fracasado. Objetivo: Evaluar la eficacia y seguridad en condiciones clínicas reales del uso de Raltegravir dentro de los esquemas de la Terapia Antiretroviral de Gran Actividad (TARGA) en pacientes con infección por VIH en un hospital de referencia del seguro social en Perú. Métodos: Se realizó un estudio observacional retrospectivo en pacientes con diagnóstico de infección por VIH que iniciaron tratamiento dentro del esquema TARGA basados en Raltegravir con seguimiento y control a los 6 meses. Se presentaron medidas de resumen de frecuencias y porcentajes para las variables cualitativas, así como medias y desviación estándar para las variables cuantitativas en base a los resultados de las pruebas de normalidad. Los datos fueron procesados y analizados en el software estadístico SPSS versión 22. Resultados: El género masculino fue el más afectado con un 76%(n=119) del total. El rango de edad más frecuente fue el comprendido entre los 45 a 55 años (25,4%; n=40). Las comorbilidades más frecuentes fueron Diabetes mellitus e Hipertensión arterial, con reducción exponencial de la carga viral y elevación de los niveles de linfocitos CD4. Conclusión: El Raltegravir es eficaz para el tratamiento de pacientes VIH. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the oral environment and the taste function of Japanese HIV-infected patients treated with antiretroviral therapy. Their median age of 73 patients taking anti-HIV drugs was 46 years. The median period of taking anti-HIV drugs was 30 months. The oral condition was evaluated by measurement of oral moisture, amount of saliva secretion, the number of oral bacteria, presence of oral candida, a taste test, and the number of missing teeth. The levels of oral moisture and secreted saliva were significantly lower in the HIV-infected group than in the healthy volunteer (control) group. The HIV-infected group showed a more robust decrease in taste sensation than the control group. The number of missing teeth was significantly higher in the HIV-infected group than in the control group. Furthermore, all of the evaluated oral conditions were worse in the HIV-infected patients whose CD4+ T lymphocyte counts were less than 500/mm3 than in the control group. It became clear that the patients taking anti-HIV drugs, especially the CD4+ count < 500/mm3 group, had a deteriorated oral environment and dysgeusia, suggesting that the management of oral hygiene is necessary to maintain oral health, which leads to systemic health. [ABSTRACT FROM AUTHOR]

Microbicides based on hydrogel have become an effective way to prevent the HIV replication and transmission because of their convenience and prolonging drug release. In this study, a hybrid thermo-sensitive hydrogel constituted by nanosized layered double hydroxides and poloxamer 407 (P407) was constructed and co-loaded with both hydrophobic and hydrophilic drug. The LDH-P407 hydrogel could achieve sol–gel transition at body temperature. The in vivo experiment showed that LDH-P407 hydrogel can achieve controlled release of theaflavin and Nile red (hydrophobic drug model) into blood by vaginal drug delivery, meanwhile the hydrogel showed barely mucosal irritation. In addition, ex vivo experiment showed that the nifeviroc-loaded LDH-P407 hydrogel was able to specifically bind co-receptor CCR5 of DCs cells. Therefore, the LDH-P407 hydrogel would be a promising carrier for intravaginal delivery of anti-HIV drugs. [ABSTRACT FROM AUTHOR]

The development of new antiretroviral drugs is a dynamic process that is continuously fueled by identification of new molecular targets and new compounds for know targets. The current available drugs can be classified into five categories: nucleoside analogues reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and entry inhibitors (fusion inhibitors and CCR5 antagonist). In addition, the maturation inhibitors may be considered as potential target for chemotherapeutic intervention. This review presents some anti-HIV agents that have already gone through the advance development process for final approval for the treatment of AIDS.

OBJETIVOS: Como iniciar a terapia anti-retroviral é uma questão amplamente discutida no manejo de crianças infectadas pelo HIV. O objetivo deste estudo foi comparar a efetividade da terapia dupla e tríplice em uma coorte de crianças infectadas pelo HIV. MÉTODO: Este estudo foi realizado em um serviço de referência para assistência à criança infectada da Faculdade de Medicina da UFMG. Foram incluídas crianças que iniciaram o primeiro regime anti-retroviral entre janeiro de 1998 e dezembro de 2000, com seguimento até dezembro de 2001. O evento final para análise foi a primeira falha terapêutica ou óbito. RESULTADOS: Foram analisados 101 pacientes, sendo 58 (57,4%) e 43 (42,6%) com terapia dupla e tríplice, respectivamente. Não houve diferença entre os grupos quanto ao sexo, idade, contagem de linfócitos CD4+ e carga viral basal. A média de duração da terapia dupla foi de 26,3 meses (IC95% 21,3-31,3) e da terapia tríplice, de 34,3 meses (IC95% 29,2-39,5%). Falha terapêutica ocorreu em 33 (56,9%) pacientes em terapia dupla e 11 (25,6%) em terapia tríplice (log rank 5,03; p = 0,025). O risco relativo de falha para terapia dupla foi 2,2 vezes maior (IC = 1,3-3,9). O percentual de linfócitos T CD4+ inicial foi preditor de risco para falha terapêutica (p = 0,001). Pacientes em terapia tríplice apresentaram maior redução da carga viral (p = 0,001). CONCLUSÃO: A terapia tríplice permaneceu eficaz por mais tempo e apresentou melhor resposta virológica do que a terapia dupla nesta coorte de crianças infectadas pelo HIV, justificando a sua escolha como regime preferencial de tratamento.OBJECTIVE: The use of antiretroviral therapy in HIV-infected children has been a widely discussed issue. The aim of this study was to compare the effectiveness of dual nucleoside analogue reverse transcriptase inhibitor (NRTI) regimens and three-drug regimens [2NRTI+ non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)] in a cohort of HIV-infected children. METHODS: The study was carried out in a referral center for the management of infected children, which is affiliated with the School of Medicine of Universidade Federal de Minas Gerais (UFMG). Those children whose antiretroviral therapy was implemented between January 1998 and December 2000 and who were followed up until December 2001 were included in the study. Therapeutic failure or death was regarded as the endpoint in our analysis. RESULTS: A total of 101 patients were assessed, 58 (57.4%) on dual therapy and 43 (42.6%) on triple therapy. No statistically significant difference was observed between the groups in terms of gender, age, CD4+ count and baseline viral load. The average duration of dual therapy was 26.3 months (95%CI 21.3-31.3) and that of triple therapy was 34.3 months (95%CI 29.2-39.5%). There was therapeutic failure in 33 (56.9%) patients on dual therapy and in 11 (25.6%) patients on triple therapy (log rank = 5.03; p = 0.025). The relative risk of therapeutic failure of the dual therapy was 2.2 times higher (95%CI = 1.3-3.9). The percentage of initial CD4+ T cells was a predictor of risk for therapeutic failure (p = 0.001). Patients on triple therapy showed a more remarkable reduction in their viral load (p = 0.001). CONCLUSION: Triple therapy was efficient for a longer time period and showed better virologic response than dual therapy in this cohort of HIV-infected children. Therefore, triple therapy should be the treatment of choice.

A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class. [ABSTRACT FROM AUTHOR]

In this work, density ( ρ ) and speed of sound ( u ) data were measured for aqueous solutions of two drugs namely Emtricitabine and Lamivudine in the various concentrations, m from (293.15 to 318.15) K and at 0.1 MPa pressure. The measured density and speed of sound data were used to calculate the apparent molar volume ( V ϕ ) and the isentropic compressibility ( κ s ), using Laplace–Newton's equation. The apparent molar volume at infinite dilutions ( V ϕ ∞ ) of drugs has been evaluated from linear equation. The temperature dependence of apparent molar volume at infinite dilution ( V ϕ ∞ ) can be expressed as the second-order polynomial equation, in turn apparent molar expansibility ( E ϕ ∞ ) at infinite dilution was calculated. These parameters have been used to understand the effect of temperature on interactions between drugs and water. Moreover, the structure making and breaking ability of drugs are analyzed at experimental conditions. [ABSTRACT FROM AUTHOR]

In recent years, there is a sharp increase in the number of HIV infections, which have become a major threat to human health diseases. In order to research deeply the status and development trends of anti-HIV drugs, we retrieved the anti-HIV drugs' patents in the Derwent Innovations Index, and used the TDA to cleaning the data. We used the method of patentometrics by visual analysis tools to analyze patent literatures of anti-HIV drugs on number of patent application quantity, priority countries, patent assignees and technical fields. After analyzing and processing, we found that the number of anti-HIV drugs' patent applications is relatively stable in recent years; patent applications are mainly in the United States, Canada and China; technical fields of anti-HIV drugs are mainly concentrated in natural products, fermentation industry and heterocyclic compounds. The number of patent applications in the United States is far ahead of other countries, owing strong technical strength. Although China has certain advantages in the number of patent applications, there is still a wide gap as compared with foreign countries. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies have shown that HIV infection is independently associated with heart failure. Diastolic dysfunction (DD) is frequent in HIV patients, but it is unclear whether this is an effect of the HIV infection itself or of the anti-retroviral therapy (ART). Our aim was to compare diastolic function in HIV treatment-naïve, HIV-ART patients and controls. Methods: We prospectively enrolled 206 consecutive patients with HIV-1 infection and 30 controls, selected by frequency matching for age and sex. HIV patients were divided in two subgroups: ART-naïve ( n = 88) and ART ( n = 118). Diastolic function was assessed and graded by echocardiography, according to modern consensus criteria and using tissue Doppler analysis. Results: Compared to controls, ART-naïve patients had lower E' velocities (E' septal: 10.2 ± 2.4 vs 11.9 ± 2.6 cm/s, p = 0.02), higher E/E' ratio (7.8 ± 1.9 vs 6.9 ± 1.6, p = 0.02) and higher prevalence of DD (19 % vs 3.3 %, p = 0.05). HIV patients under ART also had worse diastolic function compared to controls (E' septal: 10.3 ± 2.5 cm/s; p < 0.01; E/E'ratio: 8.0 ± 2.0, p < 0.01; DD prevalence: 23 %; p = 0.01), but no significant differences were found between ART-naïve and ART HIV subgroups. In multivariable logistic regression analysis, age and body mass index were the only independent predictors of reduced diastolic reserve in HIV patients. Regarding systolic function, there were no significant differences in ejection fraction or S' velocities between controls and HIV subgroups. Conclusions: HIV treatment-naïve patients have reduced diastolic reserve that is not worsened by ART. These data reinforce the association of diastolic dysfunction with the HIV infection itself and not with the anti-retroviral therapy. [ABSTRACT FROM AUTHOR]

Polycaprolactone (PCL) matrices were simultaneously loaded with the antiviral agents, tenofovir (TFV) and nevirapine (NVP), in combination to provide synergistic activity in the prevention of HIV transmission through the vaginal route. TFV and NVP were incorporated in PCL matrices at theoretical loadings of 10%TFV–10% NVP, 5%TFV–5%NVP and 5%TFV–10%NVP, measured with respect to the PCL content of the matrices. Actual TFV loadings ranged from 2.1% to 4.2% equating to loading efficiencies of about 41–42%. The actual loadings of NVP were around half those of TFV (1.2–1.9%), resulting in loading efficiencies ranging from 17.2% to 23.5%. Approximately 80% of the initial content of TFV was released from the PCL matrices into simulated vaginal fluid (SVF) over a period of 30 days, which was almost double the cumulative release of NVP (40–45%). The release kinetics of both antivirals over 30 days were found to be described most satisfactorily by the Higuchi model. In vitro assay of release media containing combinations of TFV and NVP released from PCL matrices confirmed a potential synergistic/additive effect of the released antivirals on HIV-1 infection of HeLa cells. These findings indicate that PCL matrices loaded with combinations of TFV and NVP provide an effective strategy for the sustained vaginal delivery of antivirals with synergistic/additive activity. [ABSTRACT FROM AUTHOR]

A novel three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 34 wild-type DAPYs, 33 mutant form L100I, 30 mutant form Y181C and 29 mutant form Y188L as anti-HIV drugs. Here four quantitative structure activity relationship models were built by partial least square regression. The estimation stability and prediction ability of models were strictly analyzed by both internal and external validations. The correlation coefficient ( R), leave-one-out cross-validation correlation coefficient ( Q) and predicted values versus experimental ones of external samples ( Q) were 0.925, 0.769 and 0.949 for 34 diarylpyrimidines; 0.899, 0.788 and 0.889 for 33 mutant form L100I; 0.844, 0.761 and 0.935 for 30 mutant form Y181C; 0.890, 0.757 and 0.912 for 29 mutant form Y188L. These values indicated that the built PLS models had both favorable estimation stability and good prediction capabilities. Furthermore, the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of DAPY derivatives. [ABSTRACT FROM AUTHOR]

The treatment of human immunodeficiency virus (HIV)-related tuberculosis (TB) includes combination therapy, in which antiretroviral drugs and anti-TB drugs are co-administered. The complexities associated with the treatment of dual infection by Mycobacterium tuberculosis and HIV include occurrence of drug-drug interactions, in addition to pill burden, overlapping drug toxicity, and immune reconstitution inflammatory syndrome. Drug-drug interactions can occur between these drugs toward cytochrome P450 3A4 (CYP3A4), a drug-metabolizing enzyme. A thorough understanding of these interactions can prevent occurrence of treatment failures and drug toxicity. Molecular docking studies were carried out for FDA-approved drugs, to predict binding mechanism of anti-TB drugs with CYP3A4 and to compare them with our previous studies on antiretroviral drugs, in order to infer possible occurrence of drug-drug interactions. The core regimen of anti-TB treatment viz., rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA) showed similar binding mode (i.e., competitive binding) via utilizing the same binding residue, Arg212 in CYP3A4. This regimen also shared similar binding mode with antiretroviral protease inhibitors except tipranavir, nelfinavir, lopinavir, and atazanavir. Contraindicated drug interactions were not observed between non-nucleoside reverse transcriptase inhibitors, delavirdine, efavirenz, and etravirine; and anti-TB drugs, RIF, INH, and PZA. The contraindications occurring within anti-TB drugs can be negated with inhibitory effect of INH to induction effect of RIF toward CYP3A4. We evaluated the importance of Arg212 along with Ser119, Ala370, Arg372, and heme moiety for mediating oxidative metabolism of drugs. These drug interaction details were incorporated into our web server by creating a database called 'CYP3A4 DDI' and it is open accessible from . [ABSTRACT FROM AUTHOR]

Cabotegravir, a novel HIV integrase inhibitor, shares structural similarity with dolutegravir and bictegravir. Its oral half-life is 32 hours, but cabotegravir nanosuspension for intramuscular injection yields half-lives ranging from 25 to 54 days, enabling extended interval dosing. Drug interactions are minimal, although oral doses require spacing from polyvalent cations, and potent uridine glucuronosyltransferase induction (e.g., rifampin, carbamazepine) requires avoidance due to anticipated subtherapeutic cabotegravir exposure through extended intervals. Randomized clinical trials combined cabotegravir treatment with rilpivirine to demonstrate treatment efficacy in patients living with HIV who had attained virologic suppression, lacked known/suspected mutations to either component, and had not experienced prior HIV treatment failure. Together, oral cabotegravir and rilpivirine maintained viral suppression in the LATTE study while the combination, given intramuscularly, performed comparably to conventional oral therapy in LATTE-2. FLAIR and ATLAS, respectively, demonstrated HIV suppression maintenance for monthly injections in treatment-naive participants and treatment-experienced patients, with ATLAS-2M supporting the efficacy of injections given every 2 months. Investigations to date show an excellent safety profile. Injectable cabotegravir causes short-lived, mild injection site reactions (primarily administration site pain/soreness) that decrease in frequency over time, produce attributable discontinuation rates of at least 2%, and generate satisfaction scores that favor injectable therapy over oral therapy. Virologic failure with resistance development is rare, primarily occurs in the first year of therapy, and is associated with baseline proviral DNA mutations to coadministered rilpivirine. A key component of the first U.S. Food and Drug Administration (FDA)-approved injectable maintenance treatment program for HIV, injectable cabotegravir heralds a new era in HIV treatment innovation. Here we provide a detailed review of the clinical pharmacology, administration and available formulations of the novel HIV integrase inhibitor cabotegravir with in-depth analysis of the clinical trial data, safety, satisfaction and viral resistance development when combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection., (Copyright 2022 Clarivate.)