Optimizing HIV PrEP Persistence: Does Your Pharmacy Matter?

Persistence to human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is integral to preventing new HIV infections. Previous studies have shown real-world PrEP persistence is low and insight is needed into PrEP delivery strategies that improve persistence. This single-center, retrospective, cohort study measured persistence in patients filling PrEP through an integrated health-system specialty pharmacy (HSSP) compared to those filling at external pharmacies. The Kaplan-Meier estimates for persistence probability at 6, 12, and 18 months were 0.87 (95% CI 0.79-0.95), 0.75 (95% CI 0.66-0.86), and 0.64 (95% CI 0.53-0.76) for the HSSP cohort compared to 0.65 (95% CI 0.51-0.83), 0.41 (95% CI 0.28-0.62), and 0.32 (95% CI 0.2-0.53), respectively, for the non-HSSP cohort (log-rank p < 0.001, [Formula: see text] = 11.2). Cox PH modeling showed that patients using a non-HSSP were 2.7 times more likely to be non-persistent than HSSP patients (HR 2.7, 95% CI 1.6-4.7, p < 0.001, [Formula: see text] = 12.61), demonstrating patients were better maintained on PrEP therapy when their prescriptions were filled with the HSSP.

Anandenanthera colubrina (Vell.) Brenan as an inhibitor of HIV-1 BaL infection.

We reported the in vitro anti-HIV-1 activity, cytotoxicity, cytokines expression and chemical profile of Anadenanthera colubrina. Cytotoxicity was evaluated on TZM-bl, HL2/3 cells and macrophages. Anti-HIV-1 activity was determined by Luciferase assay (TZM-bl cells) and by HIV-p24 quantification (macrophages) assessed by ELISA. TZM-bl and HL2/3 cells were used to determine cell-cell fusion inhibition. Cytokines expression was assessed by ELISA. Chemical composition was determined by Gas Chromatography Coupled to Mass Spectrometry. At 66.6 µg/mL, the extract maintained the cell viability above 90%. At 33.28 µg/mL, the extract reduced 82.8% of HIV-1 infection (TZM-bl cells) and HIV-p24 expression (macrophages). The extract inhibited approximately 70% of TZM-bl and HL2/3 cells fusion. Extract did't induce inflammatory response. Phytochemical analysis showed presence of flavonoid, phenolic acids, fatty acids and sugars. This is the first study presenting the anti-HIV effect of A. colubrina, showing low cytotoxicity and no inflammatory stimuli, important requirements for a microbicide development.

Gp41 inhibitory activity prediction of theaflavin derivatives using ligand/structure-based virtual screening approaches.

Gp41 and its conserved hydrophobic groove on the NHR region is one of the attractive targets in the design of HIV-1 entry inhibitory agents. This hydrophobic pocket is very critical for the progression of HIV and host cell fusion. In this study different ligand-based (structure similarity search) and structure-based (molecular docking and molecular dynamic simulation) methods were performed in a virtual screening procedure to select the best compounds with the most probable HIV-1 gp41 inhibitory activities. In silico pharmacokinetics and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties filtration also was considered to choose the compounds with best drug-like properties. The results of molecular docking and molecular dynamic simulations of the final selected compounds showed suitable stabilities of their complexes with gp41. The final selected hits could have better pharmacokinetics properties than the template compound, theaflavin digallate (TF3), a naturally-originated potent gp41 inhibitor.

Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview.

As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular factors which are also involved in the replication of HIV and hence their role as potential candidates will be discussed. HIV/AIDS being an exceptional epidemic, demands an exceptional approach and that forms very much focus for the current review.

Development of a receptor model for efficient in silico screening of HIV-1 integrase inhibitors.

Integrase (IN) is a key viral enzyme for the replication of the type-1 human immunodeficiency virus (HIV-1), and as such constitutes a relevant therapeutic target for the development of anti-HIV agents. However, the lack of crystallographic data of HIV IN complexed with the corresponding viral DNA has historically hindered the application of modern structure-based drug design techniques to the discovery of new potent IN inhibitors (INIs). Consequently, the development and validation of reliable HIV IN structural models that may be useful for the screening of large databases of chemical compounds is of particular interest. In this study, four HIV-1 IN homology models were evaluated respect to their capability to predict the inhibition potency of a training set comprising 36 previously reported INIs with IC50 values in the low nanomolar to the high micromolar range. Also, 9 inactive structurally related compounds were included in this training set. In addition, a crystallographic structure of the IN-DNA complex corresponding to the prototype foamy virus (PFV) was also evaluated as structural model for the screening of inhibitors. The applicability of high throughput screening techniques, such as blind and ligand-guided exhaustive rigid docking was assessed. The receptor models were also refined by molecular dynamics and clustering techniques to assess protein sidechain flexibility and solvent effect on inhibitor binding. Among the studied models, we conclude that the one derived from the X-ray structure of the PFV integrase exhibited the best performance to rank the potencies of the compounds in the training set, with the predictive power being further improved by explicitly modeling five water molecules within the catalytic side of IN. Also, accounting for protein sidechain flexibility enhanced the prediction of inhibition potencies among the studied compounds. Finally, an interaction fingerprint pattern was established for the fast identification of potent IN inhibitors. In conclusion, we report an exhaustively validated receptor model if IN that is useful for the efficient screening of large chemical compounds databases in the search of potent HIV-1 IN inhibitors.