Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

Abstract

The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DD Systems (DDS) currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.

Keywords: Antiretroviral drugs (ARV); Drug delivery targeting; HIV/AIDS; Long-acting/extended-release (LA/ER); Nanomedicine; Nanotechnology; Pre-exposure prophylaxis (PrEP).

Fig 1. Approximate timeline for establishing HIV infection after vaginal exposure to HIV[3]

This timeline suggests a window of opportunity for PrEP therapy. Given the difficult logistics of diagnosing and initiating treatment immediately post transmission, PrEP delivers effective drug concentrations for at risk populations prior to exposure (adapted from [3]).

Fig 2. Colorectal Mucosal Barriers and HIV Transmission Pathway

A single epithelial layer provides a barrier between the intestinal lumen and the lamina propria. The cells most susceptible to/or responsible for propagating early HIV infection, CD4⁺ T-cells, macrophages, dendritic cells, Langerhans cells and M-cells are located in the Lamina Propria. The lymphatics play an important role in the dissemination of HIV into the systemic circulation. (Image adapted from [79] with permission)