Nanodrug Formulations to Enhance HIV Drug Exposure in Lymphoid Tissues and Cells: Clinical Significance and Potential Impact on Treatment and Eradication of HIV/AIDS

Abstract

Although oral combination antiretroviral therapy effectively clears plasma HIV, patients on oral drugs exhibit much lower drug concentrations in lymph nodes than blood. This drug insufficiency is linked to residual HIV in cells of lymph nodes. While nanoformulations improve drug solubility, safety and delivery, most HIV nanoformulations are intended to extend plasma levels. A stable nanodrug combination that transports, delivers and accumulates in lymph nodes is needed to clear HIV in lymphoid tissues. This review discusses limitations of current oral combination antiretroviral therapy and advances in anti-HIV nanoformulations. A ‘systems approach’ has been proposed to overcome these limitations. This concept has been used to develop nanoformulations for overcoming drug insufficiency, extending cell and tissue exposure and clearing virus for treating HIV/AIDS.

Harnessing nanostructured systems for improved treatment and prevention of HIV disease

“…The goal of ARV therapy is to suppress viral replication to the greatest extent possible and for the longest time possible . When used as recommended, CART is extremely effective at reducing viral load; it suppresses viral replication in more than 80% of those beginning treatment . Plasma viral load (the number of HIV RNA copies detected per ml of a patient's blood) is the best stand‐alone, prognostic marker for progression to AIDS .…”

“…The concentrations of ARV drugs in lymph node mononuclear cells (LNMCs) have been shown to be 66–99% lower than their respective concentrations in peripheral blood mononuclear cells (PBMCs) . Residual viruses isolated from these reserve tissues are still known to be responsive to the CART regimen of the patient . This indicates that the continued existence of these active viruses may be due to insufficient concentrations of ARV therapeutics in the tissue rather than acquired resistance to the drugs, especially since sequencing of the recovered viral genome revealed no known drug resistance sequences .…”

“…Furthermore, ARVs are known to have significant adverse side effects, toxicity due to off‐target binding or accumulation, and common and often complicated interactions with other drugs . CART requires once or twice daily doses for the lifetime of the patient, thereby increasing the likelihood that patients will develop serious adverse effects due to long‐term use and making patient compliance to the regimen difficult . Up to 20% of the HIV infected population in the United States has failed to attain full HIV viral load suppression (<200 copies/mL) under sustained CART, a problem that is attributed to patient noncompliance to the treatment regimen .…”

“…Up to 20% of the HIV infected population in the United States has failed to attain full HIV viral load suppression (<200 copies/mL) under sustained CART, a problem that is attributed to patient noncompliance to the treatment regimen . Patients with difficulty swallowing such as children, others with neurologic, gastrointestinal, or psychiatric disease, and intravenous drug users are at particular risk of not adhering to this self‐administered, oral regimen . Fluctuating levels of ARVs in the body can lead to a rebound in viral load and the development of drug resistance .…”

“…Initially, nanostructured delivery systems were designed to increase the plasma half‐lives of ARVs in order to create a long‐acting therapy . While longer dosing intervals would be well received by patients and could lead to improved adherence, these systems do not necessarily result in improved targeting of viral reservoirs …”