Antiretroviral Therapy: New Mechanistic and Therapeutic Insights for HIV Single-Entity and Combination Drug Products.

Abstract

With approximately 39 million people having died from AIDS-related causes so far, HIV is the world’s leading infectious killer. The large majority of the 35 million people currently living with the virus reside in low-/middle- income countries, but only 36% of the population eligible for therapy is receiving antiretroviral therapy in these regions. In order to promote the development of antiretroviral therapy, we have conducted research that pertains to both early- and late-stage aspects of antiretroviral products: investigating the mechanisms underlying HIV-1 infectivity in order to identify molecular targets to impede HIV infection and providing a biopharmaceutical rationale to accelerate and simplify the regulatory pathway for co-formulated, fixed-dose combination antiretroviral drug products. Data from the first half of this research demonstrate that HIV-1 infectivity is limited by the virus’ ability to efficiently engage target cells. The results show that the extent of non-specific interactions between HIV-1 and target cells is directly influenced by the amount of envelope spike glycoproteins on virus particles. Non-specific, receptor-independent interactions, which are more prevalent when there is a high virus-to-cell ratio, significantly impair the efficiency of HIV-1 infection and promote the degradation of virus particles in the lysosome. Therefore, our data identify molecular mechanisms that can be exploited as targets for alternative HIV treatment strategies. In the second half of this work, approved and investigational antiretroviral drug products were provisionally classified and evaluated relative to global bioequivalence standards. According to this provisional BCS classification, 36% of antiretroviral drug combination products were composed of high solubility compounds and potentially eligible for biowaivers under the current regulatory framework. By providing this evidence to justify simpler, yet science-based, regulatory routes to approval, and emphasizing that dissolution methodologies with in vivo relevancy can theoretically also be utilized in place of in vivo bioequivalence studies for products comprised of low solubility compounds, we are promoting development pathways that can lead to increased availability of effective combination drug products to address the health care disparities and significant unmet medical need in developing countries. Both aspects of this research present novel insights to aid the advancement of therapeutic approaches to combat HIV/AIDS.