Mechanism and Therapies for HAART Induced Diarrhea

Sipos, Tibor

Abstract

The overall objective of this project is to establish the scientific rationale for the exogenous administration of a bicarbonate-buffered and enteric-coated pancrelipase to human immunodeficiency virus (HIV) positive patients who experience diarrhea due to High Activity Antiretroviral Therapy (HAART). As a side effect of HAART, many HIV patients experience mild to severe diarrhea with greasy and oily stool that is similar to the one experienced by cystic fibrosis (CF) patients. Drug induced diarrhea causes maldigestion of food, malabsorption of fat-soluble vitamins and nutrients, reduces the absorption of exogenously administered drugs, and leads to reduced immunocompetence. The technical approach for establishing the scientific rationale for the use of a bicarbonate-buffered and enteric-coated pancrelipase for the treatment of diarrhea and steatorrhea in HIV positive patients is to demonstrate that the HAART drugs interfere with any one of the key digestive processes that are responsible for handling the breakdown of fats and lipids, i.e., lipase/colipase and enterokinase catalyzed activation of zymogens to active enzymes. To achieve this goal the inhibitory effect of HAART drugs on pancreatic lipase/colipase, proteases and activation of prolipase to active lipase will be determined by employing specific enzyme assays. The results of these inhibitory studies will help to elucidate how these antiretroviral drugs interfere with the digestive activity of pancreatic lipase/colipase and the zymogen activation cascade that leads to HAART induced diarrhea and steatorrhea. Furthermore, the information gained from these in vitro studies will establish the therapeutic rationale for initiating the Phase II clinical program. The objective of the Phase II program is to demonstrate the efficacy of the exogenously administered bicarbonate-buffered and enteric-coated pancrelipase to HIV positive patients for the treatment of diarrhea due to HAART.