Risk of artery plaques increased by use of HIV drugs

An Italian study has provided evidence that HIV drugs called protease inhibitors may increase the risk of artery "plaques."

Dr. Paolo Maggi from the University of Bari used ultrasound to study the association between anti-HIV drugs and artery plaques in 293 HIV-infected patients. They looked for plaques in a blood vessel in the neck called the carotid artery. The findings are reported in the medical journal AIDS.

105 patients were treated with regimens that included protease inhibitors. The remaining patients were either treated with regimens that didn't include protease inhibitors or with nothing at all.

On follow-up, 52 percent of patients treated with protease inhibitors displayed plaques on ultrasound. In contrast, the rate among other patients was only about 15 percent. Age, smoking, and immune status all seemed to influence the risk of plaques, but the strongest predictor was the use of protease inhibitors, the authors note.

Protease inhibitor regimens appear to be "major" players in the development of artery plaques, the authors conclude. Additional studies, they say, are needed to clarify exactly how such drugs may cause plaques.

Protease inhibitors used in combination with reverse transcriptase (RT) inhibitors represent the most effective anti-HIV therapies developed to date. Several studies have reported that combination therapies reduce HIV viral load to undetectable levels for sustained periods of time in up to 90% of patients.

The use of RT inhibitors not only results in synergism but also substantially reduces the likelihood of protease or multiple-resistant HIV strains developing. Monotherapy, especially low dose therapy, often results in the rapid emergence of protease resistant HIV strains. Resistance has been mapped to several key amino acid residues and cross-resistance among the protease inhibitors has been observed. Most current protease inhibitors are complex peptidomimetic compounds with poor aqueous solubility, low bioavailability and short plasma half-lifes. The complexity of these agents not only contributes to their high cost but also increases the potential for unwanted drug interactions.

The development of protease inhibitors has been facilitated by the determination of a three dimensional structure of the HIV protease, extensive knowledge gained from other aspartyl proteases and their inhibitors, such as renin, and the identification of the HIV protease cleavage sites (Tyr | Pro, Phe | Pro, Leu | Ala, Met | Met, Phe | Tyr, Phe | Leu, and Leu | Phe). All of the HIV protease inhibitors that have been approved and most that are in development, are non-hydrolysable transition state peptidomimetics in which the cleavage site peptide linkage is replaced is replaced by transition state isosteres, such as statine, norstatine, hydroxyethylene, a reduced amide, hydroxyethyl, or dihydroxyethylene. Many inhibitors have been designed to be symmetrical to take advantage of the C2 symmetry of the dimeric enzyme. Although symmetrical inhibitors can result in tighter binding as well as a simpler design and synthetic pathway, symmetrical compounds may be more susceptible to viral resistance since single mutations in the protease have multiplicative effects on inhibitor binding.

Rational iterative drug design based on structural studies of the HIV protease in conjunction with molecular modeling has yielded many compounds in a brief period of time with significant clinical potential. Four protease inhibitors, saquivanir (Invirase®, Hoffman-LaRoche), ritonavir (Norvir®, Abbott), indinavir (Crixivan® , Merck) and nelfinavir (Viracept® , Agouron) have already been approved and several others are in the late stages of clinical development. Current efforts are underway to develop simpler compounds with higher bioavailability and less susceptibility to viral resistance. Pharmacokinetic problems are also being addressed through the development of prodrugs, the improvement of formulations and the development of inhibitors of liver metabolizing enzymes.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
Post a new comment
Post
You might also like... ×
Medicinal plants: from genes to drugs