Currently, there are 15 approved antiretroviral agents that are categorized into 3 distinct classes each with a different mechanism of action. In prescribed 3 drug combinations, viral replication can be optimally controlled and immune reconstitution observed. Because of the complexity of the various treatment regimens, the poor pharmacokinetic properties of many of the drugs, the acute and long term adverse event profiles of all the current agents, and the patients’ difficulty in strict adherence to these regimens, treatment failure, defined as virologic rebound and/or return of clinical events, occures in over 50% of individuals observed in various
cohort studies. Treatment success is even lower in second line therapy. This is due in part to cross resistance within class and lack of tolerable agents needed to comprise a new and effective treatment regimen. Current antiretroviral drug development goals include the discovery of agents with improved safety and tolerability profiles, improved pharmacokinetic properties, drugs that are not cross resistant within class, and drugs with entirely different modes of action. Currently, new agents are indevelopment and several will become available within the next year. Some of these drugs offer a unique advantage over existing choices for first line and subsequent therapies. Tenofovir, a nucleotide, is a potent agent with very unique resistance
properties and demonstrated activity against isolates resistant to all other nucleosides, including those with the Q151M mutation which connotes multidrug resistance. Additionally, tenofovir has a long half life and can be dosed once daily; in vitro studies suggest no significant mitochondrial toxicity and clinical studies to date show excellent short and long term tolerability with a good safety profile. DAPD, a nucleoside also has a novel resistance profile and is highly active. T-20 and T-249 are peptides that inhibit fusion, a new and novel mechanism of action. These drugs must be administered subcutaneously, however tolerability is relatively good and no significant safety concerns have arisen to date. Atazanavir is a potent protease
inhibitor that may only have to be administered once daily. Of specific interest, there appears to be no effect on serum lipid levels, a potentially significant advantage over other protease and non-nucleoside reverse transcriptase inhibitors. The only problem to date has been elevations in indirect bilirubin of unknown clinical consequence. Tipranvir is a non peptidic protease inhibitor active against most mulitply resistant isolates. The new agents in development are likely to provide further options and significant benefit for patients initiating therapy and for those requiring therapy following treatment failure.
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