Nucleoside Analogue-Sparing Strategy for the Treatment of Chronic HIV Infection: Potential Interest and Clinical Experience

Abstract

Nucleoside analogue-sparing antiretroviral combinations may be interesting as first-line therapies as they spare a complete class of drugs that will remain fully active for later use and prevent the risk of mitochondrial toxicity related to exposure to nucleoside reverse transcriptase inhibitors (NRTIs). This strategy is also used in patients failing NRTIs with cross-resistance to compounds in this class. Different combinations of antiretroviral drugs are theoretically available. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) associated with protease inhibitor (PI) and boosted double-PI combinations have been studied through small, non-comparative clinical studies and preliminary results suggest that they are efficient and often well-tolerated. However, NNRTIs and PIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions; a good knowledge of the interactions between NNRTIs and PIs, or between PIs, is helpful in assisting physicians in clinical practice in choosing drugs and doses. Access to a therapeutic drug monitoring service to confirm that appropriate drug exposures are achieved is useful when using such regimens. Some negative kinetic interactions may lead to complicated combinations with a high pill burden that reduces their applicability. Gastrointestinal toxicity often remains a limiting factor in the use of boosted double-PI combinations. Non-comparative studies have allowed selection of NRTI-sparing options that now need to be compared with the current standard of care in comparative clinical trials before being considered as valuable options. Other NRTI-sparing therapeutic strategies are emerging: PI monotherapy with lopinavir/ritonavir has been evaluated in a small group of naive patients and appears promising. Drugs belonging to new classes currently under investigation, such as entry inhibitors, might be included early in the antiretroviral treatment of patients as soon as compounds with a convenient route of administration are available, increasing the number of therapeutic combinations without NRTIs.