Structured Antiretroviral Treatment Interruption in Heavily-Experienced HIV-Infected Patients

Viral resistance to antiretroviral drugs is a major cause of treatment failure in HIV-infected patients. A significant number of patients have been treated for several years, and in some cases even for a decade. Since initial treatments were not potent enough to provide maximal viral suppression, and because of the complexity and the poor tolerability of highly active antiretroviral therapies, more and more patients with an often long prior history of treatment have accumulated in their different body compartments viruses harbouring multiple mutations associated to resistance in the reverse transcriptase and the protease genes. It is estimated that overall in 40-60% of patients the viral genotype and phenotype resistance profile can predict the response to drugs, with a most potent antiviral response observed confronting wild type viruses.Structured treatment interruption (STI) in heavily-experienced patients consists of a cessation of all drugs which suppress the drug pressure exerted on HIV with the objective of a resurgence of wild type virus and a disappearance of the resistant ones. Subsequently, as shown now through different pilot open and preliminary studies, the reversibility of resistance associated mutations can be obtained, particularly in the protease gene or for the 184V mutation associated to 3TC resistance. The time to reversibility of any mutations appears to require a minimum of 6 to 8 weeks drug interruption. It might be more difficult to obtain for some other RT mutations. The reversibility of the mutations is due to the shift from a predominant mutant virus to the initial wild type variant, as suggested by an increased replicative capacity of HIV after drug interruption. The negative effect of the switch from mutant to wild type HIV is linked to this better replicative capacity, which causes an increase in virus load and, which is more preoccupying, a decrease in CD4 lymphocytes. Therefore, randomised controlled trials need to analyse the potential benefits of STI in treatment-experienced patients in terms of reversibility of resistance mutations and the efficacy of subsequent salvage therapies.