HIV resistance to raltegravir François Clavel

Similar to all antiretroviral drugs, failure of raltegravirbased treatment regimens to fully supress HIV replication almost invariably results in emergence of HIV resistance to this new drug. HIV resistance to raltegravir is the consequence of mutations located close to the integrase active site, which can be divided into three main evolutionary pathways: the N155H, the Q148R/H/K and the Y143R/C pathways. Each of these primary mutations can be accompanied by a variety of secondary mutations that both increase resistance and compensate for the variable loss of viral replicative capacity that is often associated with primary resistance mutations. One unique property of HIV resistance to raltegravir is that each of these different resistance pathways are mutually exclusive and appear to evolve separately on distinct viral genomes. Resistance is frequently initiated by viruses carrying mutations of the N155H pathway, followed by emergence and further dominance of viral genomes carrying mutations of the Q148R/H/K or of the Y143R/C pathways, which express higher levels of resistance. Even if some natural integrase polymorphisms can be part of this evolution process, these polymorphisms do not affect HIV susceptibility in the absence of primary mutations. Therefore, all HIV-1 subtypes and groups, together with HIV-2, are naturally susceptible to raltegravir. Finally, because interaction of integrase strand transfer inhibitors with the HIV integrase active site is comparable from one compound to another, raltegravir-resistant viruses express significant cross resistance to most other compounds of this new class of antiretroviral drugs. BASIC PRINCIPLES OF HIV DRUG RESISTANCE Viral resistance is an almost unavoidable consequence of the failure of antiretroviral drugs to fully suppress active HIV replication in treated patients. Two principal mechanisms explain this phenomenon. First, the large majority of HIV-producing cells in vivo are highly activated CD4 T-cells with a remarkably short half-life [7, 24, 41]. In spite of the short lifespan of these infected cells, the amounts of plasma virus, hence the total number of infected cells in the body, is usually stable over time in the absence of treatment. This implies that there exists a steady state between the rapid clearance of infected cells and the infection of new target cells by the virus. In consequence, the continuous regeneration of the pool of infected cells requires that infectious cycles by the virus be constantly reinitiated. Second, because of the intrinsically error-prone nature of reverse transcription of RNA into DNA [43, 46], each HIV infectious cycle introduces at least one random error per viral genome. As persistent HIV infection requires that multiple cycles of virus replication be constantly repeated, the population of viruses found in a single infected individual is highly diverse and constantly fluctuating over time [6, 36]. In this context, when the pharmacological pressure exerted by antiretroviral drugs is unable to fully suppress ongoing cycles of HIV replication, emergence of viral variants carrying mutations that reduce HIV susceptibility to these drugs is almost inevitable. Resistance is the consequence of mutations that modify the interaction between antiretroviral drugs and their viral target. Resistance mutations have been identified in all viral proteins targeted by antiretroviral drugs such as RT, protease and the envelope glycoprotein. Even when the drug does not directly target the virus but is directed against a cellular protein that is required for viral replication (the CCR5 or CXCR4 receptors, for example), mutations in the viral protein that interacts with the cellular target have been found to emerge under appropriate conditions [55]. In some instances, single mutations able to express high-level resistance : this is the case of reverse transcriptase mutations M184V, which mediates HIV resistance to 3TC and FTC [3], or of several mutations mediating resistance to non-nucleoside RT inhibitors (NNRTI) [2, 45]. These drugs are described as having a low genetic barrier to resistance. For other drugs, high-level resistance requires that multiple mutations accumulate over time, with no single mutation able to promote significant resistance : these drugs are said to have a high genetic barrier to resistance [8, 12, 27, 37, 54]. The best examples of such drugs are protease inhibitors, to which individual changes in the HIV protease express only minor changes in susceptibility and for which development of clinically relevant resistance levels requires gradual accumulation of multiple different mutations [8, 27, 37]. The historical efficacy of highly active antiretroviral therapy (HAART) in HIV-infected individuals is based both on its antiviral potency, which most often leads to complete suppression of active viral replication, and on its ability to raise a high genetic barrier to viral resistance. In this context, raltegravir (RAL), the first integrase strand transfer inhibitor (INSTI) that has been approved for clinical use, does not fundamentally differ from other antiretroviral drugs. Virological sudies conducted in patients from clinical trials evaluating RAL efficacy in vivo have found that resistance to RAL can emerge rapidly following treatment failure, identified IN mutations able to mediate high-level resistance to RAL, and revealed that the genetic barrier of resistance to RAL is relatively low. Eur J Med Res (2009) 14(Suppl. III): 47-54 © I. Holzapfel Publishers 2009 HIV RESISTANCE TO RALTEGRAVIR