raltegravir or elvitegravir.8 In The Lancet Infectious Diseases, Jean Michel Molina and colleagues9 report results of a multicentre, phase 3, non inferiority, randomised trial. They measured the effi cacy and safety of once daily ritonavir Ursolic acid boosted elvitegravir compared with twice daily raltegravir in treatment experienced adults infected with HIV 1. 702 patients in whom previous antiretroviral treatment had failed, with a plasma viral load higher than 1000 copies per mL and any CD4 cell count, were enrolled. All individuals received an investigatorselected background regimen containing a fully active ritonavir boosted protease inhibitor and a second drug. Many study participants had documented baseline resistance mutations to one or more classes of antiretroviral drugs.
None had been previously exposed to elvitegravir or raltegravir.59% vs raltegravir 58%; treatment diff erence 1·1%, 95% CI –6·0 to 8·2), and elvitegravir met the prespecifi ed criterion for non inferiority. Side eff ects were generally mild and comparable between arms, except for TNF-Alpha Signaling Pathway a signifi cantly higher frequency of grade 3 or 4 rises in alanine aminotransferase concentrations in the raltegravir arm and an excess of diarrhoea in the elvitegravir arm . Although salvage regimens used in treatmentexperienced patients are in general much less successful at controlling viraemia than primary regimens,10,11 the proportion of patients achieving viral suppression in this trial was fairly low. Molina and colleagues suggest the low overall effi cacy is attributable to the high proportion of voluntary discontinuations: these are counted as failures in the modifi ed intention to treat analysis.
They argue that this level of discontinuation refl ects a behavioural change in treatment experienced patients infected with HIV; with more treatment options available nowadays, motivation to adhere to a certain regimen wanes. Their argument is supported by fi ndings of a subgroup analysis, in which a regimen containing cryostat one active background drug is less likely to achieve virological suppression than one with two active background drugs. In this study, among patients with one active background drug, 78% in the elvitegravir group and 68% in the raltegravir group achieved viral suppression; among those with two active background drugs the proportions were 59% and 55%, respectively.
Again, patients with two active background drugs had signifi cantly higher voluntary discontinuation rates , suggesting decreasing adherence as remaining treatment options rease. This paradoxical virological response rate is, however, in stark contrast to previous observations in similar trials with raltegravir ,12 etravirine ,13 and maraviroc .14 Another indication for poor adherence comes from the genotypic analysis. In patients in whom treatment failed, emergence of genotypically documented resistance was low compared with 68% for raltegravir in the BENCHMRK trials,12 and it was most noticeable in the subgroup with one active background drug. Se both elvitegravir and raltegravir have a fairly low genetic barrier to development of resistance,15 this fi nding suggests that low concentrations of elvitegravir or raltegravir in plasma lead to minimum selection pressure. Unfortunately, the present study falls short .