Use of the HIV antiretroviral treatment raltegravir, in combination with optimum background therapy, is a safe and effective alternative to conventional combination treatment using efavirenz in patients yet to start antiretroviral treatment. Furthermore, the raltegravir regimen is faster acting and causes fewer adverse events than the efavirenz regimen. These are the conclusions of an Article published Online First (www.thelancet.com) and in an upcoming edition of The Lancet, written by Dr Jeffrey L Lennox, Emory University School of Medicine, Atlanta, GA, USA, and colleagues.
Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), and works by inhibiting the activity of the reverse transcriptase enzyme vital for producing HIV viral DNA in host cells.
It is already known from previous studies that use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. But the safety and efficacy of this raltegravir regimen in patients who have not yet begun treatment (treatment-naive) has only been studied in a much smaller study. In this randomised controlled trial, patients from 67 centres on five continents were enrolled between September 2006 and June 2008. Patients had HIV-1, had viral RNA (vRNA) concentration of more than 5,000 copies per mL of blood, and no baseline resistance to efavirenz, or to the background treatments tenofovir or emtricitabine. Patients were randomised to receive 400mg oral raltegravir twice daily or 600mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary endpoint of the trial was achievement of a vRNA concentration of less than 50 copies per mL of blood at week 48. In order to be declared 'non-inferior' to the efavirenz regimen, the proportion of patients reaching the endpoint in the raltegravir group had to be within 12% of that of the efavirenz group. (a margin of 10 or 12% is recommended by the US Food and Drug Administration in studies of this nature)
The final analysis included 281 patients given raltegravir and 282 given efavirenz. A total of 297 patients at baseline had a vRNA of more than 100,000 per mL, and 47% had CD4 counts of 200 cells per mL or less (although proportions in individual populations can vary, these are typical for what many physicians would see in practice). The main analysis (with non-completion of treatment counted as failure) showed that 86% of the raltegravir group reached the primary endpoint, compared with 82% of the efavirenz group. Patients given raltegravir also reached the endpoint faster—50% of the raltegravir group achieved virological suppression by week four of treatment, compared with less than 20% of the efavirenz group).Treatment-related adverse events were also less common in patients given raltegravir (124/44%) than efavirenz (217/77%), although serious adverse events were similar (10%) in each group.
The authors acknowledge that the need to take ralegravir twice daily, rather than once daily as with efavirenz, could have an effect on treatment adherence in clinical practice. However, they conclude: "Our findings that raltegravir-based combination treatment is effective and generally well tolerated in treatment-naive patients, compared with efavirenz, are supported by follow-up data to week 96 in a phase II study of treatment-naive patients. Raltegravir is an important additional drug for initial treatment of HIV-1 infection, and should be regarded as an alternative to efavirenz as part of a first-line combination regimen with tenofovir and emtricitabine in treatment-naive patients."
In an accompanying Comment, Dr Sean Emery, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia, and Dr Alan Winston, Imperial College London, London, UK, discuss the positive impact raltegravir could have if introduced to first line therapy, including for women of child-bearing potential, since there are concerns about the teratogenicity of efavirenz (ie, its potential to cause physical abnormalities in the unborn fetus). Raltegravir also seems to be free of any clinical drug-drug interactions and is unlikely to be vulnerable to transmitted HIV resistance. Finally, they say a new drug class (integrase inhibitors, including raltegravir) could increase the number of plausible treatment combinations that could be used during a person's lifetime.
They say: "Raltegravir seems to have an edge over efavirenz in terms of safety and tolerability...Today's data are very encouraging for treatment and research. Raltegravir is an impressive drug and we hope other integrase inhibitors in development offer similar benefits."
Dr Jeffrey L Lennox, Emory University School of Medicine, Atlanta, GA, USA T) +1 404-616-6779 E) jlennox@emory.edu
Dr Sean Emery, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia T) +61 414 949 363 E) semery@nchecr.unsw.edu.au
For full Article and Comment, see: http://press.thelancet.com/raltfinal.pdf
Journal
The Lancet