For more than a decade, efavirenz and nevirapine have been the only nonnucleoside reverse transcriptase inhibitors (NNRTIs) reaching market release. Efforts at the development of next-generation NNRTIs have been consistently unsuccessful, these investigational compounds quickly falling out of favor due to toxicity and/or lack of efficacy issues. First-line treatment initiation being recommended earlier and earlier according to recent guidelines, and given the CD4 cut-off value for the use of nevirapine, efavirenz is the preferred cornerstone of first-line treatment of HIV-1 infection , as, to date, no other antiretroviral agent has proven more efficacious in head-to-head clinical trials enrolling antiretroviral-naive HIV-1-infected patients [2–5]. Its use, however, has been hampered by its neuropsychiatric toxicity , which is frequently mild and transient, but can last longer in some cases, with the effects sometimes not yielding a complaint from the patient himself, but being recognized by the patient's friends and family.
Antiretroviral treatment being needed for a lifespan, first-line treatment is crucial in building patient's confidence in his long-term therapeutic project. The most distressing fear of HIV-infected patients starting a first-line antiretroviral combination is toxicity, and its occurrence might jeopardize patients' motivation, adherence and confidence, especially if it requires treatment modification. In the Swiss cohort, the most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%) and hepatic events (11.5%) in patients starting a first-line triple combination between 2005 and 2008, leading to switches or discontinuations because of drug toxicity at a rate of 22.4 [95% confidence interval 19.5–25.6] per 100 person-years . Close monitoring and management of adverse effects are, thus, crucial for durability of first-line combined antiretroviral therapy . For many years, the sole alternative to efavirenz as a third agent was ritonavir-boosted protease inhibitors or, more recently, raltegravir. In January 2008, after sustained vivid research in the area of NNRTIs, etravirine was the first long-awaited second-generation NNRTI to be approved by the Food and Drug Administration and to come to market. It was initially aimed to overcome the low genetic barrier to resistance of first-generation NNRTIs. Indeed, etravirine retains activity against variants resistant to nevirapine and efavirenz, rendering sequential NNRTI therapy possible in case of virological failure on a first-generation NNRTI . In treatment-experienced patients, etravirine exhibited a tolerance profile similar to that of the placebo . Twice-daily etravirine was, thus, licensed for antiretroviral-experienced patients. There are several lines of evidence that this drug has pharmacokinetic properties supporting its once-daily administration . Logically, Nelson et al.  evaluated once-daily etravirine within first-line treatment in the SENSE trial published in this issue. Unlike the vast majority of first-line antiretroviral treatment studies in which the primary end point is virological efficacy, they designed a double-blinded study to compare efavirenz and etravirine with regard to the emergence of drug-related neuropsychiatric events up to week 12 after therapy initiation. They showed a significantly lower percentage of patients experiencing at least one grade 1–4 drug-related neuropsychiatric adverse event up to week 12 in the etravirine 400 mg once-daily arm (16.5%) than in the efavirenz arm (46.2%). This difference remained significant when neuropsychiatric adverse events were analyzed using several different methods. One patient in the etravirine arm and five in the efavirenz arm discontinued study medication with neuropsychiatric adverse events. In addition, unlike previous reports in heavily pretreated HIV-infected patients , the percentage of patients with grade 2–4 cutaneous rash was lower in this antiretroviral-naive population and similar between etravirine (10.1%) and efavirenz (11.5%) arms, none of the patients experiencing a grade 4 rash. Once-daily etravirine seemed also more lipid friendly than efavirenz. Finally, the mean change in HIV-RNA from baseline to week 12 and the percentage of individuals achieving an HIV-RNA level less than 400 cp/ml at week 12 were similar between both arms.
Altogether, these results suggest that etravirine is better tolerated than the preferred third-agent comparator efavirenz, in the short but critical period following treatment initiation. Notably, drug-related neuropsychiatric adverse events were also reported in the etravirine arm, emphasizing the fact that analysis of neuropsychiatric adverse events and identification of a culprit drug are complex because of the high background of underlying neuropsychiatric problems in the HIV-infected population, especially during the early phase of treatment initiation. Major limitations of the SENSE study include the short-term virological efficacy data provided herein (but follow-up until week 48 is ongoing), as well as the need for longer follow-up to determine whether the improved neuropsychiatric adverse event profile of etravirine over efavirenz might translate into better long-term adherence to antiretroviral treatment. Indeed, although it is true that there were significantly less drug-related neuropsychiatric adverse events in the etravirine arm than in the efavirenz arm, efavirenz-related neuropsychiatric adverse events were predominantly mild and transient (with a peak at week 2). With regard to virological efficacy, data on resistance mutation emerging in case of virological failure on first-line etravirine selective pressure are paramount to determine whether sequencing of NNRTIs would be still possible after first-line failure on an etravirine-containing regimen. Finally, the current pill burden of etravirine (four tablets of 100 mg) is high compared with first-generation NNRTIs, and is comparable to the pill burden associated with ritonavir-boosted protease inhibitor-containing first-line regimens. Notably, etravirine tablets may also be dispersed in water. Safety data in pregnant women will be also very valuable.
We are moving toward earlier and subsequently longer antiretroviral treatment for HIV-infection. We, thus, need antiretroviral agents that are well tolerated within the short-term and the long-term use. Etravirine has the potential for an attractive first-line alternative to currently recommended first-line NNRTIs, provided that long-term data on its virological efficacy and on mutational pattern in case of first-line treatment failure are reassuring, and that its formulation improves with a reduced number of tablets to make it more suitable for a once-daily administration.
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