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FDA Approval: Etravirine

Etravirine is highly effective against most viruses with resistance to other NNRTIs. Clinicians will need to be especially aware of the determinants of cross-resistance and of some significant drug–drug interactions.

Background
On January 18, 2008, the FDA granted accelerated approval for etravirine, the first new NNRTI in nearly 10 years. The medication (previously known as TMC125) will be licensed under the trade name Intelence.

Indications
Etravirine is indicated for treatment-experienced adults with HIV strains resistant to existing NNRTIs. Approval of the drug was based on results from the DUET studies (ACC Jul 30 2007), which compared etravirine with placebo in treatment-experienced patients with documented resistance to NNRTIs and PIs; all patients also received optimized background regimens that contained ritonavir-boosted darunavir, plus other agents selected by the investigators as indicated. At 24 weeks, viral-load and CD4-cell–count data significantly favored etravirine over placebo. In addition, pooled analysis of the two studies demonstrated a clinical benefit for etravirine, with an almost 50% reduction in the rate of HIV disease progression or death. Post hoc analyses from these studies demonstrated that, as with most recently approved antiretrovirals, virologic response to etravirine is augmented when other fully active agents are included in the background regimen.

Etravirine should not be used alone with NRTIs in patients with a history of treatment failure on standard NNRTI-based regimens. This cautionary note stems from the disappointing results of an as-yet-unpublished study, TMC125-C227, which showed that etravirine was inferior to a boosted PI when used with two NRTIs in patients with previous virologic failure on an NNRTI-based regimen (Abstract PL5.6, 8th International Congress on Drug Therapy in HIV Infection, 2006). These findings further highlight the need for etravirine to be accompanied by other fully active agents.

Resistance
The presence of certain NNRTI-resistance mutations at baseline diminishes response to etravirine, although the list of such mutations differs somewhat between the package insert and resistance findings from the DUET studies. According to the package insert, the presence of V179D/F/T, Y181V, or G190S can reduce response to etravirine, as can any combination of at least three NNRTI mutations as defined by the International AIDS Society–USA. According to the DUET resistance analysis, however, response is diminished only when patients have at least three of the following mutations (which are also included in the IAS–USA set): V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S (Abstract 32, XVI International HIV Drug Resistance Workshop, 2007). Importantly, baseline presence of the K103N mutation alone — the most common mutation seen in patients with treatment failure on efavirenz — does not affect response to etravirine. We do not yet know whether specific "archived" mutations that are no longer detected on genotyping will influence response, or whether the predictors of resistance will change when patients use less-robust optimized background regimens than those used in the DUET studies. According to the manufacturer, genotype and phenotype testing for etravirine resistance — including the "virtual phenotype" genotype interpretation developed by Virco (a company affiliated with the makers of etravirine) — will be available soon.

Pharmacology and Dosing
Etravirine is available in 100-mg tablets, with a recommended dosage of 200 mg twice daily following meals. Taking the drug under fasting conditions diminishes systemic exposure by 50%. Although the average half-life of etravirine (41 hours) is long enough to support once-daily dosing, such dosing has not been tested in controlled trials and is hence not approved.

Like nevirapine and efavirenz, etravirine is hepatically metabolized by the cytochrome P450 system. It is both a substrate and an inducer of CYP3A4; by contrast, it is an inhibitor of CYP2C9 and CYP2C19. Consequently, numerous drug–drug interactions must be considered when prescribing etravirine. Several antiretroviral agents are not recommended when using etravirine, including all unboosted PIs as well as ritonavir-boosted tipranavir, fosamprenavir, and atazanavir. Importantly, as demonstrated in DUET, ritonavir-boosted darunavir can be coadministered with etravirine; ritonavir-boosted saquinavir is also likely to be a safe option. Because lopinavir/ritonavir increases etravirine exposures by 85%, this combination should be used "with caution," according to the package insert. No significant drug–drug interaction is anticipated between etravirine and raltegravir because raltegravir is not metabolized by the cytochrome P450 system; indeed, many patients in the etravirine expanded-access program have also received raltegravir. Maraviroc can be coadministered with etravirine, but the dose of the CCR5 inhibitor should be adjusted to 600 mg twice daily if a boosted PI is not also used; the dose for maraviroc when administered with a boosted PI is 150 mg twice daily.

Adverse Effects
The most common adverse effect of etravirine in the DUET studies was rash, which occurred in 16.9% of recipients (vs. 9.3% of placebo recipients). Rash was usually mild to moderate, occurred within the first 2 weeks of therapy, and resolved with continued dosing. However, 2% of study participants had to discontinue etravirine because of rash, and, as with other NNRTIs, etravirine has been associated with severe, potentially life-threatening cutaneous reactions (Stevens-Johnson syndrome, erythema multiforme). Patients with a history of NNRTI-related rashes did not appear to be at increased risk for developing a rash with etravirine.

Cost and Availability
According to the manufacturer, etravirine was scheduled to be in pharmacies approximately 1 week after approval. The wholesale cost for a 100-mg tablet will be US$5.45, or $21.80 for the daily dose. As usual, government payers (such as Medicaid, AIDS Drug Assistance Programs, and the Veterans Health Administration) will receive a discounted price.

Comment: The development of NNRTIs has been remarkably challenging, in that several candidate compounds have failed because of lack of efficacy, excess toxicity, cross-resistance, or lack of anticipated benefit over the current incumbents, efavirenz and (to a lesser extent) nevirapine. The most notable characteristic of etravirine is its activity against many NNRTI-resistant strains; according to the DUET studies, about 85% of NNRTI-treated patients can be expected to have viruses susceptible to this drug (Abstract P7.3/11, 11th European AIDS Conference, 2007). To assess the suitability of patients for etravirine therapy, clinicians will need to be alert to some relatively unfamiliar NNRTI mutations (the most common being Y181C and G190A) and also be aware of several drug–drug interactions that may have clinical relevance. These caveats notwithstanding, the availability of etravirine helps to ensure that treatment-experienced patients can include at least two active drugs in their next regimen. The importance of this strategy cannot be overemphasized; given that development of new antiretrovirals for patients with highly drug-resistant virus is about to enter a relatively fallow phase, the consequences of virologic failure and resistance may be dire indeed.

— Paul E. Sax, MD

Published in Journal Watch HIV/AIDS Clinical Care January 28, 2008

Citation(s):

Intelence (etravirine) tablets [prescribing information]. Raritan, NJ: Tibotec, Inc.; Jan 2008. (http://www.intelence-info.com/intelence/assets/pdf/INTELENCE_PI.pdf)

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