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Published on 22 September 2008

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Etravirine: the first second-generation non-nucleoside reverse transcriptase inhibitor

teaser

With increasing resistance in HIV-1-infected patients, there is an urgent need for new NNRTIs. Given its excellent tolerability, etravirine is set to become an important treatment

Christian Hoffmann
MD PhD

Internal Medicine Specialist
IPM Study Centre
Hamburg
Germany

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly and noncompetitively to a hydrophobic pocket of HIV-1 reverse transcriptase, the viral enzyme that conducts reverse
transcription of the viral RNA genome into DNA. The resulting complex blocks the catalyst-activated binding site of the reverse transcriptase, slowing viral polymerisation significantly. Although the three currently available NNRTIs – nevirapine, efavirenz and delavirdine – are generally potent and well tolerated, a major limitation is the low genetic barrier to resistance. Given the increasing prevalence of NNRTI resistance not only in treatment-experienced but also in treatment-naive patients – almost 10% of patients in Europe with an acute HIV infection currently harbour viruses with at least one NNRTI-resistant mutation[1] – there is an urgent need for the development of new NNRTIs.

Discussion
Etravirine (TMC 125, from Tibotec, a subsidiary of Johnson
& Johnson) is the first second-generation NNRTI. Etravirine exhibits potent in-vitro antiviral activity in the nanomolar range, comparable to that of the commonly prescribed NNRTIs. There is an EC50 against wild-type HIV-1 of 1.4 nm, and little or no loss of activity against HIV-1 variants harbouring key NNRTI-resistant mutations. The most common NNRTI mutation, K103N, which confers resistance to nevirapine and efavirenz, is not associated with resistance to etravirine. In contrast to other NNRTIs, etravirine also showed some in-vitro activity in the micromolar range against HIV-2. Although this is not clinically relevant, it reflects a broader spectrum of activity.[2]

As a diarylpyrimidine (DAPY) NNRTI, etravirine can bind flexibly to the HIV-1 reverse transcriptase.[3] The conformational flexibility allows multiple binding conformations in the drug-binding pocket of the enzyme, making the resistance barrier of etravirine probably higher than that of other NNRTIs.[4]

In phase I/II studies, etravirine reduced HIV plasma
viraemia by 1.99 log10 copies/ml in treatment-naive patients after one week of monotherapy,[5] and still by 0.89 log10copies/ml in the presence of NNRTI mutations.[6] In a phase II trial with 199 treatment-experienced patients with NNRTI and protease inhibitor (PI) mutations, the viral load was significantly less than with placebo after 48 weeks.[7]

However, the effect of etravirine decreases with increasing numbers of NNRTI-resistant mutations.[7] Patients infected with HIV-1 harbouring at least three NNRTI mutations achieved a mean reduction of 0.66 log10copies/ml. Although this was substantially higher than in the control group (–0.19 log10copies/ml), it was lower than the overall response to etravirine (–1.18 log10copies/ml). Moreover, a phase II study with 116 patients with previous NNRTI failure, in which
etravirine was compared with a PI chosen by the investigator,
was stopped prematurely because etravirine was significantly inferior.[8] It was argued that the baseline resistances in this study, which was conducted mainly in South Africa and  Thailand, were more prevalent than expected. Moreover, the formulation used in that trial showed poor bioavailability and is no longer used.

The efficacy, safety and tolerability of etravirine have been investigated in the two identically designed phase III studies, DUET-1 and DUET-2.[9,10] In these large continuing trials, 1,203 HIV-1-infected patients who had failed antiretroviral therapy with evidence of resistance to currently available NNRTIs and who had at least three primary PI mutations, were randomised to receive either etravirine or placebo, combined with the second-generation PI darunavir, investigator-selected NRTIs and optional enfuvirtide. After 24 weeks a significantly higher proportion of patients who received etravirine achieved a plasma viraemia of less than 50 HIV-1 RNA copies/ml than did those in the placebo group (56% vs 39% in DUET-1, and 62% vs 44% in DUET-2). Pooled analysis of both trials also revealed significant clinical benefit in terms of opportunistic infections and
mortality in individuals with etravirine vs controls.[11] Again, the activity of etravirine correlated well with the number of NNRTI-resistant mutations.[12]

Etravirine has, so far, been well tolerated. The type and incidence of adverse events, including neuropsychiatric events, seen with etravirine in the DUET studies were generally comparable with placebo, except for rash. Also observed with other NNRTIs, rash occurred more frequently during treatment with etravirine (17% vs 9%), but it was usually self-limiting and mild.

[[HPE39.31]]

There seem to be clinically relevant interactions with other antiretroviral agents. The protease inhibitors tipranavir, atazanavir, fosamprenavir and lopinavir are not recommended when using etravirine. In contrast, etravirine has no clinically relevant effect on the pharmacokinetics of methadone, and the bioavailability of etravirine is not decreased when co-adminstered with H2-antagonists or proton-pump inhibitors.

The etravirine dose being used in the DUET trials is two 100mg tablets twice a day. Etravirine should be taken with food, as exposure is 50% higher in the fed state. There are currently no data on etravirine in paediatric patients or in pregnant women.

In February 2007 an expanded-access programme was launched in Europe for patients who had limited treatment options, due either to virological failure or to intolerance to multiple antiretroviral regimens. Etravirine was licensed by the FDA in January 2008 under the proprietary name IntelenceTM.

Tibotec has also submitted applications for approval of etravirine to the European Medicines Agency (EMEA). European marketing authorisation for treatment-experienced adults with HIV strains resistant to existing NNRTIs is anticipated in 2008.

Conclusion
Etravirine is the first second-generation NNRTI for the treatment of HIV infection. Given its excellent tolerability, etravirine may become an important option for HIV-1-infected individuals with virological failure or intolerance to the three currently approved NNRTIs. However, the efficacy of etravirine is reduced in the presence of multiple NNRTI-resistant mutations.
Moreover, the current formulation, requiring a daily pill burden of four tablets, may limit its widespread use. A smaller and more bioavailable reformulation of this compound is in development.

References
1. Wensing AM, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe. J Infect Dis 2005;192:958-66.
2. Andries K, et al. TMC125. Antimicrob Agents Chemother 2004;48:4680-6.
3. Vingerhoets J, et al. TMC125 displays a high genetic barrier to the development of resistance. J Virol 2005;79:12773-82.
4. Das K, et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem  2004;47:2550-60.
5. Gruzdev B, et al. A randomized, double-blind, placebo-controlled trial of TMC125. AIDS 2003;17:2487-94.
6. Gazzard BG, et al. An open-label assessment of TMC125. AIDS 2003;17:F49-54.
7. TMC125-C223 Writing Group. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1. AIDS 2007;21:F1-10.
8. Etravirine. Drugs R D 2006;7:367-73.
9. Lazzarin A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2. Lancet 2007;370:39-48.
10. Madruga JV, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1. Lancet 2007;370:29-38.
11. Hirschel B, Perneger T. No patient left behind. Lancet 2007;370:3-5.
12. Vingerhoets J, et al. Impact of baseline NNRTI mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2. Antiviral Therapy 2007;12(S34):Abstract 32.

Resources
Expanded-Access Program in Europe:
W: www.tibotec.com/bgdisplay.jhtml?itemname=EAP2_ROW

Further information about etravirine:
www.intelence-info.com



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