This site is intended for health professionals only!
HAART therapy is now challenged by toxicity and resistance, and in available NNRTIs a single mutation may lead to class resistance. However, the second-generation NNRTI etravirine may offer options
Head of HIV Clinic
Medical Clinic I
University Clinic Bonn
Efficacy of human immunodeficiency virus (HIV) therapy has improved tremendously with the introduction of highly active antiretroviral therapy (HAART). This combination therapy – usually two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and either a low-dose ritonavir-boosted protease inhibitor (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) – was shown to be effective in achieving a sustained suppression of HI-virus replication. The great success of HAART is challenged by short- and long-term toxicity and by development of drug-resistant HIV strains. NNRTIs are often used in HIV therapy because of their comparably favourable adverse-event profile and low pill burden. Indeed, the current gold standard of HIV therapy is Atripla® – a fixed-dose combination of tenofovir, emtricitabine and efavirenz enabling a one-pill-per-day effective HAART therapy. But in this class of antiretrovirals the emergence of a single mutation (K103N) in the reverse transcriptase gene causes resistance to all commercially available NNRTIs in Europe. To overcome this disadvantage, new NNRTIs that are still effective in the presence of resistance mutations have been developed. Etravirine, also known as TMC125 or ETR, is the first “second-generation” NNRTI to be approved by the FDA, in January 2008. Applications for approval have also been submitted to the EMEA and other drug-regulating authorities.
Etravirine is a diarylpyrimidine analogue (DAPY) that exhibits at least three different properties that facilitate binding to an alternated NNRTI-binding pocket. Firstly, DAPY analogues can bind in at least two conformationally distinct modes. Secondly, torsional flexibility of DAPY analogues permits access to numerous conformational variants (described as “wiggling”). And thirdly, the compact design of the DAPY analogues permits significant repositioning and reorientation (translation as well as rotation) within the NNRTI-binding pocket (“jiggling”). These attributes allow etravirine to inhibit reverse transcriptase activity even in the presence of HIV variants with NNRTI mutations that show decreased or diminished inhibition by older NNRTIs.
A seven-day monotherapy course of TMC125 at a dosage of 900 mg twice daily was given to 12 HIV-infected, antiretroviral therapy (ART)-naive patients in the TMC125-C208 trial conducted in the Russian Federation in 2001. Treatment duration was limited to seven days in order to prevent selection of NNRTI-resistant mutants, as rapid emergence of resistant mutations has been observed for first-generation NNRTIs when given as monotherapy. A median drop in viral load of 0.89 log 10 was observed. Results for TMC125-C208 were compared with historical data from the Dutch ERA study, which evaluated a five-drug, triple-class ART regimen in ART-naive patients in 1997–2000. Analysis indicated that one week of TMC125 monotherapy resulted in a similar reduction in viral load compared with one week of therapy with a five-drug regimen.
DUET-1 and DUET-2 are two randomised, double-blind phase III trials that evaluated the safety and efficacy of etravirine compared with placebo. All enrolled patients had documented treatment-resistant HIV with at least three primary protease inhibitor (PI) mutations and at least one NNRTI resistance-associated mutation (RAM). Both treatment and control arms were administered in combination with background antiretroviral therapy that contained ritonavir-boosted darunavir, nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. A 200 mg dose of a new formulation of etravirine was administered twice-daily.[4,5] This new formulation was reported to result in exposure comparable to the 800 mg used in the phase IIb trials.
Pooled analysis of the DUET-1 and -2 trials – which enrolled 1,203 patients – at week 48 showed that etravirine was statistically superior to the control arm. A total of 61% of patients receiving etravirine had a viral load less than 50 copies/ml compared with 40% of patients in the control arm in the intent-to-treat analysis.
Also, the increase in CD4 cell count in the etravirine-receiving arm was significantly higher (98 vs 73 cells/µl from baseline). Of patients with de novo usage of enfurvitide, 71% in the treatment arm and 59% in the control arm achieved a viral load of less than 50 copies/ml (see Table 1).[7,8]
In vitro, etravirine has equipotent activity against wild-type HIV and various NNRTI-resistant variants that encode L100I, K103N and Y181C mutations. In the DUET-1 and -2 trials, 13 baseline RAMs were associated with a decreased response to TMC125 (TMC125 RAMs): V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V and G190A/S. The greatest added benefit in the TMC125-vs-placebo group was seen in patients with fewer than three TMC125 RAMs in the pooled 24-week interims analysis for undetectable viral load (see Table 2). A Spanish group analysed 1,470 genotypes of patients with virological failure who were treated with NNRTI. Only 4.6% of genotypes showed three or more TMC125 RAMs, while 63.1% did not harbour any. The mean number of TMC125 RAMs was significantly higher in nevirapine-experienced than in efavirenz-experienced patients (0.66 ± 0.92 vs 0.43 ± 0.78). Similar results were reported by a British group. Thus, the majority of NNRTI-experienced patients, having experienced virological failure, are predicted to be sensitive to etravirine.
Overall, etravirine’s safety and tolerability in the DUET-1 and -2 trials in the 48-week analysis was comparable to the control group (see Table 3). There was no significant difference in number of grade 3 and 4 adverse events (AEs) or rate of discontinuation due to AEs. The only significant difference was observed in the incidence of rash (19% vs 11%). Typical onset was in week two of treatment and of limited duration – 14 and 18 days (median). Severity was mild to moderate. Only 1% and 1.4% grade 3, and no grade 4 rashes were observed. Incidence was higher in women in DUET-1 but there was no clear difference in severity. Unlike other NNRTIs, etravirine seems to have low rates of nervous-system-related AEs. The total rate of central nervous system (CNS) toxicity in the etravirine group was 17% vs 20% in the placebo group.[7,8]
Etravirine is a substrate and inducer of CYP3A4 and a substrate and inhibitor of CYP2C9 and CYP2C19. Interactions with multiple drugs were identified or are to be expected. Especially, interactions with PI complicate combinations involving etravirine. Use of other NNRTIs or unboosted PIs is not recommended, nor is the combination with boosted tipranavir/r, fosamprenavir/r and atazanavir/r. Also, the concentration of benzodiazepines, antiarrhythmics, anticoagulants and antifungals and other substances can be affected by etravirine (US INTELENCE Prescribing Information).
Etravirine represents the first licensed NNRTI to retain considerable antiretroviral efficacy even in the presence of prior-acquired NNRTI mutations. Taking into account the fact that up to now, development of one NNRTI primary mutation under nevirapine or efavirenz has led to broad crossresistance within the NNRTI class and thereby limited its use in further antiretroviral combinations, this new NNRTI, with its distinct resistance profile, represents an important asset in the current antiretroviral armamentarium. With the introduction of more potent protease inhibitors also working in the presence of several prior-acquired PI mutations, as well as drugs from new classes with novel mechanisms of action, exciting potent new drug combinations can be composed. This even allows the achievement of undetectable viral loads in heavily pretreated patients, leading to a redefinition of the treatment goal: undetectability in all patients regardless of prior antiretroviral treatment experience.
Clearly, etravirine’s efficacy depends on the number of RAMs, highlighting the importance of not leaving patients for a long time on a failing NNRTI regimen in order to prevent accumulation of further NNRTI mutations. Etravirine’s safety profile is promising, with no major differences in AE occurrence rates, other than rash, to placebo. Rash, although occurring somewhat more frequently, was usually mild and seldom led to treatment discontinuation. Moreover, CNS toxicity was low, again underlining this drug’s favourable adverse-event profile. Nevertheless, long-term follow-up is needed to further assess tolerability issues over time. ■
1. Andries K, et al. TMC125. Antimicrob Agents Chemother 2004;48:4680-6.
2. Das K, et al. J Med Chem 2004;47:2550-60.
3. Sankatsing SU, et al. AIDS 2003;17:2623-7.
4. Madruga JC, et al. Lancet 2007;370:29-38.
5. Lazzarin A, et al. Lancet 2007;370:39-48.
6. Schöller M, et al. Substantial improvement of oral bioavailability of TMC125 using new tablet formulations in healthy volunteers. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil, 24–27 July 2005. Abstract TuPe31B11.
7. Johnson M, et al. DUET-2. 15th Conference on Retroviruses and Opportunistic Infections; Boston, USA, 3–6 February 2008. Abstract 791.
8. Haubrich R, et al. DUET-1. 15th Conference on Retroviruses and Opportunistic Infections; Boston, USA, 3–6 February 2008. Abstract 790.
9. Vingerhoets J, et al. Antivir Ther 2007;12:S34.
10. Vingerhoets J, et al. J Virol 2005;79:12773-82.
11. Katlama C, et al. Pooled 24-week results of DUET-1 and DUET-2. 11th European AIDS Conference, Madrid, Spain, 24–27 October 2007. Abstract P7.3/11.
12. Poveda E, et al. J Antimicrob Chemother 2007;60:1409-10.
13. Scott C, et al. Is there a role for next generation non-nucleoside reverse transcriptase inhibitors (ngNNRTI)? 11th European AIDS Conference, Madrid, Spain, 24–27 October 2007. Abstract P3.1/04.