Etravirine, a Next-Generation Nonnucleoside Reverse- Transcriptase Inhbitor

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1 INVITED ARTICLE REVIEWS OF ANTI-INFECTIVE AGENTS Louis D. Saravolatz, Section Editor Etravirine, a Next-Generation Nonnucleoside Reverse- Transcriptase Inhbitor Leonard B. Johnson and Louis D. Saravolatz Department of Internal Medicine, St. John Hospital and Medical Center, and Wayne State University School of Medicine, Detroit, Michigan Etravirine is the first next-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) that is approved for the treatment of HIV infection in patients who have experienced virologic failure while receiving an NNRTI-containing regimen. The drug is taken as two 100-mg tablets twice daily after a meal. Because the drug is metabolized by cytochrome P450 isoenzymes, it cannot be coadministered with a number of other drugs (fosamprenavir, high-dose ritonavir, atazanavir, rifampin, and several antiepileptic medications). Etravirine demonstrates potent in vitro activity against wild-type and NNRTI-resistant strains of HIV. In vitro resistance and treatment failure is associated with the development of multiple NNRTI resistance mutations other than the K103N mutation. Several large clinical studies have documented the benefit of adding etravirine to an optimized background regimen in patients with virologic failure who are infected with multidrug-resistant HIV. The major adverse effects of etravirine therapy are nausea and rash, which are typically self-limiting and do not lead to treatment discontinuation. The dramatic reduction in morbidity and mortality that has been achieved through the use of HAART has created new challenges for clinicians. Appropriate management of antiretroviral therapy includes not only concern for efficacy and safety but also consideration of pill burden, drug tolerability, and durability. Furthermore, treatment of patients who have received multiple regimens and are infected with highly resistant virus is becoming increasingly common. The use of nonnucleoside reverse-transcriptase inhibitors (NNRTIs) such as nevirapine and efavirenz has been increasing early in HIV treatment because of their low pill burden, high potency, and favorable adverse-effect profile [1 3]. A low genetic barrier to resistance has limited the duration of effectiveness for nevirapine and efavirenz, because single mutations result in large reductions in susceptibility to both agents. The frequencies of NNRTI resistance ant the transmission of resistant viruses are increasing [4, 5]; thus, the in-class substitution of NNRTIs has generally been limited to treatment switches because of drug intolerance. Previous efforts at the development of next-generation NNRTIs were limited by toxicity and lack of efficacy. In January 2008, the US Food and Drug Administration (FDA) approved etravirine for use in patients infected with HIV-1 strains that are resistant to an NNRTI and other antiretroviral agents. Etravirine is a diarylpyrimidine NNRTI that has demonstrated potent in vitro activity against both wild type HIV-1 and strains that are resistant to the currently approved NNRTIs. Therapeutic efficacy has been demonstrated both when used to replace failing NNRTIs therapies and when used in a new regimen in patients infected with NNRTI-resistant virus. As with other NNRTIs, adverse effects include rash that may be severe, and there are a large number of drug interactions that must be considered. Resistance has been reported to etravirine, but it is rare in patients who have not previously received etravirine. The use of this drug is likely to increase significantly as patients live longer and are frequently exposed to NNRTIs earlier in their treatment course. We will review the pharmacologic characteristics, in vitro activity, clinical data, and adverse events associated with etravirine. PHARMACOKINETICS Received 1 October 2008; accepted 8 December 2008; electronically published 10 March Reprints or correspondence: Dr. Leonard B. Johnson, Mack Ave, Ste. 340, Grosse Pointe Woods, MI (leonard.johnson@stjohn.org). Clinical Infectious Diseases 2009; 48: by the Infectious Diseases Society of America. All rights reserved /2009/ $15.00 DOI: / Etravirine is available in 100-mg tablets, and the approved dosage is 200 mg twice daily. Maximal plasma concentrations are reached in 2 4 h, and the elimination half-life is 40 h [6]. Absorption is increased by 50% when taken with meals; thus, it is recommended to take etravirine after meals. Absorption is not affected by coadministration with drugs that increase REVIEWS OF ANTI-INFECTIVE AGENTS CID 2009:48 (15 April) 1123

2 gastric ph, such as ranitidine and omeprazole. The drug is highly protein bound, and its distribution to compartments other than plasma has not been evaluated. Drug metabolism is primarily performed by cytochrome P450 isoenzymes (CYP3A4, CYP2C9, and CYP2C19), and the drug is mainly excreted unchanged in feces. In cell culture, the major metabolites are 90% less active than etravirine against wild-type HIV [6]. Etravirine is an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. The use of ritonavir and rifabutin decreases etravirine levels, whereas etravirine can have variable effects on the levels of coadministered protease inhibitors. In particular, tipranavir-ritonavir, atazanavir-ritonavir, fosamprenavir-ritonavir, and high-dose ritonavir (600 mg twice daily) should not be used with etravirine [7, 8]. Other protease inhibitors (lopinavir-ritonavir, darunavir, and saquinavir) must be taken with low-dose ritonavir (100 mg) when administered with etravirine [9 11]. No dosage adjustments are recommended when taking etravirine with tenofovir or raltegravir [12]. Etravirine may lower levels of atorvastatin and sildenafil, and their doses may need to be altered depending on clinical effect. Coadministration with omeprazole resulted in a 41% increase in the area under the plasma concentration-time curve for etravirine, because of CYP2C19 inhibition [13]. Among 18 healthy HIV-negative volunteers who were receiving omeprazole and were given 1 dose of etravirine, 1 developed a grade 3 increase in lipase level [13]. Etravirine should not be coadministered with carbamazepine, phenobarbital, phenytoin, rifampin, or products containing St. John s wort, because all are potent inducers of CYP450 enzymes and would likely reduce etravirine levels. A summary of the significant drug interactions for etravirine is provided in table 1. Etravirine is a pregnancy category B drug, but because of its Table 1. Significant drug interactions with etravirine (ETV). uncertain safety in infants, women are instructed to not breastfeed while taking etravirine. Although 4 mg/kg of etravirine provided comparable exposure to the adult dosage (200 mg twice daily) in children aged 6 17 years; etravirine is not approved for use in children [14]. No renal dosage adjustment is required. Although there is no dosage adjustment for mild or moderate hepatic impairment (Childs-Pugh class A or B), there are no data regarding patients with severe hepatic impairment (Childs-Pugh class C) [15]. IN VITRO ACTIVITY AND RESISTANCE The molecular structure of etravirine allows it to accommodate mutational changes in the binding pocket of the reverse-transcriptase enzyme, even in the presence of significant mutations [16]. Etravirine is highly active against HIV-1, with a 50% effective concentration of nmol/l, which is similar to that of efavirenz (50% effective concentration, nmol/ L) [17]. Etravirine demonstrated activity against 1049 (97%) of 1081 viral isolates that were resistant to FDA-approved NNRTIs [17]. A lower cutoff for etravirine resistance has been set at a 2.9-fold change in 50% inhibitory concentration with use of phenotypic assays (Monogram Biosciences). A sequential passage experiment including both wild-type and NNRTI-resistant HIV isolates was performed to identify mutations selected by etravirine in vitro [18]. The development of resistance was dependent on the presence of multiple coexisting mutations, demonstrating the high genetic barrier of etravirine. Mutations selected by etravirine included well-known NNRTI resistance mutations (L100I, Y181C, G190S, M230L, and Y318F), as well as newly recognized mutations (V179L and V179F). Clinical studies demonstrated that the presence of 3 NNRTI resistance mutations (including V90I, A98G, L100I, K101E/P, Drug Effect of ETV on drug concentration Effect of drug on ETV concentration Recommendation Atazanavir 47% Decrease in C min 50% Increases in C max, AUC, and C min Avoid use Atazanavir-ritonavir 38% Decrease in C min 30% increases in C max, AUC, and C min Avoid use Fosamprenavir 69% Increase in AUC Not available Avoid use Ritonavir Not available 46% Decrease in AUC Avoid use Tipranavir-ritonavir 24% Increase in C min 76% Decrease in AUC Avoid use Darunavir-ritonavir 15% Increase in AUC 37% Decrease in AUC No adjustment Lopinavir-ritonavir 20% Decrease in AUC 17% Increase in AUC No adjustment Saquinavir-ritonavir No effect 33% Decrease in AUC No adjustment Clarithromycin 39% Decrease in AUC 42% Increase in AUC Consider alternative treatment Rifabutin 17% Decrease in AUC 35% Decreases in C max, AUC, and C min May be used a Omeprazole Not available 41% Increase in AUC No adjustment Sildenafil 57% Decrease in AUC No effect No adjustment Atorvastatin 37% Decrease in AUC No effect No adjustment NOTE. AUC, area under the plasma concentration-time curve; C min, minimum concentration; C max, maximum concentration. a Cannot use rifabutin in combination with ETV and darunavir-ritonavir or saquinavir-ritonavir because of decrease in ETV levels CID 2009:48 (15 April) REVIEWS OF ANTI-INFECTIVE AGENTS

3 V106I, V179D/F, G190A/S, and Y181C/I/V) at baseline resulted in significantly reduced virologic response to etravirine [19, 20]. The prevalence of 3 of these mutations among viral isolates from patients experiencing NNRTI treatment failure ranges from 4.6% 10% [21 24]. The lowest frequency of 3 NNRTI resistance mutations among these studies was seen in a study of 1470 isolates recovered from NNRTI-experienced patients in Spain [24]. In this study, most patients had experienced treatment failure with efavirenz, and the K103N mutation was more frequently associated with efavirenz failure than with nevirapine failure (54.3% vs. 26.2%). Because K103N is not associated with etravirine resistance, Poveda et al. [24] suggested that efavirenz use may be less likely to lead to etravirine resistance than nevirapine. In addition, the duration of initial NNRTI exposure was associated with an increasing likelihood of developing in vitro etravirine resistance [23]. Therefore, the choice and treatment duration of the initial NNRTI may affect the subsequent etravirine response. CLINICAL STUDIES A phase IIa trial (TMC125-C208) was performed to evaluate the antiviral effect of etravirine (TMC125) when given as monotherapy in treatment-naive HIV-positive patients [25]. On day 8, the decrease in median viral load from baseline was 1.99 log 10 copies/ml, and the median increase in CD4 cell count from baseline was 104 cells/ml. A retrospective comparison of etravirine monotherapy demonstrated a rate of viral elimination (as measured by viral decay rate) that was comparable to that in treatment-naive patients treated with a 5-drug regimen [26]. An open-label phase IIa trial was performed to evaluate the efficacy of substituting etravirine for an approved NNRTI in 16 patients (3 receiving efavirenz and 13 receiving nevirapine) with an HIV RNA level copies/ml and phenotypic resistance to the NNRTI they were receiving [27]. At day 7, a decrease in the median viral load of 0.89 log 10 copies/ml (range, log 10 copies/ml) from baseline was observed, although CD4 cell counts were not significantly higher than at baseline. A phase IIb, multicenter, open-label, randomized trial was performed to evaluate the efficacy of 2 doses of etravirine in highly treatment-experienced patients who had an HIV load copies/ml and were infected with virus that had 3 protease inhibitor resistance mutations and genotypic resistance to approved NNRTIs [28]. The doses of etravirine used were 400 mg twice daily and 800 mg twice daily (when using a prior formulation of the drug with lower bioavailability). All patients received an optimized background regimen consisting of a nucleoside reverse-transcriptase inhibitor (NRTI), lopinavir-ritonavir, and/or enfuvirtide. The optimized background regimen was chosen using Virtual Phenotype (Virco) and treatment history. At week 24, the mean decrease from baseline viral load was 0.19, 1.04, and 1.18 log 10 copies/ml in the control, 400- mg etravirine ( P p.005), and 800-mg ( P!.001) etravirine groups, respectively. In addition, the proportion of patients with a viral load decrease of 1.0 log 10 copies/ml was significantly higher among the patients receiving 400 mg (36.3%; P p.005) and 800 mg (41.8%; P!.001) of etravirine, compared with patients in the control group (7.5%). The mean increase in CD4 cell counts was greater in the 400-mg (47 cells/ml) and 800-mg (48 cells/ml) etravirine groups, compared with the control group (10 cells/ml). A phase II study was performed to compare the efficacy of an etravirine-based regimen with that of a protease inhibitor based regimen in protease inhibitor naive, NNRTI-experienced patients who were receiving a failing first regimen of NRTIs and NNRTIs [29]. Patients had a viral load copies/ml and a history of treatment failure or treatment interruption after failure of a first-line NNRTI regimen. Of note, the study was performed in several resource-limited countries. All patients were given an optimized background regimen of 2 NRTIs chosen on the basis of drug resistance testing. Patients were randomized to receive a protease inhibitor (boosted or unboosted) or etravirine. Etravirine was given as 800 mg twice daily with use of the older formulation. A total of 106 patients (53 in each group) participated. At a planned week 12 analysis, patients in the etravirine group had a smaller decrease in viral load than did patients in the protease inhibitor group (decrease, 1.39 log 10 copies/ml vs log 10 copies/ml), and a smaller percentage of patients in the etravirine group had a viral load!50 copies/ml (difference, 27.8%; 95% CI, 8.8% 46.8%). After the 12-week analysis, the etravirine group was discontinued, and treatment for these patients was switched to the protease inhibitors that the control group had been receiving. The numbers of baseline NRTI and NNRTI resistance mutations were high and predicted treatment failure. Thus, in patients receiving a failing NNRTI-based regimen with a high number of baseline NRTI and NNRTI resistance mutations, treatment with an etravirine-based regimen appeared to be inferior to treatment with a protease inhibitor based regimen. The usefulness of etravirine in patients with extensive antiviral resistance was evaluated in an open-label, single-arm study of 10 HIV-infected patients [11]. All patients were infected with HIV that had extensive NRTI, NNRTI, and protease inhibitor resistance at baseline. Patients were given 200 mg of etravirine (approved formulation), 600 mg of darunavir, and ritonavir twice daily, along with 2 NRTIs with or without enfuvirtide. By week 24, 9 of 10 patients had undetectable viral loads; the median viral load was 2.7 log 10 copies/ml less than that at baseline, and the median CD4 cell count was 113 cells/ ml greater than that at baseline. This study was primarily focused on pharmacokinetics and safety; thus, the sample size was small. The relative contributions of etravirine are difficult REVIEWS OF ANTI-INFECTIVE AGENTS CID 2009:48 (15 April) 1125

4 to determine, because the patients were also treated with 2 other active agents (darunavir and enfuvirtide). Two large, randomized, double-blind, placebo-controlled, phase III studies (DUET-1 and DUET-2) were performed to evaluate the benefit of adding etravirine at the time of a drug switch [30 33]. The study design in both studies was identical. Patients had a viral load copies/ml, were infected with virus with 13 primary protease inhibitor resistance mutations and 11 NNRTI resistance mutation, and had received the same antiretroviral regimen for at least 8 weeks before screening. Patients were randomized to receive 200 mg of etravirine or placebo plus an optimized background regimen that included darunavir-ritonavir and the optional use of enfuvirtide. Patients were followed up for 48 weeks, and treatment responses were measured. At 48 weeks, the proportion of patients with a viral load!50 copies/ml was 60% and 61% in the etravirine arms of DUET-1 and DUET-2, respectively, compared with 39% and 41% in the placebo arms ( P!.001, for both analyses). In addition, the mean change in CD4 cell count at 48 weeks was higher in the etravirine groups of the DUET-1 and DUET-2 studies (103 and 94 cells/ml, respectively), compared with control groups (74 and 72 cells/ml, respectively). A pooled analysis of the 2 studies demonstrated that the addition of etravirine reduced the risk for clinical progression of HIV by one-half over 24 weeks [34]. A pharmacokinetic analysis of DUET-1 and DUET-2 demonstrated that achievement of a viral load!50 copies/ml at week 48 was not influenced by the area under the plasma concentration-time curve or trough concentrations of etravirine [35]. DRUG TOXICITY The most common significant adverse effects associated with the first-generation NNRTIs are cutaneous reactions (including Stevens-Johnson syndrome), hepatotoxicity with nevirapine, and neuropsychiatric adverse effects with efavirenz [36, 37]. Etravirine has been well tolerated in clinical studies, with low rates of discontinuation attributable to adverse effects [30, 31]. The discontinuation rates in the DUET studies were similar to those for placebo ( 5%) [30, 31]. The primary adverse effects observed have been rash and gastrointestinal effects, primarily nausea. In the DUET studies, the rate of nausea among etravirine recipients was 13.9%, compared with 11.1% in the placebo group. Patients receiving etravirine did not have a higher frequency of hepatoxicity or CNS adverse effects, compared with those receiving placebo [25, 27, 28, 30, 31]. Rash occurred at a higher rate among patients receiving etravirine (16.9%) than among patients receiving placebo (9.3%) in the DUET studies [30, 31]. Most episodes of rash were mild to moderate in severity, and only 2% of patients discontinued etravirine treatment because of rash. The rash typically occurred early during therapy (median time of onset, 11 and 14 days in DUET-1 and DUET-2, respectively). In the DUET studies, women experienced rash more frequently than did men (30% vs. 18%; P!.037) [38]. Patients with rash generally notice that the rash resolved with continued therapy (median time of resolution, 12 and 16 days in DUET-1 and DUET-2, respectively). Stevens-Johnson syndrome and other severe life-threatening reactions occurred in!0.1% of all etravirine recipients. In patients who experience a severe rash, etravirine should be discontinued permanently. Patients with a history of rash associated with receipt of NNRTIs (nevirapine and efavirenz) did not appear to have an increased risk of rash when receiving etravirine. The frequency of rash among patients in the DUET studies was 21.7% among those with a history of NNRTIassociated rash and 19.0% among those without a history of NNRTI-associated rash ( P p.65) [38]. SUMMARY Etravirine is the first of a long-awaited new generation of NNRTIs and demonstrates potent antiviral activity against strains of HIV that are resistant to other NNRTIs. The drug has demonstrated efficacy when added to an optimized background regimen in patients who have experienced treatment failure with multiple drug classes, including NNRTIs. Although the pill burden (4 pills daily in 2 doses) is currently higher than that for other NNRTIs, the drug appears to be both safe and tolerable, although severe skin reactions may occur rarely. In addition, because this medication has only been used in patients infected with antiretroviral-resistant HIV, it will likely prove to be highly useful in patients with limited treatment options. Etravirine should be used with at least 1 other active agent to ensure efficacy and minimize the risk of developing resistance. The presence of 3 characteristic NNRTI resistance mutations is needed to develop etravirine resistance. Adverse effects attributable to other NNRTIs do not predict adverse events that will be associated with etravirine. Thus, clinicians should be able to use this drug in most patients with prior NNRTI exposure. The long-term (96-week) durability of response and safety of etravirine are being evaluated in the DUET studies. Acknowledgments Potential conflicts of interest. L.B.J. is a member of the speakers bureau for Pfizer. 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