Brand Name: INTELENCE
Generic Name: etravirine
Manufacturer: 1 Tibotec Therapeutics, Inc
Drug Class: 2 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
Use: 2 Treatment of human immunodeficiency virus infection (HIV) in treatment-experienced patients.
Mechanism of Action: 2,3 Etravirine binds directly to reverse transcriptase, causing a disruption of the enzyme’s catalytic site. This blocks the RNA- and DNA-dependent polymerase activity and halts viral replication.
Pharmacokinetics:1,2,3
Tmax |
2.5 – 4 hours |
Vd |
N/A |
T 1/2 |
41 hours |
Clearance |
N/A |
Protein binding |
99.9% (99.6% to albumin) |
Bioavailability* |
Unknown |
*Systemic exposure is decreased by about 50% when etravirine is given under fasting conditions compared to when it is given following a meal.1
Metabolism: Etravirine undergoes metabolism primarily in the liver by cytochrome P450 enzymes CYP3AF, CYP2C9, and CYP2C19. The major metabolites are formed by methyl hydroxylation of the dimethylbenzonitrile moiety and are at least 90% less active than the parent drug.
Elimination: After a single dose, 93.7% of administered etravirine is recovered in the feces (81.2% - 86.4% unchanged) and 1.2% in the urine (0% unchanged).
Efficacy:
Gruzdev B, et al. A randomized, double-blind, placebo-controlled trial of TMC125 (etravirine) as 7-day monotherapy in antiretroviral naïve, HIV-1 infected subjects. AIDS. 2003 Nov; 17(17):2487-94.
Study Design: This was a randomized, double-blind, placebo-controlled, phase IIA clinical trial.
Description: The study included 19 male patients over age 18 with documented HIV-1 infection and plasma HIV-1 RNA of 5000 – 125,000 copies/mL at screening. Patients were randomized 2:1 to receive either etravirine 900mg twice daily (12) or placebo (7) for 7 days. The primary outcome measure was change in HIV-1 RNA from baseline (assessed at twice daily visits). Secondary measures included change in viral load AAUCMB (average area under the curve minus baseline log10), nadir of viral load, and change in absolute and % CD4 counts. At study’s end, the etravirine group had an HIV-1 RNA level fall of 1.99 log copies/mL compared to a fall of 0.06 log copies/mL in the placebo group (p < 0.001). The difference between groups for viral load AAUCMB and nadir HIV-1 RNA values was also statistically significant in favor of etravirine (P < 0.001). Mean CD4 count increase was 104×106 cells/l in the etravirine group, with a decrease of 150×106 cells/L in the placebo group (p = 0.016). There was a significant decrease in percent of CD4 cells in the placebo group (6.3%, p = 0.031) compared to a non-significant change in the etravirine group (1.1%). Three subjects in the etravirine group reported somnolence compared to one in the placebo group. One patient in the placebo group discontinued study medication on day 3 due to mild gastroenteritis. No HIV events or deaths were reported. No consistent changes in blood chemistry, hematology, urinalysis, vital signs, ECG, or physical examination were observed.
Limitations: This Phase II study was small and power could not be calculated since no comparable studies had been done at this point. It was necessarily of short duration, since patients were withholding other antiretroviral therapy. In addition, etravirine is being marketed for use in treatment-experienced patients, so although this study was necessary before Phase III studies could begin, it carries little weight now in regard to the patient population.
Conclusion: Based on the results of this study, etravirine is effective in reducing viral load and maintaining CD4 count in treatment-naïve HIV patients. The only significant side effect was somnolence, which subsided after one day of treatment. Further, long-term studies are needed to show the drug’s effect in combination therapy and for treatment-experienced patients.
Nadler JP, Berger DS, Blick G, et al (TMC125-C223 Writing Group). Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS. 2007 Mar; 21(6): F1-10.
Study Design: This was a multi-center, open-label, partially-blinded, randomized Phase IIb clinical trial.
Description: 199 treatment-experienced HIV-1 patients with multi-drug resistance and plasma viral load > 1000 were randomized in a 2:2:1 fashion. Eighty patients received etravirine 400mg twice daily, 79 patients received etravirine 800mg twice daily, and a 40-patient control group received only their previous standard of care regimen. Investigators were blinded to etravirine dose, but not randomization to etravirine or control. The primary outcome measure was change in HIV-1 copies/mL from baseline at week 24. Secondary outcomes were proportion of patients showing viral load reduction of ≥ 1.0 log copies, and with less than 400 or less than 50 HIV-1 copies/mL. Safety analyses included EKGs, laboratory tests, and incidence of adverse effects and HIV-related events. Use of enfuvirtide was not balanced among groups, but authors adjusted for this in their statistical analysis. There was a statistically significant change in viral load in both 800mg and 400mg groups compared to placebo (-1.18 copies, -1.04 copies, -0.19 copies respectively, p < 0.005). A significantly higher proportion of etravirine patients had viral loads <400 (38%, 30%, vs 7.5%, respectively) and a change ≥ 1.0 log copies (42%, 36% vs 7.5% respectively). The proportion of patients with viral load < 50 was not statistically different for etravirine, although it was greater than for controls. When adjusting for enfuvirtide use, the 800mg dose performed better than the 400mg dose. Although not statistically significant, the mean change in CD4 count from baseline was greater with etravirine 400 and 800 than with controls (+47, +48, and +10 cells/µL respectively). The most common adverse events with etravirine were diarrhea, pyrexia, fatigue, nausea, headache, and insomnia. 15.1% of etravirine patients experienced rash believed to be related to the treatment. 8.2% of etravirine patients experienced pancreatic amylase elevation. Overall, 26%, 24%, and 95% of patients discontinued in the 400mg, 800mg, and control groups, respectively. In the control group, 75% of those discontinuations were due to virological failure.
Limitations: Since patients had already developed resistance to different antiretroviral drugs, background study treatment could not be standardized among patients. In addition, a high number of dropouts made analysis of both long-term outcome and adverse events difficult. Authors did not statistically analyze adverse events, choosing instead to speculate whether they were due to etravirine based on other risk factors for each individual. Since the study was only partially blinded, adverse effects may have been assessed unfairly.
Conclusion: Although the study had population limitations, they are representative of the patient population in which etravirine will be marketed. Statistically significant reductions in viral load among drug-resistant patients were sustained over 24 weeks with etravirine 400mg or 800mg twice daily. The 800mg dose was chosen for further investigation. Adverse effects of etravirine were not analyzed and require further study before the drug can be marketed.
Lazzarin A, et al (DUET-2 study group). Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet. 2007 Jul; 370(9581):39-48.
Study Design: This was a randomized, double-blind, placebo-controlled, phase III trial.
Description: The study included 591 patients infected with HIV-1 and failing antiretroviral therapy with evidence of resistance to NNRTIs and PIs, who had a viral count greater than 5000 copies/mL. They were stratified by enfuvirtide use, which was optional, then randomized to either etravirine 200mg* or placebo twice daily with darunavir-ritonavir and investigator-selected NRTI. The primary endpoint was proportion of patients with viral load below 50 copies/mL at week 24. Secondary endpoints were change from baseline in viral load, change in CD4 count, proportion of patients with viral load < 400 copies/mL and safety and tolerability. Adverse events, physical examinations, EKGs, vital signs, and laboratory abnormalities were assessed regularly. Analyses were by intention to treat, power was 95% for the primary endpoint, and p-values were two-tailed.
In the etravirine group, 62% of patients achieved viral load < 50 copies/mL compared to 44% in the placebo group (18% difference, 95% CI 11-26%; p = 0.003). Proportion of patients with viral load < 400 copies/mL was 75% with etravirine compared with 54% in placebo (p=0.001). Mean change in viral load at week 24 was -2.34 copies/mL with etravirine compared to -1.68 copies/mL with placebo (< 0.0001). Change in CD4 count was not significant, although count increased in both groups. The number of AIDS-defining illnesses/deaths was similar in both groups, but there were four total deaths with etravirine and seven with placebo (p = 0.217). Other adverse events were similar between groups, with the most common side effects being nausea, diarrhea, rash, headache, and fatigue. Rashes in the etravirine group typically resolved after 1-2 days, and 7 patients (2%) discontinued the study due to rash. Overall discontinuation rates did not vary by group.
*Due to a new formulation, this 200mg dose is equivalent to the 800mg dose used in previous studies.
Limitations: Investigators’ discussion of adverse events was limited in scope, and did not include statistical analysis for significant differences between groups. For example, triglycerides increased in 7% of etravirine patients compared to 4% of placebo patients, but we do not know if this was a significant increase. Rash and nausea also occurred more often in etravirine, but were not analyzed. Authors tended to minimize adverse effects.
Conclusion: This study was well-designed, well-executed, and generally well-interpreted by authors. Etravirine decreased viral load to < 50 copies/mL in 62% of treatment-experienced HIV patients with known resistance to NNRTIs. It appears to be an effective treatment option for combination use in those patients who have developed resistance to traditional NNRTIs and PIs.
Contraindications:1 none yet determined.
Precautions:
Adverse Effects: 1,2,3
Drug Interactions:1,2
Etravirine should not be administered with the following drugs:
Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19. Administration with drugs that induce or inhibit these enzymes may alter the therapeutic or adverse effects of etravirine. Antifungals, rifampin, and St. John’s Wort are examples of these drugs.
Etravirine is an inducer of CYP3A4 and inhibitor of CYP2C9 and 2C19. Administration with drugs that are substrates of these enzymes may alter the therapeutic and adverse effects of these drugs. Antiarrhythmatics, clarithromycin, warfarin, and HMG-Co-A reductase inhibitors are examples of these drugs.
Dosing/Administration:1,2
Usual Adult Dose: 200 mg by mouth twice daily following meals.
Pediatric Dose: Safety and efficacy have not been established.
Renal impairment dose: No dosage adjustments are required in patients with renal impairment.
Hepatic impairment dose:
Administration: Patients who are unable to swallow Etravirine tablets whole may disperse the tablets in a glass of water, stir well, and drink immediately. To ensure the entire dose is consumed, the glass should then be rinsed several times with water and each rinse swallowed.1 Note that if the patient is unable to swallow food, absorption will be greatly impaired. Etravirine should not be given under fasting conditions.
Use in special circumstances:
Pregnancy: Category B.1,2,3 Women who are using etravirine as part of antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective.3 A pregnancy registry is available for antiviral treatment. Register patients by calling 1-800-258-4263.1
Lactation: According to the Centers for Disease Control and Prevention (CDC), HIV-positive mothers should not breastfeed due to potential for HIV transmission, even if they are receiving antiretroviral therapy.1,3
Pediatric: Safety and efficacy have not been established.1,2,3
Conclusion: It has been greater than twenty years since the first antiretroviral therapy for Human Immunodeficiency Virus (HIV) was introduced. A myriad of drugs are available, and HIV patients are living longer lives than ever before. As their lifespan increases, however, drug resistance increases. The standard treatment today involves a combination of drug classes, (HAART: highly active antiretroviral therapy) and NRTIs or NNRTIs are central to this treatment. Mutations have led to considerable resistance to currently available NNRTIs, and there is an unmet clinical need to expand the class, especially for treatment-experienced patients. Etravirine is a new NNRTI that has activity against NNRTI-resistant virus, and has proven in several clinical studies to produce a significant virological response even in treatment-experienced patients. Adverse effects are similar to other drugs in the NNRTI class, but the drug’s effects on the population at large should still be monitored closely in this initial post-marketing period. Etravirine represents an appealing NNRTI option for combination use in patients who have developed multiple NNRTI-resistance.
Recommended References:
Prepared by: Keri Delsignore, Doctor of Pharmacy Candidate