Pharmacology Update

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Tablets (Complera™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The FDA has approved a second three-drug fixed combination for the treatment of HIV-1 infections. This combination contains two nucleoside analog HIV-1 reverse transcriptase inhibitors (emtricitabine and tenofovir) and a non-nucleoside reverse transcriptase inhibitor (NNRTI; rilpivirine). This differs from the first fixed combination, Atripla®, which contains efavirenz as the NNRTI. The new fixed combination is marketed by Gilead Sciences as Complera.

Indications

Emtricitabine/rilpivirine/tenofovir (FTC/TDF/rilpivi-rine) is indicated for the treatment of HIV-1 infection in treatment-naïve adults.1

Dosage

The recommended dose is one taken once daily with a meal. Each tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate.

Potential Advantages

Rilpivirine appears to be better tolerated than efavirenz with fewer grade 2-4 adverse events and a lower frequency of discontinuation of therapy due to adverse events.1-3

Potential Disadvantages

In patients with baseline HIV-1 viral load greater than 100,000 copies/mL, the rate of virologic failure is higher with rilpivirine compared to efavirenz.1 These virologic failures have a higher rate of overall treatment resistance and cross-resistance to the NNRTI class. FTC/TDF/rilpivirine is not recommended for patients with creatinine clearance below 50 mL per minute.1 CYP3A4 inducers or inhibitors may affect the plasma level of rilpivirine. Drugs that increase gastric pH (i.e., antacid, H-2 antagonist, PPI) may decrease levels of rilpivirine.

Comments

FTC/TDF/rilpivirine provides a complete regimen for the treatment of HIV-1 infections. The efficacy of ERT was shown in two international randomized, double-blind, double-dummy, Phase 3 studies of identical design. Treatment-naïve subjects with a baseline plasma HIV-1 viral load of 5000 copies or greater were randomized to efavirenz (600 mg daily) or rilpivirine (25 mg daily) in combination with a background regimen. In one study, ECHO (n = 690), the background regimens were emtricitabine and tenofovir and the other, THRIVE (n = 678); the investigators had the option of emtricitabine/tenofovir, lamivudine/zidovudine, or abacavir/lamivudine.1-3 The primary outcome was noninferiority of rilpivirine to efavirenz in terms of a confirmed virological response at week 48 with non-inferiority defined as a margin of 12% (i.e., lower limit of a two-sided 95% confidence interval [CI] is greater than -12%). Secondary outcomes included, but were not limited to, non-inferiority with a 10% margin, change in CD4 cell count, and safety and tolerability. Response rates from ECHO were 83% for both rilpivirine and efavirenz and 86% and 82% for THRIVE. The lower 95% CI were -5.9% and -1.7%, respectively, meeting the criteria for non-inferiority at the -12% and -10% margin. In comparison of the same background regimen (ECHO), virological failure was higher for rilpivirine (11% vs 4% in ECHO) and appeared to be associated with baseline HIV-1 RNA viral load. In patients with viral load of 500,000 copies/mL, response rates were 62% for rilpivirine compared to 81% for efavirenz compared to 90% vs 83% in patients with viral load of 100,000 copies/mL or less.2 Grade 2-4 adverse events were lower for rilpivirine, 16% compared to 31% for both ECHO and THRIVE. Rash (8% vs 2%), dizziness (7% vs 1%), and abnormal dreams (5% vs 1%) were more common with efavirenz.2 Increases in plasma lipids were lower with rilpivirine.

Clinical Implications

FTC/TDF/rilpivirine is the second three-drug fixed combination to be approved and provides an alternative to atripla. These provide a complete regimen, reduces pill burden, and may improve adherence. Rilpivirine appears to be better tolerated than efavirenz but may be less effective in patients with high viral load (100,000 copies/mL). Atripla is one of the initial regimens recommended by the Health and Human Services Panel for treatment-naïve patients.4 Others are ritonavir-boosted atazanavir + tenofovir/emtricitabine, raltegravir + tenofovir/emtricitabine, and ritonavir-boosted darunavir + tenofovir/emtricitabine.

References

1. Complera Prescribing Information. Foster City, CA: Gilead Science; August 2011.

2. Molina JM, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): A phase 3 randomised double-blind active-controlled trial. Lancet 2011;378:238-246.

3. Cohen CJ. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): A phase 3, randomised, non-inferiority trial. Lancet 2011;378:229-237.

4. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed August 29, 2011.