- Category: Approved HIV Drugs
- Published on Tuesday, 02 August 2011 00:00
- Written by Liz Highleyman
The recently approved next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (Edurant) continued to show efficacy comparable to efavirenz (Sustiva) at 96 weeks, but with fewer central nervous system side effects and a more favorable lipid profile in the Phase 3 ECHO and THRIVE trials.
Jean-Michel Molina from Saint Louis Hospital in Paris and colleagues reported 48-week findings from the ECHO study in the July 16, 2011, issue of The Lancet. Cal Cohen from the Community Research Initiative of New England and colleagues presented 48-week data from THRIVE in the same issue.
Cohen also presented a 96-week pooled analysis of both trials at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) last month in Rome.
ECHO and THRIVE were similar multinational Phase 3 randomized, controlled trials with a combined total of 1368 treatment-naive HIV patients. Both studies compared 25 mg once-daily rilpivirine vs 600 mg once-daily efavirenz, but used different NRTI backbones. All ECHO participants received tenofovir plus emtricitabine (the drugs in Truvada). THRIVE participants could used either tenofovir/emtricitabine or zidovudine/lamivudine (Combivir) or abacavir/lamivudine (Epzicom).
ECHO 48-Week Results
- In a 48-week intention-to-treat (ITT) time to loss of virological response (TLOVR) analysis of 690 participants in ECHO, 83% of patients in both the rilpivirine arm and the efavirenz arm achieved viral load < 50 copies/mL.
- The difference of 0.4% easily fell within the 12% non-inferiority margin.
- Virological failure -- either failure to achieve undetectable viral load or viral rebound -- was more common in the rilpivirine arm, 11% vs 4% in an ITT-TLOVR analysis.
- Conversely, grade 2-4 (moderate to severe) adverse events occurred significantly less often in the rilpivirine arm (16% vs 31%), and there were fewer discontinuations due to adverse events (2% vs 8%).
- Central nervous system side effects including dizziness and abnormal dreams or nightmares were more common with efavirenz, as was skin rash.
- People in the rilpivirine arm had significantly smaller increases in blood lipids (LDL "bad" cholesterol and triglycerides).
Based on these findings, the study authors concluded, rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological failure rate, but a more favorable safety and tolerability profile."
THRIVE 48-Week Results
- In a 48-week ITT-TLOVR analysis of 680 participants in THRIVE, 86% in the rilpivirine arm and 82% in the efavirenz arm achieved viral load < 50 copies/mL.
- The difference of 3.5% was again within the 12% non-inferiority margin.
- 7% of rilpivirine recipients experienced virological failure compared with 5% of efavirenz recipients.
- Again, grade 2-4 treatment-related adverse events were significantly less common in the rilpivirine arm (16% vs 31%), as were treatment discontinuations for this reason (4% vs 7%).
- Here, too, rash and dizziness occurred significantly less often and lipid increases were significantly lower with rilpivirine than with efavirenz.
"Despite a slightly increased incidence of virological failures," the researchers concluded, "a favorable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1."
Combined 96-Week Results
- In a combined ITT-TLOVR analysis at week 96, both rilpivirine and efavirenz had a virological response rate of 78%.
- Additional virological failures after week 48 were uncommon in both arms, 3% and 2%, respectively.
- Proportions of failing patients who developed NNRTI resistance mutations were also similar, 57% vs 54%, respectively; NRTI resistance mutations however, were more common with rilpivirine (56% vs 31%).
- CD4 cell gains were similar in both arms, 228 vs 219 cells/mm3, respectively.
- No new safety issues were identified between weeks 48 and 96.
- Grade 2-4 treatment-related adverse events remained less frequent in the rilpivirine arm, 17% vs 33%, respectively.
- Rates of treatment discontinuation due to adverse events were 4% and 9% respectively.
- Central nervous system symptoms and rash remained more common and lipid increases remained larger in the efavirenz arm.
"Rilpivirine gave sustained antiviral efficacy that was similar to efavirnez over 96 weeks," the researchers concluded. "While the [virological failure] rate was higher with rilpivirine than efavirenz, similar small increases in [virological failure]for both groups beyond Week 48 were observed."
Lancet ECHO: Community Research Initiative of New England, Boston, MA; Department of Infectious Diseases, University of Paris, Paris, France; Helios Salud, Buenos Aires, Argentina; Faculty of Medicine, Khon Kaen, Thailand; Vita-Salute, San Raffaele University, Milan, Italy; Abbott Northwestern Hospital, Minneapolis, MN; ICH Study Center, Hamburg, Germany; Department of Infectious Diseases, PUMCH, Beijing, China; Tibotec BVBA, Beerse, Belgium; Tibotec, Titusville, NJ.
Lancet THRIVE: Community Research Initiative of New England, Boston, MA; Hospital Civil de Guadalajara, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico; Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, Universitat Autonoma de Barcelona, Barcelona, Spain; Dr J Fourie Medical Centre, Dundee, KwaZulu Natal, South Africa; Royal Free Hospital, London, UK; HIV-NAT, Thai Red Cross AIDS Research Centre and Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Beijing You'an Hospital, Beijing, China; Maternal Infant Studies Center, University of Puerto Rico, Rio Piedras, Puerto Rico; Tibotec, Beerse, Belgium; Tibotec, Titusville, NJ.
IAS 2011 presentation: Department of Infectious Diseases, Saint Louis Hospital and University of Paris Diderot, Paris, France; Fundación Huesped, Buenos Aires, Argentina; Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil; Vita-Salute, San Raffaele University, Milan, Italy; Anthony Mills MD Inc, Los Angeles, CA; Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL; Department of Medicine, Chiang Mai University, Chiang Mai, Thailand; University Health Network, Toronto, Ontario; Canada; Tibotec BVBA, Beerse, Belgium; Tibotec Inc, Titusville, NJ.
J-M Molina, P Cahn, B Grinsztejn, 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. The Lancet 378(9787):238-246 (free full text). July 16, 2011.
C Cohen, J Andrade-Villanueva, B Clotet, et al (THRIVE Study Group). 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. The Lancet 378(9787):229-237 (abstract). July 16, 2011.
R Schrijvers, BA Desimmie, and Z Debyser. Rilpivirine: a step forward in tailored HIV treatment. The Lancet 378(9787):201-203. July 16, 2011.
C Cohen, J-M Molina, I Cassetti, et al. Pooled week 96 efficacy, resistance and safety results from the double-blind, randomised, phase III trials comparing rilpivirine (RPV) versus efavirenz (EFV) in treatment-naive, HIV-1-infected adults. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. TULBPE032.
Janssen Therapeutics. Edurant 96-Week Phase 3 Safety and Efficacy Data Presented at International AIDS Society Conference. Press release. July 19, 2011.