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Switching From Atripla to Complera Safe and Effective in 12-Week Study
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Switching from the first one-pill once-daily antiretroviral regimen, Atripla, to the second, Complera, kept viral loads in check and caused no safety or tolerability problems through 12 weeks of follow-up in a 49-person single-arm trial [1].
Although Atripla (efavirenz plus tenofovir/emtricitabine) has become a popular regimen because of its efficacy, three-in-one formulation, and once-daily dosing, efavirenz-induced central nervous system (CNS) side effects can persist for months [2]. US clinical researchers mounted this trial to assess the viability of switching from Atripla to Complera, which combines the nonnucleoside rilpivirine with tenofovir/emtricitabine in a single once-daily tablet.
Phase 3 trials comparing first-line combinations built on rilpivirine or efavirenz found lower CNS toxicity rates and better lipid profiles with rilpivirine [3,4]. But switching from efavirenz to rilpivirine lowered rilpivirine trough concentrations about 25% in a study of healthy volunteers [5].
Study participants took Atripla as their first regimen and continued treatment for at least 3 months. They never had consecutive viral loads above 50 copies after initial suppression. Patients had to have a pre-Atripla genotype showing no reverse transcriptase mutations. Estimated glomerular filtration rate had to be at or above 50 mL/min. Participants said they wanted to switch from Atripla because of tolerability problems. The primary endpoint was a viral load below 50 copies 12 weeks after switching in an intention-to-treat analysis.
Forty-five of 49 study participants (92%) were men, and 39 (80%) were white. Median age stood at 39 years, median CD4 count at 653, and median Atripla duration at 2.5 years. All 49 study participants maintained a viral load below 50 copies for 12 weeks after switching to Complera.
Rilpivirine trough concentrations in the phase 3 rilpivirine trials lay between 50 and 80 ng/mL. In the current study rilpivirine troughs reached the target range within 2 weeks of dosing, averaging 52 ng/mL (coefficient of variation 47%) 2 weeks after the switch. Because of the long half-life of efavirenz, average efavirenz troughs remained above the 50% inhibitory concentration for about 4 weeks, apparently compensating for the initially low rilpivirine readings. From weeks 4 to 12 rilpivirine troughs averaged 66 to 84 ng/mL. Rilpivirine concentrations never fell below the detection limit at any study visit. The investigators concluded that the initially low rilpivirine troughs are not "clinically relevant."
No adverse events forced participants to drop out of the trial. Two grade 2 drug-related events, fatigue and increased bilirubin, arose. No grade 3 or 4 events were related to study drugs. Four grade 1 or 2 treatment-emergent events affected 2 people, both with nausea and insomnia. Serum creatinine rose by an average 0.11 mg/dL at week 12 from 0.97 mg/dL at study entry. Similar increases occurred in the phase 3 trials of rilpivirine [3,4].
References
1. Mills A, Cohen C, Dejesus E, et al. Switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) single tablet regimen (STR) to emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) STR in virologically suppressed, HIV-1 infected subjects. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H2-794c.
2. Zheng J, Scourfield A, Waters L, et al. Discontinuation of tenofovir, emtricitabine and efavirenz as a single tablet regime in HIV-1 infected individuals naive to antiretroviral therapy. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H2-783.
3. Cohen CJ, Andrade-Villanueva J, Clotet B, 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. Lancet. 2011;378:229-237.
4. Molina JM, Cahn P, Grinsztejn B, et al; ECHO study group. 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.
5. Crauwels H, Vingerhoets J, Ryan R, Witek J, Anderson D. Pharmacokinetic parameters of once-daily TMC278 following administration of EFV in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 630. http://www.retroconference.org/2011/Abstracts/41838.htm.
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