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Switch From Boosted PI to Single-Tablet Rilpivirine/TDF/FTC Maintains Suppression
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Switching from a ritonavir-boosted PI and two nucleosides to a fixed-dose formulation of rilpivirine plus tenofovir/emtricitabine (Complera) proved virologically noninferior to maintaining the PI in a 24-week open-label trial [1]. The switch significantly improved key lipid levels.
In 2011 the FDA licensed a fixed-dose combination of the nonnucleoside rilpivirine (25 mg) with tenofovir/emtricitabine (200/300 mg) for once-daily treatment of antiretroviral-naive adults [2]. But research had not assessed outcomes after people responding to a boosted PI regimen switched to the rilpivirine combination, Complera.
This randomized, open-label, international trial enrolled adults with a viral load below 50 copies for at least 6 months while taking a combination anchored on a ritonavir-boosted PI. All study participants were taking their first or second regimen, had never used a nonnucleoside, and had no known genotypic resistance to study drugs.
Researchers randomized them in a 2-to-1 ratio to switch to Complera or to maintain their current PI combo. Most people were taking atazanavir (37%), lopinavir (33%), or darunavir (20%). The primary endpoint was the proportion of treated participants with a viral load below 50 copies in a week-24 snapshot analysis (the proportion of participants responding at a given point). A between-arm difference less than 12% would indicate noninferiority.
The trial involved 476 people who took at least one dose of their study drugs, 317 taking Complera and 159 staying with their boosted-PI regimen. The Complera and PI arms did not differ in proportion of men (86% and 91%), proportions of blacks (19% and 14%), median age (42 and 43), initial average CD4 count (576 and 600), or median time since starting antiretroviral therapy (2.9 and 2.6 years).
After 24 weeks of treatment, 93.4% in the Complera arm and 89.9% in the PI arm had maintained a viral load below 50 copies (95% confidence interval -1.6% to 9.1%). That result established the noninferiority of switching to Complera from a virologically suppressive boosted PI. All 17 people with virus harboring the K103N mutation before switching to Complera (because protocol-violation exposure to Atripla or transmitted resistance) responded to Complera with a sub-50-copy load at week 24.
Defining virologic failure as a viral load at or above 50 copies at week 24 or discontinuation of study drug, the snapshot analysis determined a 0.9% failure rate with Complera and a 5.0% rate with a continued PI. Resistant virus emerged in 2 people in the Complera group and in 1 who stayed with the PI.
People who switched to Complera gained an average of 20 CD4 cells, compared with a 32-cell gain in the PI arm; that difference was not significant (P = 0.28).
Grade 3 or 4 adverse event rates were 5% with Complera and 6.9% with a continued PI. Respective grade 3 or 4 lab abnormalities were 6.3% and 11.3%. No particular grade 3 or 4 adverse event affected more than 1% of participants in either study arm through 24 weeks.
Significantly lower proportions of study participants randomized to Complera than to a continued PI reported diarrhea (17.4% versus 45.3%, P < 0.001) or stomach pain or bloating (18.3% versus 32.1%, P < 0.001). Reported rates of nausea or vomiting were statistically similar with Complera and a continued PI (7.9% and 10.7%, P = 0.31).
Pretreatment lipid values were similar in the two treatment arms. At week 24 people randomized to Complera had significantly greater declines in five lipid values (P < 0.001 for all comparisons):
-- Total cholesterol: -25 versus -1 mg/dL
-- "Bad" low-density lipoprotein cholesterol: -16 versus 0 mg/dL
-- Triglycerides: -53 versus +3 mg/dL
-- "Good" high-density lipoprotein (HDL) cholesterol: -4 versus -1 mg/dL
-- Total/HDL cholesterol ratio: -0.27 versus +0.08 (lower ratio is better)
Switching to Complera also resulted in significantly greater improvements in 10-year Framingham cardiovascular risk score at week 24 compared with maintaining a boosted PI (P = 0.001). Estimated glomerular filtration rate (by Cockroft-Gault) was significantly lower (worse) with Complera than with a continued PI after 24 weeks (105.4 versus 108.9 mL/min, P < 0.001 for change from baseline; normal values are 90 to 120 mL/min). In vitro analyses indicate that rilpivirine inhibits OCT2, a renal transporter.
Estimated pharmacy costs were 16% lower with Complera than with a continued PI through 24 weeks ($10,275 versus $12,272).
The researchers concluded that "switching to [Complera] from a ritonavir-boosted PI regimen in virologically-suppressed, HIV-1-infected participants maintains virologic suppression with low risk of virologic failure while improving total cholesterol, LDL, and triglycerides." Complera must be taken with a meal of at least 400 calories.
References
1. Palella F, Tebas P, Gazzard B, et al. SPIRIT study: switching to emtricitabine/rilpivirine/tenofovir DF (FTC/RPV/TDF) single-tablet regimen from a ritonavir-boosted protease inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIS) maintains HIV suppression. XIX International AIDS Conference. July 22-27, 2012. Abstract TUAB0104.
2. AIDSinfo Drug Database. Rilpivirine. http://aidsinfo.nih.gov/drugs/426/rilpivirine/professional. Complera. http://www.complera.com
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