Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study.
BACKGROUND
Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed.


METHODS
We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT00708162.


RESULTS
Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI -6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009).


CONCLUSIONS
Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence.


BACKGROUND
Gilead Sciences.
Hôpital Saint Louis and University of Paris Diderot, Paris, France. jean-michel.molina@sls.aphp.fr
Jean-Michel
JM
Molina
Anthony
A
Lamarca
Jaime
J
Andrade-Villanueva
Bonaventura
B
Clotet
Nathan
N
Clumeck
Ya-Pei
YP
Liu
Lijie
L
Zhong
Nicolas
N
Margot
Andrew K
AK
Cheng
Steven L
SL
Chuck
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D000069446:Atazanavir Sulfate; D018791:CD4 Lymphocyte Count; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D019438:Ritonavir / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
D044966:Anti-Retroviral Agents; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D015363:Quinolones; D012367:RNA, Viral; D061466:Lopinavir; D000068898:Raltegravir Potassium; C509700:elvitegravir; D000069446:Atazanavir Sulfate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019438:Ritonavir