- Category: HIV Treatment
- Published on Friday, 17 August 2012 00:00
- Written by Liz Highleyman
The 4-in-1 Quad pill containing the next-generation integrase inhibitor elvitegravir worked as well as both the Atripla coformulation and the boosted protease inhibitor atazanavir (Reyataz) for people with either high or low baseline viral load and CD4 T-cell counts, according to 2 poster presentations at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC.
Gilead'sQuad is a once-daily single-tablet regimen containing elvitegravir, the novel pharmacoenhancer cobicistat (a CYP3A4 inhibitor thatboosts levels of other drugs but has no antiviral activity of its own), and tenofovir/emtricitabine (the drugs in Truvada).
This past May the Food and Drug Administration's Antiviral Drugs Advisory Committee voted 13 to 1 to recommend approval of the Quad for treatment-naive HIV patients; a final decision in expected by late summer. The recommendation was based on data from pivotal Phase 3 trials comparing the Quad to 2 widely used regimens that are considered "preferred" in the U.S. HIV treatment guidelines.
Quad vs Atripla
As previously reported, study GS-US-236-0102 (funded by Gilead) compared the Quad against Atripla (efavirenz/tenofovir/emtricitabine) in 700 North American participants starting antiretroviral therapy (ART) for the first time. Findings were published in the June 30, 2012, issue of The Lancet.
Overall, the Quad was found to be non-inferior to Atripla at 48 weeks, with 88% of Quad recipients and 84% of Atripla recipients achieving HIV RNA < 50 copies/mL. In both arms 7% of participants experienced virological failure; among thesepatients, 8 (2%) in each arm developed resistance mutations. CD4 cell gains were also similar, averaging 239 vs 206 cells/mm3, respectively.
Both single-tablet regimens were generally safe and well-tolerated, with similar proportions of patients discontinuing therapy due to adverse events (4% vs 5%, respectively). Quad recipients experienced more nausea and larger serum creatinineincreases (median 13 vs 1 mcmol/L), while Atripla recipients were more likely to experience neuropsychiatric side effects such as dizziness and abnormal dreams and also had larger increases in cholesterol levels.
At AIDS 2012 Paul Sax from Brigham and Women's Hospital in Bostonand colleagues presented further analysis of virological suppression data broken down by participants' viral loads and CD4 T-cell counts at study entry as well as their adherence level.
Approximately one-third of GS-US-236-0102 participants had high baseline viral load (HIV RNA >100,000 copies/mL), including about 7% with > 400,000 copies/mL. At 48 weeks viral suppression was similar in the Quad and Atripla arms at all levels:
- < 100,000 copies/mL: 90% vs 85%;
- 100,000-400,000 copies/mL: 84% vs 79%;
- > 400,000 copies/mL: 86% vs 90%.
About 13% of participants had advanced immune deficiency with CD4 cell counts < 200 cells/mm3, approximately 30% had 201-350 cells/mm3, and nearly 60% had > 351 cells/mm3. Viral suppression rates were similar overall in the Quad and Atripla arms, but the Quad's advantage reached statistical significance at the highest level:
- < 200 cells/mm3: 74% vs 82%;
- 201-350 cells/mm3: 87% vs 84%;
- > 351 cells/mm3: 91% vs 84% (P=0.039).
Response rates were also similar between the Quad and Atripla arms in people with varying adherence levels, though not surprisingly they were higher with better adherence:
- < 95% adherence: 79% vs 75%;
- > 95% adherence: 91% vs 88%.
"In this first Phase 3 study of 2 single-tablet regimens, Quad demonstrated non-inferior efficacy to [efavirenz/tenofovir/emtricitabine] and was well tolerated at 48 weeks," the researchers concluded. "The efficacy of Quad was robust in patients regardless of baseline HIV RNA. These data support the use of Quad as a potential new single-tablet regimen option for initial HIV treatment irrespective of baseline viral load."
Quad vs Atazanavir
The second previously reported study, GS-236-0103 (also funded by Gilead), compared the Quad against ritonavir-boosted atazanavir plus tenofovir/emtricitabine in708 treatment-naive participants. These findings were also published in the same edition of The Lancet.
Again, the Quad was found to be non-inferior overall at 48 weeks, with 90% of participants in the Quad arm and 87% in the boosted atazanavir arm achieving viral load < 50 copies/mL. Virological failure was uncommon in both arms, at 5%; among these patients, 5 Quad recipients but no atazanavir recipients developed resistance mutations. Average CD4 cell gains were about the same (207 vs 211 cells/mm3).
Here, too, both regimens were generally safe and well-tolerated. Discontinuation rates due to adverse events were similar, 4% in the Quad arm vs 5% in the atazanavir arm. Quad recipients had smaller increases in fasting triglycerides and were less likely to experienceelevated bilirubin leading to jaundice. Both study arms saw small increases in serum creatinine, but these generally stabilized by week 8 and were similar at week 48 (median 11 vs 7 mcmol/L).
Edwin DeJesus from Orlando Immunology Center and co-investigators presented further findings from study GS-US-236-0103 at AIDS 2012.
In this study about 40% of participants had baseline HIV RNA > 100,000 copies/mL, including nearly 10% with > 400,000 copies/mL. Virologic response rates were again similar in the Quad and boosted atazanavir arms at all viral load levels:
- < 100,000 copies/mL: 93% vs 90%;
- 100,000-400,000 copies/mL: 85% vs 81%;
- > 400,000 copies/mL: 88% vs 86%.
About 13% of participants had baseline CD4 counts < 200 cells/mm3, 35% had 201-350 cells/mm3, and about half had > 351 cells/mm3. Viral suppression rates were similar in the Quad and Atripla arms regardless of CD4 cell level:
- < 200 cells/mm3: 80% vs 85%;
- 201-350 cells/mm3: 93% vs 89%;
- > 351 cells/mm3: 90% vs 86%.
Study 0103 included a bone mineral density (BMD) analysis. Spine BMD declined in both treatment arms through 24 weeks, but then stabilized. Hip BMD continued to decline to a similar extent in both arms through week 48.
This research team likewise concluded that the Quad demonstrated non-inferior efficacy, was well-tolerated at 48 weeks, and showed robust efficacy regardless of baseline viral load.
P Sax, E DeJesus, A Mills, et al (GS-US-236-0102 Study Group). Analysis of efficacy by baseline HIV RNA: week 48 results from a phase 3 study of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) compared to efavirenz/emtricitabine/tenofovir DF in treatment-naive HIV-1-positive subjects. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster TUPE028.
E DeJesus, J Rockstroh, K Henry, et al. Analysis of efficacy by baseline viral load: phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) versus ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF in treatment-naïve HIV-1-positive subjects: week 48 results. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Poster TUPE043.