- Category: HIV Treatment
- Published on Tuesday, 11 September 2012 00:00
- Written by Liz Highleyman
An integrated analysis of data from Phase 2 and 3 trials, presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) this week in San Francisco, showed that the newly approved Stribild (elvitegravir/cobicistat/tenofovir/emtricitabine) single-tablet regimen had antiviral efficacy at least as good as comparison regimens, and was associated with fewer adverse events than Atripla or boosted atazanavir (Reyataz).
Stribild -- Gilead Science's 4-in-1 coformulation formerly known as the Quad -- contains the next-generation integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and tenofovir/emtricitabine (the drugs in Truvada). On August 27 the U.S. Food and Drug Administration (FDA) approved Stribild for HIV positive adults starting treatment for the first time.
Approval was based on study data showing that Stribild suppresses HIV viral load as effectively as 2 widely used combinations listed as preferred regimens in the U.S. DHHS antiretroviral treatment guidelines.
At ICAAC, David Ward from Dupont Circle Physicians Group in Washington, DC, presented findings from a pre-specified integrated analysis of safety and efficacy in 3 of these trials:
- Study 102 (GS-US-236-0102): a Phase 3 head-to-head comparison of Stribild versus Atripla (Gilead's efavirenz/tenofovir/emtricitabine single-tablet regimen) in 700 treatment-naive patients.
- Study 103 (GS-US-236-0103): a Phase 3 comparison of Stribild versus ritonavir-boosted atazanavir (a popular protease inhibitor) plus tenofovir/emtricitabine in 700 previously untreated patients.
- Study 104: a smaller Phase 2 study comparing Stribild versus Atripla in 75 treatment-naive patients.
Results from Study 102 and 103 were previously reported at various medical conferences and published in the June 30, 2012, issue of The Lancet.
The combined analysis included 749 participants taking Stribild, 375 taking Atripla, and 355 taking boosted atazanavir. Baseline characteristics were similar across the 3 groups. About 90% were men, two-thirds were white, and the median age was about 38 years. They generally had well-preserved immune function, with a median CD4 T-cell count of approximately 380 cells/mm3.
- Stribild demonstrated a high rate of virological suppression in all studies, matching that of the comparison regimens, which also worked well.
- Virological response -- defined as HIV RNA < 50 copies/mL at week 48 -- was achieved by 88.8% of Stribild recipients, 84.0% of Atripla recipients, and 86.8% of atazanavir recipients.
- Differences in efficacy favored Stribild over Atripla by 5.1%, and Stribild over boosted atazanavir by 1.9%.
- Stribild efficacy was consistent across subgroups stratified by demographic characteristics, baseline HIV viral load, and baseline CD4 T-cell count.
- CD4 cell gains at week 48 were similar in all regimen arms (224, 203, and 211 cells/mm3, respectively).
- Rates of study discontinuation were also similar in all arms, at around 12%.
- Stribild was generally safe and well-tolerated, with mostly mild-to-moderate adverse events.
- Rates of adverse events leading to study drug discontinuation were similar in the 3 regimen groups (3.5% for Stribild, 5.1% for Atripla, and 5.1% for atazanavir).
- Rates of serious adverse events were also similar (9.2%, 6.7%, and 8.7 %, respectively).
- Deaths were rare in all regimen groups (0.1%, 0.5%, and 0.8%, respectively).
- Stribild was associated with significantly fewer neuropsychiatric side effects such as abnormal dreams or dizziness (42.9% vs 62.1%) and less skin rash (17.5% vs 27.7%) compared with Atripla.
- Stribild was less likely to cause elevated bilirubin levels than boosted atazanavir.
- Stribild was associated with significantly smaller increases in total, LDL ("bad"), and HDL ("good") cholesterol compared with Atripla, and smaller triglyceride increases compared with atazanavir.
- Stribild recipients experienced an early increase in serum creatinine -- a potential marker of impaired kidney function.
- Creatinine levels soon stabilized, however, and at 48 weeks the increase in the Stribild arm (median +0.13 mg/dL) was greater than that seen with Atripla (+0.01 mg/dL), but similar to that of atazanavir (+0.08 mg/dL).
- Less than 1% of participants across all study arms discontinued therapy due to kidney toxicity; however, 4 of the 6 Stribild discontinuations for adverse events were kidney related.
- Patients who stopped Stribild due to renal problems showed improvement after discontinuation, but not necessarily all to baseline levels, according to Ward.
Based on these findings, the researchers concluded, the Stribild single-tablet regimen "demonstrated high rates of virologic suppression comparable to [Atripla] and [atazanavir/ritonavir + tenofovir/emtricitabine] with potential to overcome toxicities, such as neuropsychiatric symptoms, rash, and hyperlipidemia."
"[An] early small increase in creatinine that stabilizes is expected" with Stribild due to inhibition of renal tubule secretion by cobicistat, they added.
While this change is not thought to be problematic in itself, Ward explained that it raises the issue of how to differentiate a cobicistat-related creatinine increase from uncommon kidney toxicity associated with tenofovir. The new Stribild prescribing information will include a threshold level indicating that the regimen should be stopped if the mean creatinine change plus 2 standard deviations reaches 0.4 mg/dL.
D Ward, G Crofoot, D Shamblaw, et al. Efficacy and Safety of Elvitegravir/cobicistat/emtricitabine/tenofovir DF from an Integrated Analysis of Phase 2 and 3 Clinical Trials. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-555.