www.hivandhepatitis.com

IAS 2013: Stribild 'Quad' Pill Continues to Show Good Efficacy at 96 Weeks

The 4-in-1 Stribild single-tablet regimen maintains HIV viral load suppression through 96 weeks and remains generally well-tolerated, researchers reported at the recent 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this month in Kuala Lumpur. Another study found that Stribild and its component cobicistat appear safe for people with mild-to-moderate kidney impairment.

David Cooper from St. Vincent's Hospital in Sydney and colleagues performed a pooled analysis of data from 2 randomized clinical trials comparing Stribild against existing standard-of-care antiretroviral regimens.

Formerly known as the "Quad," Gilead Science's Stribild combines the HIV integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and 2 NRTIs, tenofovir and emtricitabine, in a single once-daily tablet.

As previously reported, Stribild was found to be non-inferior at 48 weeks in a pair of Phase 3 trials comparing it against another Gilead single-tablet regimen, Atripla (efavirenz/tenofovir/emtricitabine), and against the ritonavir-boosted protease inhibitor atazanavir (Reyataz), also combined with tenofovir/emtricitabine (the drugs in Truvada).

The 2 trials both included about 700 participants randomly assigned (1:1) to receive either Stribild or one of the standard regimens, both of which are rated as preferred regimens in current U.S. antiretroviral therapy (ART) guidelines. In both studies most participants were white men around 38 years old with a median CD4 cell count of approximately 400 cells/mm³ who were starting HIV treatment for the first time.

Results

• At 96 weeks, rates of virological suppression (HIV RNA < 50 copies/mL) remained high for all 3 regimens: 83%-84% for Stribild, 82% for Atripla, and 82% for atazanavir/Truvada.
• These findings were consistent across demographic subgroups divided by age, sex, and race/ethnicity.
• Findings were also consistent for subgroups sorted by baseline viral load and CD4 T-cell count.
• CD4 cell gains were similar across regimen groups: 275, 273, and 261 cells/mm³, respectively.
• Stribild continued to be generally safe and well-tolerated, with no novel or unexpected side effects since the 48 week endpoint.
• Rates of adverse events leading to study drug discontinuation were similar in all 3 regimen arms (5%, 7%, and 6%, respectively).
• Neuropsychiatric adverse events -- a prominent side effect of efavirenz -- were less common in the Stribild group compared with the Atripla group; 14% vs 1%, respectively, experienced abnormal dreams.
• Discontinuations due to kidney-related adverse events were uncommon overall through 96 weeks, but occurred more often in the Stribild group (1.4% vs 0% with Atripla and 0.6% with atazanavir/Truvada).
• The median change in serum creatinine at 96 weeks was larger in the Stribild group (+0.13 vs +0.01 vs +0.08 mg/dL, respectively), but in all groups levels did not increase further after 48 weeks.
• No new cases of proximal tubulopathy were observed beyond the 4 that occurred prior to week 48.

"Through week 96, Stribild demonstrated high rates of virologic suppression and was well tolerated," the researchers concluded. "The efficacy of Stribild was consistent across demographic subgroups, baseline HIV-1 RNA, and CD4 cells." 

Kidney Impairment

Kidney impairment has been a potential concern with Stribild, both because it contains tenofovir -- which can cause kidney impairment in susceptible individuals -- and because cobicistat inhibits kidney tubular secretion, which affects a biomarker of kidney function known as estimated glomerular filtration rate (GFR). The results above showing no further changes in serum creatinine and no more cases of proximal tubulopathy after an additional year of therapy are reassuring.

Frank Post from Kings College Hospital in London and colleagues looked at safety and adverse events in an open-label trial (Study 118) of Stribild and cobicistat-containing regimens in people with mild-to-moderate kidney impairment at baseline.

The Stribild cohort included 33 treatment-naive participants. The cobicistat cohort included 73 people on suppressive ART containing either ritonavir-boosted atazanavir or darunavir (Prezista) plus 2 NRTIs who switched their booster from ritonavir to cobicistat.

Here too, most participants were men, but the average age was a bit older than in the pivotal trials above (50 and 54 years in the 2 cohorts, respectively), and the Stribild cohort included more people of African descent (39%). Older age and being black are both risk factors for kidney disease.

In both cohorts, participants had creatinine clearance of 50 to 89 mL/min (median 73 in the Stribild group and 71 in the cobicistat group); Stribild is licensed for use in patients with > 70 mL/min. Because cobicistat is known to affect estimated GFR, the researchers measured actual GFR using iohexol clearance in a subset of 14 participants. 

At 24 weeks, small reductions from baseline in creatinine clearance were observed in both the Stribild and cobicistat cohorts (-5.2 and -3.7, respectively). These changes occurred soon after starting the drugs then stabilized.

No significant changes in actual GFR were seen in the tested subset of patients. No kidney-related serious adverse events occurred. However, 3 people discontinued Stribild due to reduced creatinine clearance, all of whom returned to normal after stopping and none of whom showed signed of proximal tubulopathy.

"In patients with mild to moderate renal impairment," the researchers concluded, "both Stribild and cobicistat were well-tolerated with no new renal safety signal."

8/1/13

References

D Cooper, A Zolopa, J Rockstroh, et al. Subgroup analyses of 96-week efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract TUPE281.

F Post, J Andrade Villanueva, M Fisher, et al. Renal safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB) and cobicistat-boosted protease inhibitor regimens in HIV-1-infected patients with mild to moderate renal impairment. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract TUPE280.