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ICAAC 2014: Cobicistat Long-term Efficacy Matches Ritonavir as PI Booster

Long-term rates of viral suppression and side effects were similar among people using cobicistat and those using ritonavir as a booster for atazanavir (Reyataz), according to 3-year data presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy last week in Washington, DC. Another study found that cobicistat was well-tolerated by people with mild-to-moderate kidney impairment.

The HIV protease inhibitor ritonavir is widely used to "boost" or increase levels of other medications because it slows down drug processing by enzymes in the liver. A newer pharmacoenhancer, Gilead Sciences' cobicistat, plays a similar role but is not itself active against HIV. Cobicistat is a component of the Stribild single-tablet-regimen (elvitegravir/cobicistat/tenofovir/emtricitabine). It has been approved as a stand-alone (brand name Tybost) in Europe, but not yet in the U.S.

Joel Gallant from the Southwest CARE Center in Santa Fe and colleaguespresented long-term data from Gilead's Study 114, which compared cobicistat versus ritonavir as boosters for atazanavir.

This multinational Phase 3 trial included 692 participants starting HIV treatment for the first time. Most (about 80%) were men, about 60% were white, and the average age was 38 years. The mean baseline CD4 T-cell count was approximately 350 cells/mm³ and they had normal kidney function at baseline, with an estimated glomerular filtration rate (eGFR) >70 mL/min (median 114 mL/min).

Participants were randomly assigned to receive once-daily atazanavir boosted with either cobicistat or ritonavir, both in combination with tenofovir and emtricitabine (the drugs in Truvada).

Results

• As previously reported, the study's primary analysis at 48 weeks showed that 85% of people taking cobicistat and 87% taking ritonavir had HIV RNA below 50 copies/mL, indicating that cobicistat is non-inferior to ritonavir.
• At 144 weeks, viral suppression rates remained similar in the cobicistat and ritonavir arms -- 72% vs 74%, respectively -- again indicating non-inferiority.
• No participants with virological failure in either arm developed resistance to atazanavir or tenofovir.
• Mean CD4 cell gains at 144 weeks were also similar, 310 and 332 cells/mm³, respectively.
• Long-term cobicistat was generally safe and well-tolerated, with most adverse events being mild to moderate.
• The most common adverse events were similar in both arms: jaundice and yellowing of the eyes (known side effects of atazanavir), diarrhea, nausea, and headaches, with frequency increasing only slightly (<+1% to +3%) after week 96.
• 11% of participants in both treatment arms discontinued therapy early due to adverse events, including 3 in the cobicistat arm and 4 in the ritonavir arm who did so after week 96.
• Rates of discontinuation due to kidney-related adverse events were similar, 2.9% with cobicistat vs 3.2% with ritonavir.
• 6 people taking cobicistat and 7 taking ritonavir stopped therapy due to proximal renal tubulopathy.
• Median changes in serum creatinine were similar in both arms -- +0.13 and +0.07 mg/dL, respectively -- and were unchanged from week 48.
• Median changes in eGFR were -15 and -8 mL/min, respectively, again unchanged from week 48.
• Rates of discontinuation due to hepatobiliary adverse events (e.g., elevated bilirubin) were similar as well, 5.2% and 3.5%, respectively.
• There were no significant changes in total cholesterol, LDL ("bad") cholesterol, HDL ("good") cholesterol, triglycerides, or blood glucose in either treatment arm.

Cobicistat-boosted atazanavir plus tenofovir/emtricitabine "demonstrated durable efficacy through week 144," the investigators concluded. "Once-daily cobicistat is as safe and effective as ritonavir as a pharmacoenhancer of the protease inhibitor atazanavir."

Gallant noted that fixed-dose coformulations of atazanavir/cobicistat and darunavir/cobicistat are currently under development, as well as a new Stribild formulation containing the better-tolerated tenofovir alafenamide.

Kidney Impairment

Cheryl McDonald from Tarrant County Infectious Disease Associates and colleagues presented findings from Study 118, a trial that evaluated the safety of switching to a cobicistat-containing regimen for people with mild-to-moderate kidney impairment.

Cobicistat is associated with small increases in serum creatinine due to its effect on a transporter protein involved in tubular secretion -- reflected in the estimated glomerular filtration rate, or eGFR -- but prior studies found that it did not affect actual glomerular filtration.

This open-label study was designed to look at people with creatinine clearance (CrCl) of 50-89 mL/min at baseline. Because Stribild contains tenofovir -- which can cause renal impairment in susceptible patients -- it is approved for those with CrCl >70 mL/min, and this was an entry criterion in previous Phase 3 trials.

Most of the 73 participants were men, nearly 80% were white, 19% were black (a population with a higher rate of kidney disease), and the average age was 54 years. Median creatinine clearance at baseline was 71 mL/min; 15% had CrCl of 50-60 mL/min, 27% had 60-70 mL/min, 25% had 70-80 mL/min, and 22% had 80-90 mL/min. Some had kidney disease risk factors including hypertension (38%) and diabetes (18%), and one-third had proteinuria (protein in the urine) at baseline.

Participants started on a regimen of atazanavir or darunavir (Prezista) boosted with ritonavir plus 2 nucleoside/nucleotide reverse transcriptase inhibitors, and then switched from ritonavir to cobicistat. At the time of switching they had suppressed viral load (HIV RNA <50 copies/mL for more than 6 months) and the mean CD4 count was high at 627 cells/mm³.

Results

• At 48 weeks, 82% of participants who switched to cobicistat maintained viral suppression.
• Cobicistat was generally well-tolerated, with 10% discontinuing due to adverse events.
• Small decreases in creatinine clearance occurred soon after starting treatment, but stabilized after week 4 (median -3.8 mL/min).
• People with CrCl <70 mL/min did not experience greater changes than those with higher baseline levels (median -1.1 vs -6.6 mL/min).
• There were no clinically relevant changes in eGFR (by cystatin-C) through week 48 (median -4.7 mL/min).
• Actual GFR (by iohexol clearance) increased by +7.0 mL/min at week 4, but then declined, so overall actual GFR did not change significantly.
• 3 people experienced serum creatinine increases of >0.4 mg/dL, none of whom had confirmed proteinuria or hypophosphatemia (low phosphate).
• 1 other person developed confirmed proteinuria and 1 had confirmed hypophosphatemia.
• No participants had laboratory evidence of proximal renal tubulopathy, as indicated by more than 1 concurrent abnormality, and no one discontinued treatment for this reason.

Based on these findings, the researchers concluded, "Cobicistat may be an option for patients with CrCl 50 to <70 mL/min." They added that the safety profile in people with mild-to-moderate kidney impairment was consistent with that seen in people without impairment in previous Phase 3 studies.

9/16/14

References

JE Gallant, E Koenig, J Andrade, et al. Efficacy and Safety of Cobicistat (COBI) compared to Ritonavir (RTV) as Pharmacoenhancer for Atazanavir (ATV) plus Emtricitabine (FTC) /Tenofovir DF (TDF): Week 144 results. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-647.

C McDonald, C Martorell, M Ramgopal, et al. Efficacy And Safety of Switching the Pharmacoenhancer from Ritonavir (RTV) to Cobicistat (COBI) in HIV Patients with Renal Impairment Who Are Virologically Suppressed on a Protease Inhibitor Containing Regimen. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-1006.