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ICAAC 2011: Cobicistat Matches Ritonavir as Booster, Studies Clarify Effects on Kidney Function

The experimental pharmacoenhancing agent cobicistat continues to work as well as ritonavir for boosting other antiretroviral drugs, according to findings published in the September 24, 2011, issue of AIDS.

In addition, 2 studies presented this week at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) shed further light on cobicistat's impact on the kidneys, indicating that it reduces estimated but not actual glomerular filtration rate (GFR) by altering activity in the proximal renal tubules.

Cobicistat (formerly GS 9350) inhibits the activity of the CYP3A enzyme in the liver, which slows processing and raises blood levels of other drugs metabolized by the same pathway. But unlike the sole approved booster, ritonavir (Norvir), cobicistat itself is not active against HIV. Cobicistat is a component of the investigational "Quad" single-tablet regimen (combined with elvitegravir, tenofovir, and emtricitabine) and a pipeline dual combination pill with darunavir (Prezista).

Richard Elion and fellow investigators with the GS-US-216–0105 Study Team assessed the safety and efficacy of cobicistat versus ritonavir as pharmacoenhancers for atazanavir, when administered with tenofovir/emtricitabine (Truvada) for first-line HIV treatment.

This double-blind, partially placebo-controlled study included 85 treatment-naive patients with HIV viral load of at least 5000 copies/mL and CD4 T-cell count > 50 cells/mm³ (mean of about 350 cells/mm³) at baseline. Most participants (about 90%) were men, more than half were white, and the mean age was about 35 years.

Participants (stratified by viral load above or below 100 000 copies/mL) were randomly assigned (2:1) to receive either 150 mg cobicistat or 100 mg ritonavir once-daily, both with open-label atazanavir and fixed-dose tenofovir/emtricitabine.

Results

• 84% of cobicistat recipients and 86% of ritonavir recipients achieved undetectable HIV RNA (< 50 copies/ mL) at week 24.
• At week 48 the corresponding percentages were 82% and 86%, respectively.
• Average CD4 cell increases at week 24 were 203 cells/mm³ in the cobicistat arm and 199 cells/mm³ in the ritonavir arm (208 and 177 cells/mm³, respectively, at week 48).
• 36% of cobicistat recipients and 48% of ritonavir recipients experienced treatment-related adverse events.
• Almost all participants (96% and 100%, respectively) developed hyperbilirubinemia -- a known side effect of atazanavir -- and 14% and 17%, respectively, developed jaundice or ocular icterus (yellowing of the skin or eyes).
• 4% of cobicistat recipients and 3% of ritonavir recipients discontinued treatment due to adverse events through week 48.
• Mean estimated GFR (eGFR; Cockcroft-Gault, mL/min) -- a marker of kidney function -- decreased by -9 in the cobicistat arm and by -4 in the ritonavir arm.
• The decline in estimated GFR was evident by week 2, reached a low point by week 24 (-15 and -14, respectively), and remained stable through week 48 (-13 and -14, respectively).

Based on these findings, the study authors concluded, "Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with [emtricitabine/tenofovir] achieved comparable rates of virologic suppression and CD4 cell count increase with satisfactory safety profiles."

"Mean eGFR decreased from baseline in both treatment groups, was statistically significantly greater only at week 2, reached a nadir by week 24, and did not progress further through week 48," they elaborated in their discussion.

"Three [atazanavir/cobicistat] participants had confirmed grade 1 elevation of serum creatinine," they continued. However, "[n]o participant receiving either treatment developed persistent serum electrolyte or urinalysis abnormalities, or discontinued or interrupted study treatment due to change in serum creatinine or eGFR."

Kidney Function

Researchers and patient advocates are carefully watching for signals of kidney toxicity with cobicistat, given the significantly greater early estimated GFR increase in studies to date. This is especially a concern if cobicistat is used with tenofovir, which can also cause kidney problems in susceptible individuals.

Gilead scientists presented 2 related posters at ICAAC, one looking at the effect of cobicistat on GFR in people with normal and impaired kidney function, the other examining the effect of cobicistat and other drugs on proximal renal tubule cell uptake and efflux transporters.

The glomeruli and the proximal renal tubules are 2 distinct parts of the kidney with different functions. Creatinine is eliminated by a combination of tubular secretion and glomerular filtration. Agents that affect transporters of creatinine in the tubules therefore can cause changes in serum creatinine that do not reflect actual impaired filtration in the glomeruli.

In Phase 1 and 2 studies, some participants using cobicistat experienced small increases in serum creatinine. Due to the way creatinine clearance is calculated and GFR is estimated, creatinine increases can lead to corresponding decreases in estimated GFR.

To tease out the true impact of cobicistat on kidney function, the first Gilead team compared estimated GFR and actual GFR using iohexol, a probe drug excreted exclusively by glomerular filtration.

They found that while cobicistat can cause mild increases in serum creatinine, leading to a small decrease in estimated GFR, it does not affect actual GFR as measured by iohexol.

"Alteration in eGFR but not in aGFR suggests cobicistat affects proximal tubular secretion of creatinine," they concluded. "The time to onset, magnitude and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of transporters in the kidney tubules."

A number of widely used drugs have effects on eGFR related to creatinine elevation. A second Gilead team looked at the effect of cobicistat and other drugs on creatinine uptake in the proximal renal tubules and efflux into the urine.

The researchers used in vitro laboratory models to evaluate the effect of various drugs on proximal renal tubule cell transporters thought to play a role in tubular creatinine secretion (including P glycoprotein, OCT2, OCTN1, MATE1, MATE2-K, MRP2, and BCRP).

Cobicistat was among the drugs -- along with the gastric acid blocker cimetidine and the antibiotic trimethoprim -- that affected creatinine efflux into the urine. In contrast, the experimental HIV integrase inhibitordolutegravir facilitated uptake from plasma into the proximal tubules.

These findings suggest that the early increase in serum creatinine observed in some people taking cobicistat may be due to an effect on tubular secretion, not impaired glomerular filtration of creatinine.

The first team also found that cobicistat exposure was similar in patients with severe kidney impairment and people with normal function.

Taken together, they concluded, these findings are "consistent with renal excretion being a minor pathway (< 10%) for cobicistat elimination."

Investigator affiliations:

AIDS report: Whitman Walker Clinic, Washington, DC; Community Research Initiative of New England, Boston, MA; Therapeutic Concepts P.A., Houston, TX; TribalMed, Seattle, WA; Southwest C.A.R.E. Center, Santa Fe, NM; Gilead Sciences Inc., Foster City, CA.

ICAAC H2-804: Gilead Sciences, Foster City, CA.
ICAAC A1-1724: Gilead Sciences, Foster City, CA.

9/23/11

References

R Elion, C Cohen, J Gathe, et al (GS-US-216–0105 Study Team). Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir DF in the initial treatment of HIV infection. AIDS25(15): 1881-1886 (abstract). September 24, 2011.

P German, C Liu, D Warren, et al. Effect of Cobicistat on Glomerular Filtration Rate (GFR) in Subjects with Normal and Impaired Renal Function. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract H2-804.

EI Lepist, BL Murray, L Tong, et al. Effect of Cobicistat and Ritonavir on Proximal Renal Tubular Cell Uptake and Efflux Transporters. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract A1-1724.