In TreatmentUpdate 191, we extensively reviewed available data from clinical trials on the Quad. This is the nickname given to a combination of the following four drugs in one pill:
- elvitegravir – an experimental integrase inhibitor
- cobicistat – a drug used to boost and maintain the concentration of elvitegravir in the blood so that once-daily dosing of the Quad is possible
- tenofovir – a popular anti-HIV drug sold under the brand name Viread and found in co-formulations with other drugs under the brand names Truvada, Atripla and Complera
- FTC (emtricitabine) – found in some co-formulations such as Truvada, Atripla and Complera
The Quad is expected to be licensed in the U.S. in August 2012 and in Canada and the European Union in the autumn of 2012.
Focus on the kidneys
The kidneys are two bean-shaped organs near the lower back. These organs filter blood, removing wastes, diverting waste into urine and returning vital substances back to the blood. The Quad contains tenofovir and because tenofovir (and many other drugs and health conditions) can affect the kidneys, monitoring kidney health from time to time is routinely done as part of the care of HIV-positive people, including those who take tenofovir-containing regimens.
A routine method of assessing kidney health is to calculate the estimated glomerular filtration rate, or eGFR. This relies on a measurement of a waste product called creatinine and one of several equations. Creatinine plays a major role in routine assessments of kidney health because when kidneys become dysfunctional, levels of creatinine in the blood rise. To measure the actual GFR (aGFR), a person’s output of urine over 24 hours would need to be collected and later analysed. When performing aGFR assessments, patients receive a non-radioactive substance called iohexol, which is filtered by the kidneys. Iohexol is given intravenously over a few minutes.
In experiments with 54 healthy HIV-negative volunteers (almost evenly balanced between men and women), researchers gave them either cobicistat, ritonavir (Norvir and in Kaletra) or placebo for seven days. Participants had either normal or mildly dysfunctional kidneys.
In analyzing participants’ kidney function, researchers found that among cobicistat users there were small decreases in eGFR, (around 10 ml/minute) and small increases in the amount of creatinine in the blood, suggestive of very mild kidney dysfunction. However, when aGFR was assessed, there were no statistically significant changes detected in cobicistat users. This shows that short-term exposure to cobicistat is safe and that eGFR is not a reliable way of assessing kidney health in cobicistat users.
Neither ritonavir nor placebo resulted in any significant changes to kidney function.
Monitoring the kidney health of Quad users will be an important part of their regular care. eGFR is the mainstay of routine kidney assessment, but if exposure to cobicistat alters eGFR in an apparently harmless way, physicians will need other ways of assessing kidney health.
What are doctors to do?
Researchers who conducted phase III clinical trials using cobicistat have suggested that doctors assess the kidney health of Quad users in the following way:
- monitor the amount of sugar in the urine
- monitor the amount of protein in the urine
- check blood samples for levels of phosphorus
These tests are highly specific and abnormal results would strongly suggest kidney dysfunction, particularly if such abnormal results persist.
A long-term view
One clinical trial testing the Quad is called GS-US-236-0102. In this study, researchers are analyzing data from nearly 700 participants who are taking either the Quad or a triple-drug co-formulation called Atripla (efavirenz + tenofovir + FTC). Gilead Sciences is continuing its trial of GS-US-236-0102 for a total of 192 weeks (four years). This study is double blind and placebo controlled—participants will not be told which combination of drugs they are taking until they leave the study. This long-term monitoring will provide important data about the safety of the Quad, as both elvitegravir and cobicistat are new drugs.
Such monitoring is important because cobicistat modestly increases the concentration of tenofovir in the blood. As a result, it is possible that in some people with pre-existing kidney issues caused by co-infection with hepatitis C virus, type 2 diabetes and higher-than-normal blood pressure, tenofovir may accumulate in the filtering apparatus (the tubules) of the kidneys. This could, in theory, result in the malfunctioning of the kidneys’ ability to filter and reabsorb substances from the blood.
In the trials used to generate data to license the Quad, women comprised only about 10% of participants. Gilead plans future studies to explore the issues of safety and effectiveness in women and people with varying degrees of kidney dysfunction.
The looming arrival of the Quad will usher in a new, potent and attractive option in HIV therapy. However, regular monitoring will be needed to assess kidney health and the potential for drug-drug interactions. Studies have found the Quad to be as effective as other commonly used therapies. Common side effects with the Quad include mild headache and nausea. Kidney dysfunction occurred in a minority of Quad users and was rarely serious. When it was serious, it was typically in participants with risk factors for kidney dysfunction. Researchers who have reviewed data on the Quad recommend that this product only be used in patients who have normal kidney function (an eGFR of 70 or more). To ensure maximum absorption, the Quad must be taken with a meal.
- DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012 Jun 30;379(9835):2429-38.
- Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012 Jun 30;379(9835):2439-48.
- Schrijvers R, Debyser Z. Quad’s in it for antiretroviral therapy? Lancet. 2012 Jun 30;379(9835):2403-5.
- German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. Journal of Acquired Immune Deficiency Syndrome. 2012; in press.