CROI 2015: Tenofovir, Atazanavir & Lopinavir Associated with Raised Risk of Chronic Kidney Disease

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Three antiretroviral drugs are associated with a slowly increasing rate of chronic kidney disease over time, researchers reported at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. Although the risk of developing chronic kidney disease was low for people with normal kidney function -- with fewer than 1% of patients in the large D:A:D cohort developing it -- the use of any of these drugs was associated with 2 to 3 times higher risk of kidney disease developing over the course of 5 years on the drug.

[Produced in collaboration with Aidsmap]

In the case of tenofovir (Viread, also in Truvada and a number of single-tablet antiretroviral regimens), the rate of chronic kidney disease remained 2 to 3 times above normal levels after the drug was stopped, at least up to 2 years after it was withdrawn.

In contrast, while people taking abacavir (Ziagen, also in Epzicom) or other boosted protease inhibitors also experienced a rise in the rate of chronic kidney disease, the risk did not accumulate over time, and appeared to be related to patient factors, rather than the drug.

The D:A:D Study Findings

This study was the latest of a number of studies arising from the D:A:D (Data collection on Adverse events of anti-HIV Drugs) cohort, which has also provided data previously on the link between specific antiretroviral drugs and the risks of cardiovascular disease and diabetes.

In this analysis, 23,560 patients were studied between 2004 and 2012. During this time, 210 of them (0.9%) developed chronic kidney disease. This was defined as the development of an estimated glomerular filtration rate (eGFR) below 60 milliliters per minute per 1.73 square meters of body area (mL/min/1.73m2) after having had normal kidney function. People who already had an eGFR rate below 90 mL/min/1.73m2 at the start of the study were excluded.

A majority of the study participants (70%) were male and 41% were non-white, though detailed information on ethnic background was not gathered.

A number of factors made people more likely to develop chronic kidney disease. Unsurprisingly, the average age of those who did not develop chronic kidney disease was 39, but it rose to 47 in those who did, as kidney function tends to decline with age. Having high blood pressure was associated with twice the risk of chronic kidney disease, hepatitis C with more than twice the risk, and diabetes or cardiovascular disease with three times the risk. Having had an AIDS diagnosis or a low CD4 nadir (lowest-ever level) also increased the likelihood. Although people who inject drugs formed only 13% of study participants, 31% of those with chronic kidney disease were injection drug users. These risks are not independent -- for instance people who inject drugs are more likely to have hepatitis C.

Over the course of the 8 years of observation, 29% of participants took tenofovir, 6% took ritonavir-boosted atazanavir (Reyataz), 22% took boosted lopinavir (Kaletra), 22.5% took abacavir, and 17% took other boosted protease inhibitors such as saquinavir (Invirase) or darunavir. The average length of drug exposure varied from 2 years on abacavir to 6 months on boosted atazanavir.

In the case of 3 of the drugs, the risk of chronic kidney disease rose over time. By 6 years on tenofovir, the risk of chronic kidney disease was 2%. It was 4% after 6 years on boosted atazanavir or on boosted lopinavir. In the case of abacavir, the risk of chronic kidney disease did rise after people started the drug, but it did not accumulate over time. The same was true of other boosted protease inhibitors, where chronic kidney disease may be a temporary effect caused by the ritonavir booster. In the case of abacavir, the raised risk may be due to "channeling bias," whereby doctors prescribe it in preference to tenofovir to people who already have risk factors for chronic kidney disease.

Taking tenofovir was associated with a 12% increase in the risk of developing chronic kidney disease per each additional year on the drug, boosted atazanavir with a 27% raised risk, and boosted lopinavir with a 16% raised risk. In contrast, after adjusting for patient factors, no additional risk was observed with abacavir or other boosted protease inhibitors.

After 5 years, the risk of chronic kidney disease increased by 75% for patients taking tenofovir, 111% (i.e., 2.1 times higher) for patients on boosted lopinavir, and 227% (i.e., nearly 3.3 times higher) for patients on boosted atazanavir.

The study also looked at what happened after patients stopped taking tenofovir. The risk of developing chronic kidney disease was greatly raised for patents who stopped tenofovir, because many would stop due to kidney disease. The risk was 10 times higher than average for patients who stopped, 7 times higher than average 6-12 months after stopping, and 2-3 times higher 12-24 months after stopping. So although the risk of developing new chronic kidney disease did drop, it remained higher than average among people who had previously taken tenofovir.

Presenter Amanda Mocroft said that D:A:D still did not have enough data to look at other individual drugs, including other individual protease inhibitors. Nonetheless, this study gives more precise figures for the risk posed to patients without pre-existing kidney disease of developing chronic kidney disease. Although chronic kidney disease remains quite uncommon -- and these risk increases are lower than those posed by conditions such as hypertension and diabetes -- doctors will no doubt wish to take them into consideration when choosing antiretrovirals for people with HIV in their care.

3/10/15

Reference

A Mocroft, JD Lundgren, M Ross, et al. Exposure to Antiretrovirals (ARVs) and Development of Chronic Kidney Disease (CKD). 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 142.