Tenofovir, boosted atazanavir and boosted lopinavir are associated with cumulative risk of developing chronic kidney disease

Three antiretroviral drugs are associated with a slowly increasing rate of chronic kidney disease over time, the Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA, heard today.

Although the risk of developing chronic kidney disease (CKD) was low for people with normal kidney function, with fewer than 1% of patients in the large cohort studied developing it, the use of any one of these three drugs was associated with two to three times the risk of chronic kidney disease developing over the course of five years on the drug, delegates heard.

In the case of tenofovir, the rate of chronic kidney disease remained two to three times over normal levels after the drug was stopped, at least up to two years after it was withdrawn.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

cardiovascular

Relating to the heart and blood vessels.

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.

hypertension

When blood pressure (the force of blood pushing against the arteries) is consistently too high. Raises the risk of heart disease, stroke, kidney failure, cognitive impairment, sight problems and erectile dysfunction.

In contrast, while people taking abacavir or boosted protease inhibitors (PIs) 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 case, 23,560 individual 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 millilitres per minute per 1.73 square metres body area (ml/min/1.73m2). The development of chronic kidney disease was defined as developing it after having had normal kidney function, so people who already had an eGFR rate below 90ml/min/1.73m2 at the start of the study were excluded.

Seventy per cent of the study participants 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 in those who did not develop chronic kidney disease was 39, but it was 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 also increased the likelihood. Although people who inject drugs formed only 13% of the study participants, 31% of those with chronic kidney disease were people who inject drugs. These risks are not independent (for instance people who inject drugs are more likely to have hepatitis C).

Over the course of the eight years, 29% of participants took tenofovir, 6% boosted atazanavir, 22% boosted lopinavir, 22.5% abacavir and 17% other boosted PIs such as saquinavir or darunavir. The average length of drug exposure varied from two years on abacavir to six months on boosted atazanavir.

In the case of three of the drugs, the risk of chronic kidney disease rose over time. By six years on tenofovir, the risk of chronic kidney disease was 2.2%. It was 4% after six years on boosted atazanavir and 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 PIs, where chronic kidney disease may be a temporary effect caused by the ritonavir used to boost the PI. In the case of abacavir, the raised risk in people taking it may be due to 'channelling 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 PIs.

After five years, the risk of chronic kidney disease was raised by 75% in patients taking tenofovir, 111% (i.e. 2.1 times higher) in patients on boosted lopinavir, and 227% (i.e. nearly 3.3 times higher) in 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 in patents who stopped tenofovir, because many would stop due to chronic kidney disease. It was ten times higher than average in patients who stopped, seven times higher than average between six to twelve months after stopping, and 2-3 times higher 12-24 months after stopping, so although the risk of developing chronic kidney disease anew did drop, it remained higher than average in 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 PIs. Nonetheless, this study gives more precise figures for the risk posed to patients of developing chronic kidney disease, without pre-existing kidney disease. Although chronic kidney disease remains quite uncommon and these risks 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.

References

Mocroft A et al. Exposure to Antiretrovirals (ARVs) and Development of Chronic Kidney Disease (CKD). 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, USA, abstract 142, 2015.

View a webcast of this presentation here.

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