EuroSIDA study suggests tenofovir increases risk of chronic kidney disease

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An analysis from the large EuroSIDA study found that people who take antiretroviral regimens including tenofovir (Viread) appear to be more likely to develop chronic kidney disease, researchers reported at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) last week in San Francisco. Weaker associations were seen for indinavir (Crixivan) and atazanavir (Reyataz).

People with HIV are known to have an elevated risk of kidney impairment compared with the general population, but it is not clear whether this is due to chronic infection itself, antiretroviral drugs, traditional risk factors or some combination of factors.

While some studies have shown an increased risk of kidney disease in people who take tenofovir, other studies have failed to find the same relationship.

Glossary

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

statistical significance

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are ‘statistically significant’. 

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

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.

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

The EuroSIDA review presented at CROI is the largest study to date, with a substantial period of follow-up, and shows clearly that people taking tenofovir were more likely to suffer a decline in kidney function.

However the study also found that two other drugs – indinavir and atazanavir – were associated with an increased risk of kidney disease, with lopinavir/ritonavir also implicated in the development of kidney disease, although less so.

EuroSIDA investigators performed a study of rates and risk factors for chronic kidney disease – a persistent reduction in glomerular filtration rate (GFR) to less than 60 ml/min/1.73m2 or presence of albumin (a blood protein) in the urine. GFR is a measure of how efficiently blood is filtered in capillary bundles in the kidney called glomeruli.

For this study, confirmed chronic kidney disease was defined as persistent (two assessments at least three months apart) estimated GFR (eGFR) of 60 or less if the level at baseline was above 60, or a 25% decline if it started at 60 or below, using the Cockcroft-Gault formula.

EuroSIDA is an ongoing prospective observational study that now includes more than 16,500 HIV-positive participants seen at 103 centres. In the kidney disease study, researchers analysed data from 6843 cohort participants who had at least three available serum creatinine measurements (used to estimate GFR). They were followed for an average of about four years, accumulating a total of 21,482 person-years of data.

Three-quarters of the participants were men, more than 85% were white, and the median age was 43 years. Looking at kidney disease risk factors, about 23% were co-infected with hepatitis C, 22% had high blood pressure, and 5% had diabetes.

About 90% had ever been exposed to antiretroviral drugs. Current CD4 cell count was relatively high, at 450 cells/mm3, but about one-third had a prior AIDS diagnosis.

A total of 225 study participants (3.3%) progressed to chronic kidney disease during follow-up, for an incidence rate of 1.1 per 100 person-years. The rate increased over time, from less than 0.5% after the first year, to 1.5% after the second year, to about 4.5% after four years of follow-up.

The researchers then assessed the link between specific antiretroviral drugs and development of kidney disease. Exposure duration was divided into five categories: never used, 0-1 years, 1-2 years, 2-3 years and more than three years. There are not yet enough follow-up data to determine associations with the newest agents including darunavir (Prezista), etravirine (Intelence), maraviroc (Celsentri) and raltegravir (Isentress).

Cumulative exposure to four drugs was linked to higher likelihood of developing chronic kidney disease: the nucleotide reverse transcriptase tenofovir (Viread, also in the Truvada and Atripla combination pills), and three protease inhibitors, indinavir (Crixivan), atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra).

People never exposed to tenofovir had an incidence rate of 0.7 per 100 person-years, whilst people with three or more years of exposure had an incidence rate of 2.4 per 100 person-years. Considering drug exposure alone, the incident rate ratio (IRR) was 1.32, or about 32% higher. After adjusting for other factors, IRR fell to 1.16, which remained statistically significant.

For indinavir, the incidence rate was 0.6 per 100 person-years without exposure compared to 1.9 per 100 person-years with the longest exposure. The IRR was 1.18 – or 18% higher – in isolation and 1.12 after adjustment (also statistically significant).

For atazanavir, the incidence rate was 0.8 per 100 person-years without exposure vs 3.9 per 100 person-years with the longest exposure. Here, the unadjusted IRR was 1.48 and the adjusted IRR was 1.21 (again significant).

Lopinavir/ritonavir showed the weakest link with kidney disease; unlike the other three drugs, risk did not rise consistently with longer exposure, though it was higher after three years. The unadjusted IRR was 1.15 and the adjusted IRR was 1.08; this was statistically significant, but by a narrower margin.

Overall, general patterns for the four drugs were similar when two other methods (MDRD and CKD-EPI) were used to calculate eGFR, when applying alternative definitions of chronic kidney disease, and when 'censoring' other implicated drugs used at the same time.

No other specific antiretroviral drugs or regimen types were significantly associated with a higher risk of chronic kidney dysfunction. However, male sex, older age, lower baseline eGFR, AIDS during follow-up, higher viral load, high blood pressure, diabetes, hepatitis C, and non-AIDS malignancies were independent predictive factors.

Among study participants who stopped taking tenofovir during follow-up, the risk of developing chronic kidney disease was fourfold higher compared with never-exposed patients during the first 12 months (IRR 4.05), but was similar thereafter (IRR 1.12).

Presenter Ole Kirk suggested the high rate during the first year probably reflected patients who discontinued tenofovir due to kidney concerns. Among people who stopped atazanavir or lopinavir/ritonavir, the kidney disease risk was similar to that of unexposed patients.

The EuroSIDA investigators concluded that increasing exposure to tenofovir was associated with a higher risk of chronic kidney disease. An association was also identified for indinavir and atazanavir, but results for lopinavir/ritonavir were less clear. These findings, they noted, are consistent with other studies.

The researchers suggested that long-term kidney impairment may be due to differing mechanisms: glomerular and tubular dysfunction for tenofovir, and build-up of drug crystals or kidney stones for the three protease inhibitors.

Although biologically plausible, they added, the exact pathogenesis behind these findings remains to be elucidated.

Referencesw

Kirk O et al. Chronic kidney disease and exposure to ART in a large cohort with long-term follow-up: the EuroSIDA study. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 107LB, 2010.

Further information

You can view the abstract on the official conference website.

You can also view a webcast and slides of this session on the official conference website.