Tenofovir associated with increased risk of kidney disease

Treatment with tenofovir is associated with a modestly increased risk of three key markers of kidney disease, US investigators report in the online edition of AIDS.

The large study involved over 10,000 patients who started antiretroviral therapy between 1997 and 2007. Patients treated with tenofovir were significantly more likely to develop proteinuria (high levels of protein in urine), experience a rapid decline in kidney function and have an estimated glomerular filtration rate below 60 ml/min/1.73 m³ (chronic kidney disease, or CKD). The risk of kidney disease also remained elevated for patients who discontinued tenofovir therapy.

“Even after accounting for demographics, HIV-related factors, comorbidities, and other antiretroviral drugs, tenofovir remained associated with an increased risk for each kidney disease outcome,” write the investigators.

The authors stress the drug’s association with proteinuria and CKD, noting “each is independently associated with cardiovascular disease and death in the setting of HIV infection.”

However, they also emphasise the importance of tenofovir in HIV treatment and that the risk of kidney disease associated with the drug should be balanced against its potential benefits. Moreover, the authors do not regard their research as definitive and call for further research.

Patients with HIV have an increased risk of kidney disease. The exact causes are controversial, but appear to include the effects of HIV itself, traditional risk factors such as hypertension and diabetes, co-infection with hepatitis C, and possibly the side-effects of some antiretroviral drugs.

The research exploring the association of tenofovir (Viread, also available in the combination pills Truvada and Atripla) with kidney disease is contradictory. Although some studies found an association between the drug and kidney dysfunction, this was not the case with others.

Differences in patient populations, limited sample sizes and lack of access to the appropriate laboratory data could be the reason for the lack of concordance between studies.

It is important to establish if the drug does increase the risk of kidney disease. Tenofovir is widely used in first-line antiretroviral therapy and also has an important role in pre-exposure prophylaxis (PrEP) regimens. Moreover, kidney dysfunction is a risk factor for cardiovascular disease, which is an increasingly important cause of illness and death in patients with HIV.

Therefore investigators from the US Department of Veterans Affairs designed a study to determine the effects of tenofovir exposure on the risk of kidney disease.

Their study population comprised 10,841 patients who started antiretroviral therapy for the first time over a ten-year period between 1997 and 2007. A total of 4,303 individuals were exposed to tenofovir. There was no difference between the tenofovir-treated patients and the patients treated with alternative antiretroviral drugs in terms of the prevalence of diabetes and hypertension, hepatitis C co-infection, CD4 cell count and viral load. Prevalence of proteinuria at baseline was comparable between the two groups of patients.

The overall mean age was 46 years and 98% of individuals were men.

Mean duration of tenofovir therapy was 1.3 years. The investigators acknowledge that this short period of treatment was a limitation of their study.

The study did not report on the absolute risk of kidney disease. It is important to bear in mind that previous studies have consistently shown that kidney problems develop in fewer than one in 20 people who take the drug, and serious impairment has been seen in fewer than one in 100. The classic risk factors, such as diabetes, high blood pressure and untreated HIV infection, continue to be more important causes of chronic kidney disease in people living with HIV. Just like anyone else, people with HIV are also vulnerable to acute kidney injury due to inflammation, infection or medications that can damage the kidneys.

In the entire study population there were 3400 proteinuria events in 38,132 person-years of follow-up; 3,078 rapid declines in kidney function during 51,589 person years; and 533 CKD events in 56,416 person years.

In all the investigators’ models, both any use of tenofovir and cumulative exposure to the drug was strongly associated with a significant increase in the risk of all three markers of kidney disease (p = 0.0033 to p < 0.0001).

Therapy with tenofovir was also associated with the presence of both proteinuria and CKD (p  = 0.0014), a more stringent measure of kidney disease.

Multivariate analysis which controlled for other variables that could affect the risk of developing kidney disease showed that each year of tenofovir treatment was associated with a 34% increased risk of proteinuria (95% confidence interval 25% - 45%, p< 0.0001), 11% increased risk of rapid decline in kidney function (95% CI 3% - 18%, p=0.0033) and a 33% increased risk of chronic kidney disease (95% CI 18% - 51%, p<0.0001).

Patients who ceased tenofovir therapy continued to have an increased risk of CKD which was of borderline significance (HR = 1.22 per year; 95% CI, 0.99-1.50, p = 0.055).

“The effects of tenofovir on kidney disease risk were not reversible following discontinuation,” comment the authors.

However the presence of other risk factors for kidney disease did not increase the risk of kidney disease while taking tenofovir; indeed, the association between tenofovir treatment and kidney disease was significantly weaker in older people, diabetics and people with cardiovascular disease or hypertension when compared to younger people or those without these conditions.

Tenofovir was the only anti-HIV drug with significant associations for all three measures of kidney disease used in the study. Nevertheless, several other drugs increased the risk of individual measures of renal dysfunction. For instance, ritonavir (Norvir) increased the risk of proteinuria (p < 0.0001). Atazanavir (Reyataz) was associated with a rapid decline in kidney function (p = 0.0035), and indinavir (Crixivan) had a significant association with CKD (p = 0.0019).

The authors were well aware of the apparent significance of their findings and their potential to cause alarm among patients. They therefore believe it is important to balance the benefits and risks of therapy with the drug.

“Despite tenofovir’s association with progressive kidney disease, it is an important component of effective antiretroviral therapy that may be required in many patients to control viral load,” conclude the investigators. “The balance between its efficacy and probably adverse events requires further study.”

NOTE: this article was amended on 16.2.2012 to correct an error, which referred to a risk associated with abacavir. This should have read `indinavir`.