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Large Study Finds Tenofovir Linked to Increased Kidney Risk

HIV positive people who took tenofovir (Viread, also in the Truvada and Atripla combination pills) were more likely to show signs of impaired kidney function, according to an observational study of more than 10,000 people described in the February 4, 2012, advance online edition of AIDS.

Tenofovir is a preferred component of antiretroviral therapy (ART) according to current U.S. and European treatment guidelines, and it is among the most widely used HIV drugs in high-income countries.

Kidney disease is known to be more common among people with HIV/AIDS, but studies to date have produced conflicting data about the association between tenofovir and kidney problems. The large, randomized pivotal trials that led to the drug's approval did not show significantly increased rates of kidney impairment, but some other studies have indicated that susceptible individuals may experience symptoms of kidney toxicity such as protein in the urine (proteinuria), elevated serum creatinine, and slowed glomerular filtration rate (GFR), a measure of how efficiently the kidneys filter the blood.

Rebecca Scherzer from the University of California at San Francisco and colleagues evaluated the association between tenofovir exposure and kidney outcomes among 10,841 HIV positive patients in the Department of Veterans Affairs HIV Clinical Case Registry who were previously treatment-naive and started antiretroviral drugs between 1997 and 2007.

Out of 59,479 HIV positive people treated by the Veterans Health Administration between 1985 and 2007, a total of 19,715 initiated treatment during the era of modern combination antiretroviral therapy (ART) starting in 1997. People with pre-existing kidney failure (long-term dialysis or kidney transplant) or incomplete data were excluded, leaving 10,841 patients in the analysis.

Most study participants (about 98%) were men, the mean age was 46 years, and about 40% were white. HIV disease status (CD4 T-cell count, HIV viral load), co-existing conditions (hypertension, diabetes, hepatitis C), and other risk factors (smoking, abnormal blood lipids) were similar for patients exposed or not exposed to tenofovir. People not taking tenofovir were slightly more likely to have impaired creatinine clearance at baseline, suggesting clinicians may have avoided prescribing the drug for people with pre-existing kidney impairment.

Results

• 3400 patients experienced proteinuria (2 consecutive measurements ≥ 30 mg/dL) during a median follow-up period of 3.9 years (total 38,132 person-years).
• 3078 patients experienced rapid decline in kidney function (≥ 3 mL/min/1.73m annual decline in estimated GFR, using MDRD method, for 2 consecutive years) (total 51,589 person-years of follow-up).
• 533 people developed chronic kidney disease (estimated GFR  < 60  mL/min/1.73m on 2 consecutive measurements at least 3 months apart) over a median follow-up period of 5.5 years (total 56,416 person-years).
• After controlling for other risk factors, longer exposure to tenofovir was associated with increased likelihood of kidney impairment:

o      34% increased risk of protein in the urine per additional year of exposure (95% CI 25%-45%; P <  0.0001);

o      11% higher risk of rapid decline in kidney function per year (95% CI 3%-18%; P <  0.0033);

o      33% increased risk of chronic kidney disease per year (95% CI 18%-51%; P <  0.0001).

• Comorbid conditions and other pre-existing kidney risk factors did not appear to worsen the effects of tenofovir.
• Associations remained similar when looking only at data from 2001 onward, and only at people who were antiretroviral-naive when they started tenofovir.
• Compared with tenofovir, other antiretroviral drugs showed weaker or inconsistent associations with kidney impairment, and there was little evidence of interaction between tenofovir and other antiretrovirals.
• Risk of kidney impairment remained elevated for at least 6 months of follow-up after stopping tenofovir, relative to never-exposed patients.

Based on these findings, the study authors wrote, "Tenofovir exposure was independently associated with increased risk for 3 types of kidney disease events, and did not appear to be reversible."

"Even after accounting for demographics, HIV-related factors, comorbidities, and other antiretroviral drugs, tenofovir remained independently associated with elevated risk for each kidney disease outcome," the researchers elaborated in their discussion. "These associations were in general similar across subgroups based on baseline comorbidities and characteristics, and few statistically significant interactions were observed."

After stopping tenofovir, "[a]ll hazard ratios remained greater than unity, which suggests that the effects of tenofovir on kidney disease risk were not reversible following discontinuation," they explained. "When we instead discretized tenofovir use as never, current, or past, we found that past and current use of [tenofovir] had increased risk of outcomes, compared to those never exposed."

"The primary mechanism by which tenofovir causes renal toxicity may involve drug accumulation within proximal renal tubules, leading to mitochondrial injury and depletion," the researchers noted, suggesting that people with certain genetic variations may be more prone to tenofovir kidney toxicity. However, tenofovir-related kidney injury may also involve acute tubular necrosis and scarring, which could account for the lack of reversibility in some individuals.

"Clinicians treating HIV-infected patients should recognize that while traditional risk factors such as hypertension, older age, and diabetes may increase the risk for kidney disease, tenofovir is associated with elevated risk even in patients without pre-existing kidney risk factors," they concluded. "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. The balance between its efficacy and probable adverse effects requires further study."

[SEE ALSO: UCSF Answers Patient and Provider Questions about Tenofovir Kidney Study].

Investigator affiliations: Department of Medicine, San Francisco VA Medical Center, and University of California, San Francisco, CA; Positive Health Program, San Francisco General Hospital, San Francisco, CA; Johns Hopkins School of Medicine, Baltimore, MD.

2/10/12

Reference

R Scherzer, M Estrella, Y Li, S Deeks, C Grunfeld, and MG Shlipak. Associationof tenofovir exposure with kidney disease risk in HIV infection. AIDS 26(7):867-875. April 24, 2012 (Epub February 4, 2012).

Other Sources

University of California at San Francisco (UCSF). Tenofovir, Leading HIV Medication, Linked with Risk of Kidney Damage. Press release. February 10, 2012. 

University of California at San Francisco (UCSF). Tenofovir: Q&A for Patients and Providers. Factsheet. February 10, 2012.