The first-line HIV treatment tenofovir was associated with increased incidence of proteinuria, rapid kidney function decline, and chronic kidney disease (CKD) in a large observational study of patients from the Veterans Health Administration. The study was published online ahead of print by AIDS.
“Our findings show that all users of tenofovir who are HIV infected do in fact have higher risks either of eGFR [estimated glomerular filtration rate] decline or of proteinuria, which are both harmful outcomes and remarkably uncorrelated with one another,” said senior author Michael G. Shlipak, MD, MPH, Chief of the Division of General Internal Medicine at San Francisco VA Medical Center.
Tenofovir was first approved as an anti-HIV drug in October 2001, and it is now used in about half of all antire-troviral regimens and as part of post-exposure prophylaxis. The agent's association with kidney disease risk has been controversial, with different studies yielding disparate results.
In this new study, the link between tenofovir, which is now also indicated for hepatitis B treatment, and kidney risk was seen regardless of whether or not patients had baseline risk factors for CKD, such as hypertension or diabetes, Dr. Shlipak said.
“The corollary is that when we extended follow-up of those who stopped tenofovir, these risks did not quickly go away. We don't know how persistent they will be. As far as we know, this is persistent—permanent—until we see otherwise.”
The retrospective study started with a national sample of all 19,715 HIV-infected individuals from the Department of Veterans Affairs HIV Clinical Case Registry who initiated antiretroviral therapy between 1997 and 2007.
It excluded those with prevalent kidney failure (patients who were on dialysis or had received a transplant) and those lacking at least one HIV-1 viral load, CD4 count, outpatient visit, and assessment of kidney function—largely those who were being treated outside of the VA system—leaving 10,841 individuals for analysis.
Patients who used and did not use tenofovir as part of their regimen were similar in terms of comorbidities, HIV control on highly active antiretroviral therapy, blood pressure, and proteinuria. The proportion of white patients was higher in the tenofovir group than in the non-tenofovir group—46% vs 39%—while the proportion of patients with baseline eGFR less than 60 was slightly higher among non-tenofovir patients.
Primary outcomes were time to first occurrence of proteinuria (defined as two consecutive urine dipstick measurements of 30 mg/dL or greater), rapid decline in kidney function (defined as an annual decline of 3 mL/min/1.73 m2 or higher for two consecutive years), and chronic kidney disease (defined by two consecutive measures of eGFR below 60 mL/min/1.73 m2, where consecutive measures were taken at least three months apart and not during inpatient periods). Estimated GFR was calculated using the abbreviated Modification of Diet in Renal Disease formula.
34% Higher Proteinuria Risk
Some 4,303 participants had received tenofovir by the end of the study, and 6,538 had not. The median observation period per individual ranged from 3.9 years for proteinuria to 5.5 years for chronic kidney disease. Among the tenofovir patients, the mean duration of use was 1.3 years.
After adjustment for demographic characteristics, baseline comorbidities, use of other antiretroviral drugs, and current measurements of HIV-related and other factors, each year of exposure to tenofovir was associated with a 34% increased risk of proteinuria, 11% increased risk of rapid kidney function decline, and 33% increased risk of CKD.
“The calculated annual risks for developing proteinuria in our study were 13% for tenofovir users versus 8% for nonusers,” Dr. Shlipak said.
“For every 20 tenofovir users, there would be an extra case of proteinuria each year. … CKD is a rare outcome because most of these patients start with really high eGFR, so that is 2% versus 1%.”
Tenofovir was the only antiretroviral drug used by study participants that was statistically significantly associated with all three outcomes.
Michael J. Ross, MD, a nephrologist and Associate Professor of Medicine at Mount Sinai School of Medicine, said it has been difficult to quantify injury from tenofovir in most large studies, “and this does a better job than previous studies.”
One limitation of the study, though, is that the population was overwhelmingly male (97.7%); however, there is no mechanistic reason to believe that the drug behaves differently in women. Dr. Shlipak said he has seen the same pattern of toxicity in women and believes the findings apply to them as well.
The study was supported by the National Institutes of Health, the National Center for Research Resources, the American Heart Association Established Investigator Award, and the VA's Public Health Strategic Health Care Group, which were administered by the Northern California Institute for Research and Education, and with resources of the San Francisco VA Medical Center.
‘Good Antiretroviral Drug’
“It is important to remember that tenofovir is a good antiretroviral drug” that should not be given up too readily because of the potential for developing kidney disease, said study coauthor Michelle M. Estrella, MD, MHS, a nephrologist and Assistant Professor of Medicine at Johns Hopkins University School of Medicine.
Leah Haseley, MD, Clinical Assistant Professor of Medicine in the Division of Nephrology at the University of Washington Harborview Medical Center, agreed.
“I've very biased for tenofovir,” she said. “It is now used with HBV [hepatitis B virus] and HIV/HBV coinfection; it has low incidence of side effects, once daily dosing; patients really like it; it works really well.
“I would much rather have my HIV/hep B in remission and be walking around with a creatinine of 1.4 or 1.6 for the next ten years.”
Tenofovir treatment is not the only culprit behind kidney disease in patients with HIV, Dr. Ross noted.
“Sometimes I think kidney doctors and others are too quick to point the finger at tenofovir when the kidney function gets worse. It is important to keep in mind that patients with HIV are more prone to kidney disease. That was true even before tenofovir was available. They need to be aware that tenofovir is a possibility but that there clearly are other reasons why kidney function could be getting worse.”
While it is easy to call for more monitoring of kidney function, there is no data demonstrating that it leads to better clinical outcomes, he said. “We don't know if avoiding tenofovir is going to help them in the long run because they may end up on some less-effective regimen” for their HIV.
Monitoring Kidney Function
Dr. Estrella said that she hopes the study “will push providers to begin at least monitoring kidney function in these patients, which doesn't always happen.”
Since nephrologists tend to see this patient group only after the condition has developed and tenofovir therapy has been stopped, the physician providing HIV treatment is the one who should be most attuned to the need to regularly monitor kidney function for signs of potential tenofovir toxicity, she said.
There is a spectrum of tenofovir renal toxicity, Dr. Estrella noted. Some patients develop an abrupt rise in serum creatinine over a period of weeks. Those patients generally receive appropriate care. But other presentations can be more subtle.
“It is more of a creatinine creep over time,” she said. “Or with others, it may not necessarily be a rise in their serum creatinine but other signs of renal toxicity in terms of tubular dysfunction. They have proteinuria, leakage of phosphate in the urine, they can be leaking glucose—any of those can be present without necessarily triggering a rise in serum creatinine.”
Dr. Haseley recommended that more specific tests for signs of early tubular dysfunction be conducted.
“Retinol-binding protein is the most sensitive for tubular proteinuria,” she said. “We should be screening for that. We should be screening for transmembrane phosphate excretion, which goes up with tubular injuries. And if several of them turn positive and they indicate that there is proximal tubular damage, we should consider stopping tenofovir.
“As nephrologists we can test earlier to see if there are any signs of stress. That is what I would recommend. And if there are no signs of stress, then I would go ahead and continue the tenofovir.”
It is crucial to “understand at a very basic cellular level how tenofovir is injuring the cells,” Dr. Ross said, which would help identify biomarkers for screening patients who are at high risk of toxicity. He said he hopes such work will be done with an eye toward technologies and cost structures that are applicable to developing countries where the drug also is used.
Creatinine and proteinuria are “blunt tests that do not detect kidney disease until it is relatively advanced,” Dr. Shlipak said. He believes other measures, such as cystatin C, are earlier and better markers of kidney damage in HIV patients.
There is the suggestion that “-certain proteins are more specific to different parts of the nephron, so instead of overall proteinuria, we could say this patient has tubular damage, that sounds like tenofovir, versus albuminuria, which might be diabetes or the HIV,” Dr. Shlipak added.
He hopes to have an analysis of longer-term data from the VA registry completed by the end of the year and anticipates that the analysis will confirm and extend the researchers' initial findings.
Dr. Shlipak also is developing individual risk predictors for tenofovir toxicity that he would like to make available as an online spreadsheet for ease of clinical use.
“Right now we really have an aggregate summary, and patient care is individualized,” he said