February 13, 2012
Tenofovir Increases Risk of Irreversible Kidney Disease
by Tim Horn
The nucleotide reverse transcriptase inhibitor tenofovir is associated with an increased risk of kidney damage and chronic kidney disease that increases over time and doesn’t appear to be immediately reversible, according to a new analysis by University of California at San Francisco (UCSF) researchers that’s published online ahead of print by the journal AIDS.
According to the paper, based on a review of more than 10,000 Veterans Administration medical records, the risk of proteinuria—signs of protein in the urine, a marker of kidney damage—increased 34 percent every year a person living with HIV remained on the drug. The risk of chronic kidney disease increased, annually, by 33 percent. There was also an 11 percent higher risk of rapidly declining kidney function for every year tenofovir was continued.
Importantly, Rebecca Scherzer, MD, of UCSF and her colleagues note, these increases were independent of other factors that cause kidney disease—notably age, diabetes, high blood pressure, smoking, hepatitis C virus (HCV) coinfection and various HIV-specific parameters—confirming that tenofovir therapy itself is an important risk to consider as antiretroviral treatment is started and continued.
Tenofovir—the active ingredient in Viread and a component of Atripla, Truvada and Complera—is widely prescribed, as it is considered a first-line treatment of HIV infection. “[It] is currently used in approximately half of all antiretroviral regimens and as part of post-exposure prophylaxis,” Scherzer and her colleagues write.
Clinical trials leading up to the approval of tenofovir as Viread in 2001 didn’t find significant kidney problems, though Scherzer’s team notes that many of these studies excluded individuals living with, and at risk for, renal disease. More recent studies have reported an association with tenofovir and kidney disease, though usually in small numbers of people and typically in those who were older, with low CD4 cell counts and other HIV- and non-HIV-related health problems.
As many of these studies—some of which didn’t find any obvious connection between tenofovir and kidney disease—were small and may not have been based on appropriate laboratory data, Scherzer and her colleagues turned to a national sample of closely monitored patients, notably those receiving HIV care through the Veterans Health Administration. The analysis included 10,841 veterans living with HIV starting therapy for the first time between 1997 and 2007. Patients in the analysis were on average 46 years old when they started HIV treatment. Roughly half were black, most (more than 97 percent) were male, nearly 40 percent had high blood pressure, 7 percent had diabetes and 19 percent were smokers.
By the end of the study period, 4,303 patients had used tenofovir for an average of 1.3 years; Scherzer and her colleagues pointed out that this short follow-up time was a limitation of the study. The maximum length of tenofovir-inclusive antiretroviral therapy was about six years.
There were 3,400 incidents of proteinuria among all patients included in the analysis, notably 13 percent of those using tenofovir and 8 percent of those not using a tenofovir-inclusive regimen. Among those using tenofovir, the hazard ratio was 1.34 per year—the drug was associated with an annual 34 percent increase in the risk of protein leaking out of the kidneys, confirmed by two consecutive urine dipstick tests.
Rapid decline in kidney function—consistent drops in the estimated glomerular filtrate rate (eGFR) for at least two years—was documented 3,078 times in 9 percent of tenofovir users and 5 percent of those who never used the drug. Among those using tenofovir, the hazard ratio was 1.11—an 11 percent increase in the annual risk of a kidney-related complication associated with a higher risk of death.
As for chronic kidney disease—defined as two consecutive eGFR calculations below 60 milliliters (per minutes per 1.73 squared meters)—there were 1,712 incidents in the study population, notably 2 percent of tenofovir users and 1 percent of those who never used the drug. The annual increase in the risk was 33 percent among those using tenofovir.
All of the annual increases in the kidney disease markers were statistically significant, meaning they were too great to have occurred by chance. And importantly, the risks associated with tenofovir were documented after adjusting the data for other known risk factors. “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 authors remarked.
Interestingly, and in contrast with the findings of other studies, Scherzer and her colleagues noted that the presence of other chronic kidney disease risk factors upon starting tenofovir treatment did not affect kidney disease outcomes during therapy with the drug. “Presence of traditional [chronic kidney disease] risk factors at baseline such as pre-existing [chronic kidney disease], diabetes and hypertension did not appear to worsen the effects of tenofovir,” they wrote.
It is important to note that the risk increases reported by Scherzer's team are relative, not absolute.* The overall risk of kidney disease among people living with HIV using tenofovir remains low and depends on underlying risk factors.
Of concern was the finding that discontinuation of tenofovir didn’t reverse the signs of kidney disease—signs of kidney problems remained for at least a year after the drug was discontinued. “Among those who discontinued tenofovir use in our study,” Scherzer’s team writes, “time following cessation was not significantly associated with either higher or lower risks of proteinuria, or rapid decline, and appeared to be weakly associated with increased [chronic kidney disease] risk. Past users of tenofovir remained at increased risk of outcomes, compared to those never exposed to tenofovir.”
The authors concluded that “tenofovir is associated with increased risk of proteinuria, rapid decline [in kidney function] and [chronic kidney disease]. Clinicians treating HIV-infected patients should recognize that while traditional risk factors such as hypertension, older age and diabetes may increase the risk of kidney disease, tenofovir is associated with elevated risk even in patients without pre-existing kidney risk factors.”
The researchers add, however, that the risks of tenofovir needed to be weighed against its potential benefits. “Despite tenofovir’s association with progressive kidney disease, it is an important component of antiretroviral therapy that may be required in many patients to control viral load. The balance between its efficacy and probably adverse effects requires further study.”
* Generally speaking, the absolute risk of kidney disease in a white 40-year-old male with no other risk factors is very low, on the order of 0.2 percent over the next five years of his life, and increases with certain risk factors (e.g., with type-2 diabetes to 1.7 percent, with type-2 diabetes and high blood pressure to 7.2 percent). The 33 percent risk increase associated with tenofovir relates to the original underlying risk, and equates to a 0.066 percent increase in the person without any other risk factors (0.002 X 0.33) and a 2.3 percent increase in the tenofovir user with high blood pressure and diabetes (0.072 X 0.33). So the absolute risk of chronic kidney disease increases to roughly 0.27 percent in a 40-year-old white male without risk factors—still a low absolute risk—and a more moderate 9.5 percent absolute risk in a 40-year-old male with high blood pressure and diabetes.
Search: tenofovir, Viread, Truvada, Atripla, Complera, kidney, nephrotoxicity, renal, proteinurea, chronic kidney disease, ckd, UCSF, Scherzer
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comments 1 - 15 (of 22 total) next
Deibster, Provincetown, MA, 2012-04-12 21:36:37
Why do all of your percentages refer to the chances of a 40 yr old male becoming ill from tenovavir?? We have a large percentage of clients (30 to 50%) at my ASO are 50 yrs old or older. About half of these are 60 or older! Get with it! HIV & Aging is a big topic & growing every year.
Brian, Boston, 2012-02-29 23:25:29
I will g o back to ziagen if the kidney doctor unmasking (lisinopril does not protect from truvada it masks protein leakage!) washing out of lisinipril and my 24hr urine is way worse then it is no brainer-hate to be off BP Meds for 3-4 days but only way to know how damaged kidneys are-good kidney doctor knew this, PCP and maybe ID did not thought lisinipril was helpful-yeah in selling truvade and keeping my kidney function looking better than it may actually be? I dunno but Ziagen is 99% 4 me...
Tim, Playa Del Rey, 2012-02-26 18:58:59
I was switched to Ziagen - which may have its own set of problems (liver, cholesterol, heart) - but think it was the right choice for me.
Donald, Nashville, 2012-02-26 00:51:32
While living in Florida seeing good ID doc, he had me on Truvada, Memorial Day weekend 2010 I went into renal failure, biopsy said severe allergic reaction to a drug, but couldn't pin point it. Had to be dialysis for 3 months! The nephrologist, a genius, shocked the kidneys back online with steroids, played hell with my diabetes, now off dialysis but still have reduced kidney function, the kidney doc was the only one that new it was the Truvada, the ID doc played dumb. Wish I had someone to sue.
Alan Baker, Sydney, 2012-02-22 21:11:31
What of other Nucleotide Inhibitors?
William Steiner-Lynn, Sarasota, 2012-02-22 16:21:16
I moved to FL from AL a year ago.(Big Mistake, HIV care in FL is awful) The Doctors here switched my regiment to one that included Travada. My blood test began showing worse & worse kidney results. My normal kidney numbers went to 5 times the normal in one year. I'm now on a regiment that has more pills, but my kidney test are almost back to normal levels.
Tim, playa del rey, 2012-02-22 04:47:15
Lisinopril reduces kidney pressure (and flow) - so readings can improve temporarily. In my case, tenofovir damage continued while on lisinopril - to the point where lisinopril was no longer "masking" the continued damage. I'm now off both lisinopril and tenofovir - and getting better readings - be careful thinking that lisinopril prevents kidney damage from tenofovir.
Brian, Boston, 2012-02-21 10:44:32
Thomas, U hit nail on head-hope editors taking note-fast tracking has gotten us here-we are alive now-but meds killing us slowly-Delaney has been saying this until he left us sadly-and not much has changed-this is a wake up call-This is 1st line treatment recommendation by FDA everywhere (taking it 9 yrs)..my doc still has not DC'd it but I am freaking-one more eGFR below 60 and I am chronic kidney disease? WTF! I have never had any kidney issues. The risk is worse than stated-this needs to go.
Brian, Boston, 2012-02-21 10:28:23
It seems that the graph would be more or less show a linear risk increase with use over time but they make it very con using by saying only "certain" people will get it. As for lisiniopril, i already had high BP and have been on max dose of that for yrs. and had to add diuretics to keep BP down and not go to beta blocker-now lisinopril does help prevent kidney damage caused by high BP which alone can cause kidney damage-but I see no choice but to stop taking this for me-others? dunno
Frank Collins, Parkville, 2012-02-18 20:49:24
What are the risk factors for a black male, sixty two, and on viread and then truvada since Two Thousand. Is there a graph available so reads can more accurately assess risk?
Thanks for your patience.
Jeff, Tampa, 2012-02-17 15:14:40
I have been taking Atripla for several years. When my doctor noted that my kidney function suddently declined, he put me on Lisonopril 10mg daily (generic for Zestril) and my kidney function returned to normal at my next lab test and has remained so ever since, about two years. This is a blood pressure medication but I do not have high blood pressure. It has a side effect of preventing kidney damage, and can be prescribed for this purpose.
Tim, Playa Del Rey, 2012-02-16 14:05:07
This is not a black/white smoker/nonsmoker thing! I've never smoked - am white - have always been careful with my nutrition and I exercise regularly. I took tenofovir and my kidney function went from almost 100% to below 50 percent in about eight years time - just figured it was part of living with HIV. Anyway, the good news is that this may be somewhat reversable over time! I've been off tenofovir for about a year now, and my filtration rate is slowly improving!
Thomas Bodetti, USA, 2012-02-16 10:25:46
There is a component to this story that should be discussed, that is the nature of the status in society of an Aids/Hiv patient. There seems to be this under published idea that Aids patients are not as important as other patients...
Does that make you mad? It should, because if this were a component of some other more common medication say for high blood pressure, there would be widely called for investigations about how many peoples health had been harmed.
But not for this group?
Brian, Boston, 2012-02-16 07:16:47
I am heart broken! this is the one med I thought was safe until doc became so worried about every kidney reading that was a little off-now my eGFR is below 60, my TP at 180 and TP creatinine ratio is triple normal at .48 ((.15 is normal)-i exercise a ton to fight type 2 diabetes and take diuretics which can make it appear worse-but now I know it is NOT that--I am just beside myself-I have few alternatives as bing 30 yrs. pod have burned through many meds but this was known-its disgusting! Angry?
Brian, Boston, 2012-02-16 07:12:23
comments 1 - 15 (of 22 total) next
I am on this for 7 years, and have watched myself get weird readings over last 3 years thinking it was my diabetes (but that is controlled now) and no other conclusion-eGFR below 60 now, TP 180. TP/creatinine ration is 3 times higher than the .15 at .47..i am livid that Gilead has known about this for years (my doctor has too but I have this for 30 years and not many choices left but there were-I thought this was the only drug that was safe frankly. I am heart broken-"IRREVERSIBLE"-sickening!
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