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Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: emeraldize on February 14, 2012, 12:36:12 pm
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Large Study Finds Tenofovir Linked to Increased Kidney Risk
10 FEBRUARY 2012
WRITTEN BY LIZ HIGHLEYMAN
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."
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. February 4, 2012 (Epub ahead of print).
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.
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Tenofovir: Q&A for Patients and Providers
February 10, 2012
Scientists at the San Francisco VA Medical Center and the University of California, San Francisco have published a study showing that one of the most effective and commonly prescribed antiretroviral medications for HIV/AIDS, tenofovir, is associated with a significant risk of kidney damage and chronic kidney disease that increases over time.
What is the new finding about HIV/AIDS drugs and associated kidney problems?
Tenofovir, an anti-retroviral drug used to treat HIV, was associated with an increased risk of kidney disease in an observational study of 10,841 HIV-infected veterans who were new users of antiretroviral therapy between 1997 and 2007. The study found that tenofovir is associated with an elevated risk of kidney disease, even in persons without pre-existing risk factors for kidney disease, and that this toxicity to the kidney may not be reversible.
The study showed that for each year that a person uses tenofovir, there is a 34 percent higher risk of developing protein in the urine, which is an important sign of kidney damage; an 11% higher risk of rapidly declining kidney function, and a 33% higher risk of developing chronic kidney disease. These risks are all independent of the other factors that cause kidney disease, such as age, diabetes, hypertension, smoking, hepatitis C infection and HIV-related factors.
How much extra risk is this?
Overall in the study, the differences in risk between users and non-users of tenofovir each year were: 13% vs. 8% for protein in urine, which is an important marker of kidney damage 9% vs. 5% for rapidly declining kidney function; and 2% vs. 1% for developing chronic kidney disease. However, these numbers are based on the average risks in the study population, and patients with more risk factors for kidney disease would be put at proportionately higher risk when they use tenofovir.
Which drugs are we talking about?
In the study, the risk appeared to be unique to tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events, and none was associated with higher risk for even two of these three adverse kidney disease outcomes.
Should I stop taking these drugs if I am already taking them now?
This decision should be made on an individual basis, in consultation with your physician. The decision should involve weighing the risks/benefits and discussion of alternative treatment options. Tenofovir is an important component of effective antiretroviral therapy that you may need to control your viral load. If you remain on tenofovir, you may need more frequent monitoring of your kidney function and your level of urine protein. You are likely at increased risk of kidney disease if you have diabetes, high blood pressure, cardiovascular disease or hepatitis C. African Americans, Hispanics, Pacific Islanders, Native Americans and older adults are also at increased risk.
What are the symptoms of kidney problems? Should I be taking tests to monitor my kidney function?
Most people do not have any symptoms until their kidney disease is advanced. So, kidney disease is typically detected by screening tests of blood and urine.
Moving forward, what questions should I ask my doctors?
You should ask your doctor about whether you need routine monitoring of blood and urine samples to measure the following: serum creatinine, proteinuria, and microalbuminuria. You should also ask your doctor to calculate your estimated glomerular filtration rate (eGFR). You may want to have a discussion about alternative treatment options.
What about the prophylactic use of these drugs to prevent HIV progression and transmission?
A study of HIV pre-exposure prophylaxis (PrEP) using once-daily oral tenofovir was presented at the XVIII International Conference on AIDS (AIDS 2010), which included 323 men. This study found no indication of significant safety issues, including kidney problems or bone loss. However, this study may not have been large enough to detect increases in risk for kidney disease.
Where can I get more information?
You may get more information from HIV/AIDS websites such as Project Inform or HIV InSite. You can also contact your doctor if you have additional questions about your anti-retroviral medications or risk for kidney disease.
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The missing words in this headline are "in the VA cohort in the first 18 months after starting meds" - half of the VA cohort are smoking, drinking, overweight men over 50...
There are other things amiss with this paper but I won't go on.
It has been known since 2006 at least that tenofovir containing meds (ie Viread, Truvada, Atripla) will be bad for, say, 4-5 in 20 people's kidneys.
A review of the evidence for the new UK HIV treatment guidelines found abacavir was equal to or slightly worse than tenofovir for kidney health in the first 96 weeks of treatment.
There's another thread on this in the Side Effects forum (http://forums.poz.com/index.php?topic=41915.0). Everyone on meds should get their kidney health checked annualy, and if on tenofovir every time they do bloods.
- matt
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Hey Newt,
I just caught Buginme's thread on this topic. I'm going to ask Ann to delete it.
Thanks!
Em
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Em, because Bug's thread is in a different forum, and because you've already gotten a response here, I'll leave this thread where it is. Not everyone who reads Research reads Treatment and visa-versa. :)
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Here's a link (http://forums.poz.com/index.php?topic=41915.0) to the most active thread on the subject.