Tenofovir and the Kidneys

The anti-HIV drug tenofovir (Viread, and in Atripla and Truvada) is an effective part of combination therapy for HIV.

The kidneys process tenofovir and there have been rare cases of tenofovir users developing serious kidney dysfunction. To investigate this problem, researchers from the U.S. health care organization Kaiser Permanente reviewed their large database of information on HIV-positive people who initiated anti-HIV therapy with or without tenofovir. They found that some tenofovir users had a detectable and significant decline in kidney health. These and other details appear in this report.

Study Details

Researchers reviewed data from databases in California, Maryland, Virginia and Washington, DC. All participants began taking HAART between January 2002 and January 2006. In total, the researchers focused their analysis on data from 964 HIV-positive people who were taking tenofovir and 683 people who were not.

Tenofovir can damage part of the kidney called the renal tubules. The damage causes proximal renal dysfunction, which can lead to reduced efficiency filtering the blood, the loss of key nutrients and other problems such as the following:

• detectable protein in the urine (proteinuria)
• sugar in the urine (glucosuria)
• less-than-normal levels of the mineral phosphorus in the blood (hypophosphatemia)
• phosphorus in the urine (phosphaturia)
• acidic blood (serum acidosis)
• less-than-normal levels of potassium in the blood

Researchers checked eGFR (estimated glomerular filtration rate) to get an idea of how the kidneys were working. They divided people into the following two groups:

• tenofovir-exposed group: 964 people
• tenofovir-sparing group: 683 people

Apart from their use (or not) of tenofovir, the two groups of people were broadly similar, with the following average profile:

• 14% female, 86% mal
• age: 30 years
• CD4+ count: 205 cells
• HIV viral load: 63,000 copies
• eGFR: 100

Results

A high proportion of people in both groups achieved a suppressed viral load as follows:

At one year:

• tenofovir-exposed group: 94%
• tenofovir-sparing group: 97%

At two years:

• tenofovir-exposed group: 93%
• tenofovir-sparing group: 96%

These differences between groups were statistically significant. However, it is important to bear in mind that several randomized clinical trials have found that tenofovir-containing regimens have potent anti-HIV activity. So this particular finding from the Kaiser analysis is puzzling and unexpected and should be read with caution.

Kidney Function

Creatinine is a waste product that is removed from the blood by the kidneys. When these organs are malfunctioning, creatinine levels in the blood can rise. Modest increases in blood levels of creatinine were more likely to occur in tenofovir users. But it is important to note that large increases in creatinine were not confined to tenofovir users. Indeed, people who had large increases in creatinine tended to have the following features:

• older age
• low CD4+ counts (less than 50 cells)

Significantly more people using tenofovir developed proximal tubular dysfunction (8%) compared to people not taking tenofovir (4%). Furthermore, there was an increase in this problem over time, with the risk of proximal tubular dysfunction increasing among tenofovir users as follows:

• week 26: 19% increased relative risk; not statistically significant
• week 44: 61% increased relative risk; not statistically significant
• week 52: 95% increased relative risk; statistically significant
• week 104: 500% increased relative risk; statistically significant

Among people who developed proximal tubular dysfunction, 21% stopped taking tenofovir.

Putting It in Perspective

The findings from this Kaiser study are interesting but several points need to be taken into account when considering the results, including these:

• This was a cohort study, which is good at finding associations. But this study cannot prove that tenofovir caused any of the kidney problems detected. This is because in analyzing such studies, the problem of confounding or channeling bias can arise, making it difficult to draw firm conclusions.
• The associations found in a cohort or observational study can be later explored in a clinical trial of a more robust design, such as a randomized trial. However, bear in mind that data from clinical trials suggest that, for most people, tenofovir is a safe and effective part of combination therapy.

It is not clear why in the present Kaiser analysis tenofovir was associated with more problems than reported in other trials. It might be that the Kaiser team was unable to account for potential confounding data such as the use of other drugs, which could increase the risk of kidney damage. Such drugs can include the following prescription and non-prescription medications:

• several antibiotics
• several antiviral drugs
• several antifungal drugs
• pain medicines, including acetaminophen (Tylenol) and ibuprofen (Advil, Motrin)

For a more detailed list of drugs with the potential to cause kidney toxicity, please see CATIE's in-depth Fact Sheet on tenofovir.

References

1. Horberg M, Tang B, Towner W, et al. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients. Journal of Acquired Immune Deficiency Syndromes. 2010 Jan 1;53(1):62-9.
2. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. New England Journal of Medicine. 2009 Dec 3;361(23):2230-40.