Tenofovir (Viread) Kidney Toxicity More Likely When Used with Protease Inhibitors

Research to date has produced conflicting data about kidney toxicity (nephrotoxicity) related to the use of tenofovir (Viread). This side effect did not show up in initial clinical trials of the drug and appears to be uncommon, though some individuals -- including older people and those with pre-existing kidney disease -- are at higher risk.

A more recent analysis of data from the California Collaborative Treatment Group Study 578, reported in the January 1, 2008 Journal of Infectious Diseases, suggests that tenofovir-related kidney toxicity is more common among patients who also take protease inhibitors (PIs).

As background, the investigators noted that plasma concentrations of tenofovir may rise by as much as 20%-30% when co-administered with some ritonavir-boosted PIs, which could increase the likelihood of adverse side effects. Thus, they hypothesized that patients taking tenofovir with boosted PIs might have a greater decline in renal (kidney) function than those taking non-nucleoside reverse transcriptase inhibitors (NNRTIs).

The authors compared the estimated decline in renal function among 146 HIV patients receiving tenofovir plus a boosted PI (n=51), tenofovir plus a NNRTI (n=29), or a regimen without tenofovir (n=66). Baseline characteristics, including age, sex, race, renal function, and CD4 cell count were similar across the groups; however, participants receiving tenofovir plus a NNRTI were more likely to be treatment-naive.

Plasma tenofovir concentrations were measured at week 2. Renal function was assessed by creatinine clearance rate, estimated using the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in creatinine clearance from baseline through weeks 24 and 48.

Results

Conclusions

Based on these findings, the authors concluded, “Treatment with tenofovir and [a boosted PI] was associated with greater declines in renal function over 48 weeks compared with tenofovir plus NNRTI-based regimens.”

However, since patients taking boosted PIs did not have higher blood levels of tenofovir, and since tenofovir concentrations were not associated with impaired creatinine clearance, the reason for greater kidney toxicity in the PI group remain to be determined. In their discussion, the researchers suggested that a possible explanation may be that boosted PIs impair tenofovir excretion, leading to intracellular accumulation in the kidneys.

In an accompanying editorial, Lynda Anne Szczech of Duke University Medical Center wrote, “As a community of providers (academic, private practice, and industry), we need to recognize that we need more information, more guidance, and more answers….We need to recognize that the risk [of kidney toxicity] is likely not homogeneous among the universe of patients who require antiretroviral therapy, but that it probably varies from quite low to high in various subgroups.”

University of California, San Diego, CA; University of Southern California, Los Angeles, CA; Santa Clara Valley Medical Center, San Jose, CA; LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; University of California, Irvine, CA.

01/04/08

References

M Goicoechea, S Liu, B Best, and others. Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse Transcriptase Inhibitor-Based Therapy. Journal of Infectious Diseases 197(1): 102-108. January 1, 2008.

LA Szczech. Tenofovir Nephrotoxicity: Focusing Research Questions and Putting Them into Clinical Context. Journal of Infectious Diseases 197(1): 7-9. January 1, 2008.

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