February 8, 2006
One of the most popular and widely prescribed antiretroviral medications is tenofovir (TDF, Viread). Overall, the drug has few side effects or toxicities -- a fact that has formed the basis of recommendations for its use in multiple HIV treatment guidelines, including the U.S. DHHS treatment guidelines.1 However, limited drug-drug interactions with some protease inhibitors have been described -- an important consideration because lopinavir/ritonavir (LPV/r, Kaletra) and atazanavir (ATV, Reyataz) have been shown to increase exposure to tenofovir by about 25%. The basis of this increase in tenofovir has not been fully determined. In addition, because tenofovir is eliminated from the body by the kidney, patients with significant impairment of kidney function should have tenofovir dosing frequency adjusted.
In prospective clinical trials of tenofovir (where patients with significant pre-existing renal disease were excluded), renal toxicity has appeared to be rare (about 1% of patients), and occurred at similar rates in tenofovir-treated and non-tenofovir-treated patients.2,3 In contrast, anecdotal reports of renal toxicity have been reported,4,5 raising the possibility that even among healthier HIV-infected individuals, there may be a risk of tenofovir-induced toxicity.
At this year's Conference on Retroviruses and Opportunistic Infections, five poster presentations focused on the question of renal toxicity and tenofovir, culminating in an hour-long session about the topic. This review will summarize their findings. The methodologies and patient groups that were examined differed from study to study. Because of continued vigilance about the side effects of antiretroviral medications and the widespread use of tenofovir, the discussion drew much attention from academia, industry and the treatment community.
Dr. Melanie Thompson from Atlanta, Ga., speaking on behalf of her collaborators in the GlaxoSmithKline-sponsored ESS40006 study, reviewed changes in renal function (glomerular filtration rate, or GFR) using the MDRD (Modification of Diet in Renal Disease) formula. Patients in this now-completed salvage study received treatment with abacavir (ABC, Ziagen) + ritonavir (RTV, Norvir)-boosted amprenavir (APV, Agenerase) + either efavirenz (EFV, Sustiva, Stocrin), for patients who were naive to non-nucleoside reverse transcriptase inhibitors (NNRTIs), or tenofovir for NNRTI-experienced patients.
In this observational, non-randomized study, tenofovir use was associated with a statistically significant decline in GFR. Importantly, however, the clinical significance of small changes in GFR is unknown. Limitations of the study relate to its observational nature, failure to control for concomitantly taken medications and unequal dropout rates between the two arms of the study. Another issue is that all patients also received ritonavir; the relationship between ritonavir, tenofovir and renal toxicity remains cloudy.
In another poster, Dr. Jodie Guest and colleagues from the Atlanta Veterans Administration Medical Center looked at 12-month composite kidney toxicity among 222 patients receiving tenofovir. In this study, renal toxicity was evaluated by the Cockcroft-Gault equation (which adjusts for weight, but not race). Kidney toxicity was observed in 17% of patients; renal insufficiency (defined as a 50% change in GFR) in 4% of patients; and hypophosphatemia (defined as any phosphate level less than 2) was seen in 13% of patients. These aggregate rates of renal injury are significantly higher than in other cohort or prospective studies.
Another observational cohort of tenofovir-receiving patients was described by Dr. Heidi Crane from the University of Washington. Of 497 patients who received tenofovir, 87 developed abnormal renal function (calculated by Cockcroft-Gault and MDRD formulae). Patients with increased age, didanosine (ddI, Videx) use and lower baseline weight were found to have a greater risk of developing renal dysfunction.
A significant limitation of both Dr. Guest's and Dr. Crane's studies, however, is their non-comparative nature. Because renal disease can occur in patients with HIV who are not taking tenofovir, it's unclear to what extent these events are attributable to tenofovir, HIV or other concomitant medications. For instance, Dr. Guest noted that nephrotoxicity was associated with the use of the fungal infection treatment amphotericin B (Amphocin, Fungizone Intravenous) and that hypophosphatemia was related to didanosine use.
In one of the largest cohort analyses to date to look at tenofovir's renal effects, Dr. James Heffelfinger from the U.S. Centers for Disease Control and Prevention described an analysis from the Adult Spectrum of Disease study. This is an observational cohort analysis of more than 11,000 patients. Patients with pre-existing renal impairment were excluded from this analysis. Patients receiving tenofovir were about 60% more likely to have mild or moderate (but not severe) renal insufficiency on treatment than other patients (mild, moderate and severe renal impairment occurred in 35.1%, 6.4% and 2.6% of patients, respectively). After adjusting for multiple demographic factors (age, race, sex), the presence of a lower CD4+ cell count, lower hemoglobin, diabetes and hypertension predicted all categories of renal impairment. However, one limitation of this study was that the tenofovir patients tended to be more treatment experienced than the controls.
The experiences with tenofovir in the Gilead expanded access program and post-marketing safety reports were reported by Dr. Mark Nelson from the Chelsea and Westminster Hospital in London, United Kingdom. More than 10,000 patients and safety data from an estimated 455,000 patient-years of tenofovir treatment were included. Overall, the rate of serious renal toxicity (serious adverse events) was 0.57% in the expanded access program; concomitant nephrotoxic medications and a low baseline CD4+ cell count were found as risk factors. The study was not designed to capture data about mild or transient kidney injury.
Taken as a whole, these studies provide additional clarity on the safety and toxicity profile of tenofovir. A parsimonious view of these data is that tenofovir is usually very safe to use, with low overall rates of serious kidney injury. The largest cohort studies show that renal dysfunction occurs at low but measurable rates in patients with HIV, whether they receive tenofovir or not. However, research also suggests that kidney disease can occur at higher rates in select patient groups. Tenofovir patients with concomitant nephrotoxic medications or other risk factors for kidney disease appear to be at higher risk.
Of course, there are many caveats to these findings. Descriptive studies without comparative groups should be viewed with caution, since the risk attributable to tenofovir cannot be ascertained. In addition, because different patient groups were studied (with differing baseline risk characteristics), differences in calculating or characterizing renal injury and the incident rates of renal disease will also differ from study to study.
So what are a doctor and patient to do when selecting antiretroviral treatments? For patients without significant risk of kidney disease, these studies suggest little need to change our view of tenofovir. By contrast, for patients with a risk of renal disease, it would be prudent to carefully consider the relative risks and benefits of the use of tenofovir versus alternate treatments.
In either circumstance, patients who commence tenofovir therapy should have their renal function thoughtfully monitored -- not simply by measuring serum creatinine, but by calculations of GFR by Cockcroft-Gault or MDRD methods.
Abstract: Tenofovir-induced nephrotoxicity in the first year of therapy (Poster 778)
Authored by: J Guest, D Rimland, B Patterson, K Desilva
Affiliations: Atlanta VAMC, Decatur, GA, US; Emory Univ Sch of Med, Atlanta, GA, US; Rollins Sch of Publ Hlth, Emory Univ, Atlanta, GA, US; Univ of Missouri, Sch of Pharm, Kansas City, US
Abstract: Renal impairment associated with the use of tenofovir (Poster 779)
Authored by: J Heffelfinger, D Hanson, A Voetsch, A McNaghten, P Sullivan
Affiliations: CDC, Atlanta, GA, US
View poster: Download PDF
Abstract: Didanosine and lower baseline body weight are associated with declining renal function among patients receiving tenofovir (Poster 780)
Authored by: H Crane, R Harrington, S Van Rompaey, M Kitahata
Affiliations: Univ of Washington, Seattle, US
Abstract: The safety of tenofovir DF for the treatment of HIV infection: the first 4 years (Poster 781)
Authored by: M Nelson, D Cooper, R Schooley, C Katlama, J Montaner, S Curtis, L Hsu, B Lu, S Smith, J Rooney, the Viread Global Expanded Access Prgm
Affiliations: Chelsea and Westminster Hosp, London, UK; Univ of New South Wales, Sydney, Australia; Univ of California, San Diego, US; Hosp Pitié-Salpétrière, Paris, France; Univ of British Columbia, Vancouver, Canada; Gilead Sci, Foster City, CA, US
View poster: Download PDF
View slides: Download PowerPoint
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