Relationship between Tenofovir-Associated Renal Dysfunction and HAART Regimen

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.

Synopsis: Treatment with TDF plus PI/r was associated with a greater decline in renal function over 48 weeks compared with TDF + nnRTI-containing regimen.

Source: Goicoechea M, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis. 2008;197:102-108.

This study from the California collaborative treatment Group examined renal function over time in 146 patients included in the CCTG 578 prospective, randomized clinical trial of therapeutic drug monitoring (TDM). Creatinine clearance (CrCl) was estimated using the Cockcroft-Gault (C-G) equation and the unabbreviated Modification of Diet in Renal Disease (MDRD) equation. Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, at 48 weeks, patients receiving TDF+PI/r had a greater decline in CrCl than did the TDF+nnRTI group (-13.9 vs-6.2 mL/min/year by C-G and -14.7 vs-4.5 by MDRD). The rates of decline in CrCl between the TDF+nnRTI and non-TDF-treated patients were similar. Among the TDF-treated patients, tenofovir plasma concentration was not associated with change in CrCl over time.

Commentary

This is an important paper, with significant clinical relevance, which sheds some light in the direction of the increasingly-recognized issue of TDF-related nephrotoxicity. Tenofovir has been a very important advance in the construction of better-tolerated and more durable antiretroviral regimens. Numerous studies have now shown the superior efficacy and superior long-term tolerability of TDF-containing ARV regimens over zidovudine (AZT)-containing nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones. However, this advance has come at some cost. While clearly less nephrotoxic than Gilead Science's earlier nucleotide analogue, adefovir dipivoxil, it soon became apparent to treating clinicians that occasionally severe nephrotoxicity (with or without renal tubular acidosis) could be seen with TDF, as well as with adefovir.

Nucleotide analogues are actively transported into renal tubular epithelial cells from the basolateral border by organic anionic transporter proteins (OAT-1), then excreted out the tubular border by the ubiquitous efflux pumps, MRP-2, and possibly MRP-4. Ritonavir has been shown to be an inhibitor of MRP-2, thus accounting for potential increased renal tubular intracellular concentrations of tenofovir, resulting in potential nephrotoxicity. The lack of correlation between overall plasma levels of tenofovir and change in renal function suggests that PI/r is not affecting intestinal absorption of tenofovir and systemic exposure.

The CCTG is to be commended for looking at this important issue. It is my perception that Gilead Sciences often chooses to be in denial regarding the toxicities of their nucleotide analogue RTIs. While TDF is an excellent drug which I prescribe everyday to my patients, wider recognition of its potential nephrotoxicity, and better characterization of particular patients at risk for this toxicity, could be done by more in-depth analysis of the company's drug safety database. Greater knowledge of the types of patients at highest risk for TDF-related nephrotoxicity would serve to increase the appropriate use of this agent.

(Some of the readers of Infectious Disease Alert might be interested in a few Pharma insider anecdotes about Gilead Sciences for whom I worked from late 1997 until early 1999. While this company doesn't quite qualify for "Evil Empire" status, a few Darth Vader types work there. During my first week on the job there, Dr. Steve Barriere, the head of drug safety, started receiving a handful of adverse event reports of proximal renal tubular acidosis in patients being treated with adefovir. Steve coined the term, "Fanconi-like syndrome," which we were later ordered by management to change to "proximal renal tubular dysfunction" since the former term sounded too scary. We later received some very disturbing serious adverse event reports of acute renal failure requiring hemodialysis in patients who had adefovir continued in the presence of RTA. Steve and I immediately asked Dr. Mike Wulfsohn, the company's lead biostatistician, to perform a blinded A vs B analysis of all on-going Gilead-sponsored trials of ADV. Mike quickly pulled the data together and demonstrated that, at 24 weeks, using a number of criteria, 46% of group A vs only 5% of group B patients had developed nephrotoxicity. I later drafted a letter to Dr. Carla Petinelli, the Division of AIDS Medical Officer, informing her of this. Because of the sensitivity of this communication, it required approval at a VP level before going outside the company. My draft came back from this VP with 46% crossed out and "approximately one-third" written in. I unsuccessfully argued that even with my limited knowledge of higher mathematics you couldn't round off 46% to "one-third," but you could round that up to "one-half." Seeing that I was losing the argument, in a career-enhancing move, I told the VP, "You can take my name off the 'expletive deleted' letter, then and shove it up your a__!!" I tried to argue that we should put the recently initiated US expanded access program on hold. The project team concurred that we should definitely not start an expanded access program in Europe. A few weeks later, I hired another physician, who was personal friends with both the VP and the CEO, to help work on the project.

As her boss, I had to sign off on travel, so I was confused why she was requesting a business class ticket to Europe when the project team had just decided to not start an expanded access program in Europe due to the safety issues. This resulted in a somewhat tense confrontation between us, but was resolved by management, who decided the next day to have her report directly to the VP instead of me. Shortly after this, they stopped inviting me to my own project team meetings! I hung in there for several more months hoping for Gilead to see the light, but eventually started looking for another job. On my last day at Gilead, I insisted on giving a brief PowerPoint presentation to the entire clinical research group entitled "Principles of Disciplined Drug Development," where I detailed all the mistakes I felt Gilead made in the development of adefovir and why I was sure that FDA Division of Antiviral Drug Products would never approve adefovir for HIV. The VP was still sure that, in his words, "We're going to jam this drug down the FDA's throat!" Gilead submitted their NDA several months after I left the company, and adefovir became the only antiretroviral agent ever to be rejected for approval by FDA. I was bitter about my experience there and for a brief time even considered informing the Chairman of the Board of my concerns about Gilead management. I wisely reconsidered this, since the Chairman of the Board, Donald Rumsfeld, later became my boss for four military deployments to Iraq and Afghanistan. He probably would have just told me, "Dean, you know you go to war with the antiretroviral agent you have, not the one you'd like to have!"