July 25, 2007
Since the development of tenofovir (TDF, Viread) began, decreases in renal function among HIV-infected patients taking tenofovir-containing regimens have been reported. This was somewhat expected due to the renal clearance and metabolic pathway of this agent. So no one will argue that there isn't a degree of renal dysfunction observed in a certain number of treatment-naive and treatment-experienced patients treated with this agent.
The specific pathophysiologic mechanism that would explain this phenomenon is not completely clear. But what remains more controversial is ascertaining both the degree and the progression of this renal dysfunction, as well as clarifying its overall clinical significance.
It appears evident that for treatment-naive, otherwise healthy, HIV-infected patients participating in clinical trials, with a baseline normal creatinine clearance, who are taking a tenofovir-containing regimen with a non-nucleoside reverse transcriptase inhibitor (NNRTI), the mean degree of decrease in renal clearance is about 8 mL/min. For most of these patients, these decreases in renal function occur during their first year on treatment, after which renal function remains stable, and does not appear to worsen any further over time.1
For treatment-naive patients who are participating in clinical trials with regimens containing tenofovir and a protease inhibitor (PI) boosted with ritonavir (RTV, Norvir), the situation appears to be similar, but there have been isolated reports of more of these patients developing a larger decrease in renal function than patients taking non-PI-based regimens containing tenofovir.2
On the other hand, data collected from retrospective cohort studies have shown reductions in creatinine clearance that are somewhat larger, i.e., ~15 mL/min.3
The problem is that many of these retrospective cohorts include patients who already have underlying renal insufficiency, or who may be otherwise poor candidates for receiving tenofovir, thereby exacerbating their baseline renal dysfunction and probably accounting for the differences observed between treatment-naive studies and cohort studies. Attempts to identify which particular patients are at higher risk for developing renal insufficiency have been a bit controversial.
In a study4 presented at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, researchers from the AIDS Healthcare Foundation in Los Angeles tried to identify the changes in renal function seen in patients taking a tenofovir-containing regimen.
This study was conducted as a retrospective review of 651 patients who started a tenofovir-containing regimen from January 2001 to June 2003. Of those patients, 448 had enough follow-up data to be included in this analysis (the tenofovir arm). They were then matched to 448 other patients who started a non-tenofovir-containing regimen (the control arm). The mean baseline age of the entire cohort was 39 years, 91% were males and the most prevalent ethnic group was Hispanic. Both groups had similar baseline serum creatinine and creatinine clearance (CrCl).
The investigators then looked at the proportion of patients who developed a decrease in CrCl that was equal to or greater than 30 mL/min at various time points (6, 12 and 24 months) between the tenofovir and control arms. CrCl was measured by both the Cockcroft-Gault (CG) equation and the Modification of Diet in Renal Disease (MDRD) formula.
|Renal FX > 30 mL/min||TDF||Control|
|6 month CG|
6 month MDRD
|12 month CG|
12 month MDRD
|24 month CG|
24 month MDRD
FX = Fractional extraction
In this study, using a multivariate analysis, the predictors of decreased renal function were the use of tenofovir, substance abuse and diabetes. When controlling for variables such as diabetes, hepatitis coinfection, baseline CD4+ cell count and HIV RNA, tenofovir was found to be two to three times more likely to cause a significant decrease in renal function, with an odds ratio (likelihood) of 2.27 when measured by CG and an odds ratio of 3.25 when measured by MDRD.
The authors concluded that the use of tenofovir was associated with a greater decline in renal function at 24 months, and a closer monitoring of patients' renal function may be warranted, even in patients who have normal creatinine at baseline.
In my opinion, I do not think that the data presented here shed any more light on what we already know about tenofovir and renal function monitoring. Patients need to have their renal function checked as part of their routine follow-up before and after the initiation of antiretroviral regimens, regardless of which antiretroviral regimens they are taking. There are many other causes of renal dysfunction, and there are other antiretrovirals that need renal dose adjustment in the event of renal dysfunction.
This study does not specify how many patients started a tenofovir-containing regimen at low or borderline low baseline creatinine levels, or whether these particular patients were the ones with the most significant or critical changes in creatinine. It is expected that those patients would have worse outcomes than patients in the control arm who have not been treated with a tenofovir-containing regimen.
I think that an even more important take-home message is that, in general, we need to be vigilant about the type of patients in whom we initiate a tenofovir-containing regimen. Tenofovir-containing regimens may not be the best option for patients who already have an abnormal baseline renal function. However, for patients with an otherwise normal baseline renal function, who are not taking nephrotoxic agents or who do not have significant comorbid conditions that predispose them to renal insufficiency, routine renal monitoring -- as we do for many other patients -- should suffice before prescribing tenofovir.
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