September 15, 2003
With only two years of collected data, the GS 903 study from Gilead Sciences has already proved that the combination of tenofovir DF (TDF, Viread), 3TC (lamivudine, Epivir) and efavirenz (EFV, Sustiva) is very effective in controlling viral replication and improving immune function (see coverage from the International AIDS Society Conference [IAS] 2003).
In this study, tenofovir DF was compared to d4T (stavudine, Zerit); each was used in combination with 3TC plus efavirenz in antiretroviral-naive patients. Although the efficacy results for these two combinations were very similar, the short- and long-term adverse events are starting to favor the tenofovir arm (for details, see coverage from IAS 2003). Hypertriglyceridemia and selected toxicities associated with mitochondrial dysfunction, such as peripheral neuropathy and lipoatrophy, have been the main concerns associated with the use of d4T. No immediate safety concerns with the use of tenofovir have been raised in this naive population. Recently, however, there has been considerable interest in tenofovir's potential risk for renal and bone toxicity (see coverage from the 6th International Congress on Drug Therapy in HIV Infection).
In this poster, Dr. Joel Gallant, from Johns Hopkins University, summarizes the renal toxicities that have been observed in the GS 903 naive study at 96 weeks. The serum creatinine abnormalities were graded according to ACTG guidelines: grade 1 = creatinine >0.5 from baseline, grade 2 = creatinine between 2.1-3.0, grade 3 = creatinine between 3.1-6.0 and grade 4 = creatinine >6.0.
To assess the renal safety profile in this study, several parameters were compared between both groups, including: serum creatinine, serum phosphorus, proteinuria, glucosuria and mean change from baseline in calculated creatinine clearance.
Using these parameters to evaluate renal dysfunction through 96 weeks, the renal safety profile was found to be similar between patients receiving tenofovir DF and patients receiving d4T, when both were combined with 3TC and efavirenz. In this study, no patients discontinued the study due to tenofovir-related renal abnormalities. In addition, no patient developed Fanconi's syndrome.
It is known that tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. The pharmacokinetics of tenofovir are altered in patients with renal insufficiency. In fact, the tenofovir dose needs to be modified in patients with a creatinine clearance of less than 50 mL/min.
Although several case reports of renal dysfunction with the use of tenofovir have been recently published, the majority of these problems have occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, but it is important to point out that in some cases no apparent risk factors were identified.
Although no major renal problems were identified in the naive population that was evaluated in the GS 903 study, we need to be aware that a very small percentage of patients with other co-morbid conditions may be at a higher risk than others for the development of renal complications.
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