Nucleoside analog reverse transcriptase inhibitors (NRTIs) have recently been implicated in causing renal insufficiency in HIV-infected patients taking such drugs. In several instances, reported kidney impairment included increased levels of serum creatinine, proximal tubular dysfunction, renal failure and Fanconi-like disease.

The glomerular filtration rate (GFR), which is an indicator calculated using the patient?s age, weight, gender, body size and serum creatinine level, is considered to be an appropriate means of monitoring the renal function of patients. As such, the current study assessed the GFR of trial participants receiving long-term, first-line treatment with regimens containing abacavir (ABC, Ziagen), lamivudine (3TC, Epivir), zidovudine (AZT, Retrovir) and efavirenz (EFV, Sustiva, Stocrin) in order to evaluate the degree of renal insufficiency potentially attributable to a range of NRTIs commonly used in HIV therapy.

Led by scientists from GlaxoSmithKline (Glaxo) in Research Triangle Park, North Carolina, the data from two completed randomized clinical trials, ESS40013 and CNA30024, were used to calculate the GFR of treatment-naive patients exposed to a variety of NRTIs in combination with efavirenz.

Patients in ESS40013 received combination zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) + efavirenz for 48 weeks (n = 448), whereas CNA30024 patients were randomized to receive either lamivudine + zidovudine + efavirenz (n = 326) or abacavir + lamivudine + efavirenz (n = 324) for 48 weeks.

The GFR was calculated at baseline and throughout 48 weeks of treatment using the well-established abbreviated equation from the Modification of Diet in Renal Disease. The GFR was then categorized in accordance with guidelines from the National Kidney Foundation regarding kidney disease stage/severity among patients.

The results of this study indicate that none of the regimens employed in ESS40013 and CNA30024 affected the GFR of treatment-naive individuals throughout the course of long-term therapy.

More specifically, a retrospective analysis of 1,098 patients did not reveal any impact of drug regimen on the GFR at either 24 or 48 weeks of treatment. The overall incidence of nephrotoxicity in patients in all groups was very low at baseline (i.e., below 2%) and either remained constant or decreased over 48 weeks of therapy.

In sum, the results document that GFR is not affected by 48 weeks of therapy with any one of three separate drug regimens -- that is, zidovudine/lamivudine/abacavir + efavirenz, zidovudine + lamivudine + efavirenz, or abacavir + lamivudine + efavirenz.

Although the results of this study are reassuring, it should be recognized that a different study presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy -- namely, study ACTG 5095 -- cast doubt on the wisdom of employing zidovudine/lamivudine/abacavir + efavirenz as a combination therapeutic regimen.

Results from this phase 3 trial show that the four-drug combination does not produce superior antiviral results to those of zidovudine + lamivudine + efavirenz after three years of treatment, nor was the rate of virologic failure significantly better in the zidovudine/lamivudine/abacavir + efavirenz treatment arm versus the comparator arm at 16 weeks of treatment.

As such, the investigators of ACTG 5095, led by Roy Gulick, M.D., M.P.H, concluded that the addition of abacavir to zidovudine + lamivudine + efavirenz for initial HIV therapy cannot be justified. This notwithstanding, the results presented in abstract H-349 by Glaxo scientists do provide reassurance that a variety of NRTI-containing regimens are not associated with nephrotoxicity over the long term in treatment-naive HIV-infected trial participants receiving such therapy.