ASSERT study adds to comparative data on abacavir versus tenofovir (EACS - HIV&Hep.com - 20 Nov 2009)

HIV patients receiving antiretroviral regimens containing tenofovir (Viread, also in the Truvada coformulation) may be slightly less likely to experience virological failure than those taking abacavir (Ziagen, also in the Epzicom coformulation).

The Truvada and Epzicom fixed-dose coformulations are widely used nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) "backbones" in first-line antiretroviral therapy (ART) regimens.

Both are considered effective and generally well-tolerated, but some studies have shown that abacavir may be less effective in patients with high baseline HIV viral load. Though data are inconsistent, some research indicates that abacavir is associated with an elevated risk for heart attack and other cardiovascular events, while tenofovir has been associated with bone loss and kidney impairment in susceptible individuals.

ASSERT was a randomized trial in which 385 treatment-naive participants were randomly assigned (1:1) to receive either Truvada or Epzicom, both taken once daily in combination with 600 mg efavirenz (Sustiva).

All participants tested negative for the HLA-B*5701 genetic variation associated with abacavir hypersensitivity reactions. They were stratified according to black vs non-black race (a risk factor for kidney disease), body mass index above or below 25, and glomerular filtration rate (GFR by MDRD, a measure of kidney function) above or below 90 mL/min/1.73m2. However, they were not stratified according to baseline viral load.

Most participants (about 80%) in the intent-to-treat population were men, about 15% were black, and the median age was about 37 years. About 9% were hepatitis C virus (HCV) coinfected. Participants had relatively advanced HIV disease. The median current CD4 count was about 235 cells/mm3, and about 20% had less than 150 cells/mm3. About one-third had estimated GFR (eGFR) < 90 mL/min/1.73m2.

Results

 In a TLOVR (time to loss of virological response) analysis at week 48, 59% of Epzicom recipients achieved HIV RNA < 50 copies/mL, compared with 71% of Truvada recipients (difference 9.5%).

 The percentages with viral load below 400 copies/mL were 67% and 77%, respectively (difference 11.6%).

 3% of Epzicom recipients and 1% of Truvada recipients experienced protocol-defined virological failure.

 The median CD4 cell gain was 150 cells/mm3 in both arms.

 3 patients in the Epzicom arm, but none in the Truvada arm, developed treatment-emergence drug resistance mutations.

 33% of patients in the Epzicom arm and 23% in the Truvada arm discontinued therapy before week 48 :

— 13% vs 10%, respectively, due to adverse events ;

— < 1% and 0%, respectively, due to disease progression ;

— 6% and 1%, respectively, due to lack of efficacy (according to investigator).

 Epzicom recipients experienced a slightly smaller mean change in eGFR from baseline (the primary safety endpoint) than Truvada recipients, but the difference did not reach statistical significance (P = 0.43).

 However, patients in the Epzicom arm did have significantly smaller changes in 2 measures of kidney tubular dysfunction, beta-2-microglobulin/creatinine ratio and retinal binding protein/creatinine ratio (both P < 0.001).

 No participants in either arm discontinued therapy due to kidney dysfunction. Epzicom recipients had significantly less bone loss than Truvada recipients at the hip (P < 0.001) and lumbar spine (P = 0.036) :

— > 2% loss at hip : 48% vs 78% ;

— > 2% loss at lumbar spine : 40% vs 59% ;

— > 6% loss at hip : 3% vs 13% ;

— > 6% loss at lumbar spine : 5% vs 10% ;

 Epzicom recipients also experienced smaller changes in biomarkers of bone loss.

 Epzicom recipients experienced slightly larger changes compared with Truvada recipients in inflammatory cardiovascular risk markers, but only adiponectin reached statistical significance (P = 0.018).

 Despite HLA-B*5701 screening, 5% of Epzicom recipients reported drug hypersensitivity (vs <1% taking Truvada).

 Epzicom recipients were twice as likely as Truvada recipients to report serious adverse events (14% vs 7%, respectively) and drug-related serious adverse events (5% vs 2%).

 29% vs 20%, respectively, experienced grade 2-4 treatment-related laboratory abnormalities.

Based on these findings, the investigators concluded that the TLOVR analysis "shows a difference in favor of [Truvada]."

"No difference was observed in eGFR" in the Epzicom and Truvada arms. However, they added, but "in an exploratory analysis, markers of renal tubular dysfunction with elevated with [Truvada]."

"Total hip and lumbar spine bone mineral density declined in both arms, but the loss was significantly greater with [Truvada]," they continued. "There were significantly greater increases in markers of bone turnover with [Truvada]."

By Liz Highleyman

Reference

HJ Stellbrink, G Moyle, C Orkin, and others. Assessment of Safety and Efficacy of Abacavir/Lamivudine and tenofovir/Emtricitabine in Treatment-Naive HIV-1 Infected Subjects. ASSERT : 48-Week Result. 12th European AIDS Conference. Cologne, Germany. November 11-14, 2009.

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