Sixth International Congress

Drug Therapy in HIV Infection


17-21 November, 2002
Glasgow, UK

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Comparison of the efficacy and safety of tenofovir disoproxil fumarate (TDF) versus stavudine (d4T) when used in combination with lamivudine (3TC) and efavirenz (EFV) in HIV-1 infected patients naïve to antiretroviral therapy (ART) after 48 weeks of treatment

Anton Pozniak1, Schlomo Staszewski2, Joel Gallant3, Jamal Suleiman4, Edwin DeJesus5, Adriano Lazzarin6, San Tran, Biao Lu, Andrew Cheng, Dion Coakley7
Int Cong Drug Therapy HIV 2002 Nov 17-21;6:Abstract No. P1

Purpose: TDF is a single tablet, once daily nucleotide analogue reverse transcriptase inhibitor with potent activity against wild-type and nucleoside resistant HIV. Prior studies have demonstrated significant and sustained anti- HIV activity when TDF was added to stable background ART in treatmentexperienced patients. Study 903 was designed to evaluate the efficacy and safety of TDF as part of a fixed ART regimen in antiretroviral naïve patients over a 3-year period.

Methods: Phase III, multicenter, randomized, double-blind, active-controlled trial in patients with HIV-1 RNA >5,000 copies/mL with no requirement for entry CD4+ lymphocyte cell count. Patients were randomized to receive either TDF (300mg qd) or d4T (40mg bid or 30mg bid if weight <60kg) plus 3TC (150mg bid) and EFV (600mg qd). Patients randomized to TDF received d4T placebo bid while those randomized to d4T received TDF placebo once daily.

Summary of Results: The intent-to-treat (ITT) population included 600 patients with the following baseline characteristics: mean age 36 years, 76% male, 64% Caucasian, mean HIV-1 RNA 4.9 log10 c/mL; mean CD4 cell count 279 cells/mm3. Forty-five percent of the patients entered the study with HIV-1 RNA levels >100,000 c/mL and 39% of the patients had CD4 cell count <200 cells/mm3 at baseline. Data from a week 48 interim analysis are shown below.

    TDF/3TC/EFV
(n=299)		 d4T/3TC/EFV
(n=301)		 95% CI*
HIV RNA <400 c/mL (ITT)
   Missing equals failure 87%   87%   -6, +5  
   Missing values excluded 95%   96%   -4, +2  
HIV RNA <50 c/mL (ITT)
   Missing equals failure 82%   81%   -6, +6  
   Missing values excluded 90%   89%   -4, +5  
Mean Change CD4 cell count (cell/mm3) +169   +167  
Study discontinuation (d/c) 9%   9%     
Drug regimen d/c for adverse events 7%   6%     
≥Grade 3 adverse events 19%   17%     
≥Grade 3 laboratory abnormalities 28   31%     
* For difference in TDF arm – d4T arm


Both treatment arms had a similar virological response irrespective of baseline HIV-RNA level or CD4 cell count.

Of the laboratory markers evaluated, patients receiving d4T (n=253) had a mean increase from baseline in triglyceride levels of 74 mg/dL compared to no mean change for patients in the TDF arm (n=242; p<0.001). Increases in cholesterol levels for patients in the TDF and d4T were 25 mg/dL and 53 mg/dL, respectively (p<0.001). The incidence of nucleoside-associated toxicities in the TDF-containing arm was 3% compared to 11% in the d4Tcontaining arm (e.g. peripheral neuropathy, lactic acidosis, lipodystrophy).

Conclusions: Through 48 weeks, combination therapy with TDF was highly effective and comparable to d4T for efficacy in ART-naïve patients. Although the therapy was generally well tolerated in both treatment arms, patients in the TDF arm had no change in triglyceride levels, a significantly lower increase in cholesterol levels, and a lower incidence of nucleosideassociated toxicities compared to the patients in the d4T arm.

Presenting author: Anton Pozniak

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1 Chelsea and Westminster Hospital, London, United Kingdom.

2 University Hospital, JW Goethe-Universität, Germany.

3 Johns Hopkins University School of Medicine, USA.

4 Instituto de Infectologia Emilio Ribas, Brazil.

5 LDC Research Initiative, USA.

6 Ospedale San Raffaele, Milan, Italy.

7 Gilead Sciences, Foster City, USA.

2002-11-17
P1

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