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Tenofovir vs d4T, 96 Week Study Results
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Here is excerpt from press release distributed by Gilead Sciences regarding
the 96-week 903 study results comparing tenofovir vs d4T presented at the
Retrovirus Conference. This study compares tenofovir to d4T and shows
benefits compared to d4T related to body changes, lipids, weight gain,
neuropathy & lactic acidosis (associated with mitochondrial toxicity), while
showing good viral load reductions in both arms. Patients received efavirenz
and 3TC along with either d4T or tenofovir. It would be interesting to see a
similar study comparing tenofovir vs abacavir or AZT to see if their would be
differences. Jules Levin
Press Release
96-WEEK DATA FROM PHASE III STUDY SHOW LONG-TERM EFFICACY WITH
REDUCED RISK OF LIPID AND METABOLIC CHANGES FOR VIREAD VERSUS
STAVUDINE IN
TREATMENT-NAIVE HIV PATIENTS
Data Presented at 10th Conference on Retroviruses and Opportunistic Infections
Boston, MA, February 11, 2003 - Gilead Sciences (Nasdaq: GILD) today
presented 96-week data from a controlled clinical trial (Study 903)
demonstrating that treatment-naive patients who received Viread (tenofovir
disoproxil fumarate) experienced substantially less lipodystrophy and lower
elevations in fasting cholesterol and triglyceride levels, while achieving
similar reductions in HIV viral load and increases in CD4 cell counts,
compared to those who received stavudine (d4T).
Study 903 is an ongoing three-year, randomized, double-blind trial designed
to compare the efficacy and safety of a treatment regimen of Viread,
lamivudine (3TC) and efavirenz to a regimen of stavudine, lamivudine and
efavirenz in 600 antiretroviral-naive patients with HIV infection. The
96-week data were presented today (Abstract #564b) at the 10th Conference on
Retroviruses and Opportunistic Infections in Boston, Massachusetts.
"These data are impressive because efficacy remains strong in both arms at 96
weeks, but the Viread-containing arm has a side effect profile that has
continued to improve compared to stavudine since the 48-week point," said
Schlomo Staszewski, MD, University Hospital, J.W. Goethe-UniversitŠt,
Frankfurt, Germany and a lead investigator for the study. "The potential for
long-term efficacy with reduced side effects compared to stavudine makes
Viread an attractive antiretroviral for use in HIV therapy."
Study Results
The 96-week results presented today show that the Viread and stavudine arms
reduced HIV RNA to less than 400 copies/mL in 82 and 78 percent of patients
respectively, using the most conservative "missing equals failure" analysis.
Seventy-eight and 74 percent of patients achieved HIV RNA less than 50
copies/mL. Excluding missing data, 96 and 93 percent of patients in the
Viread and stavudine arms achieved HIV RNA less than 400 copies/mL and 92 and
88 percent of patients achieved HIV RNA less than 50 copies/mL. Patients in
both arms of the study experienced substantial increases in mean CD4 cell
counts, from the baseline mean of 276 to 537 cells/mm3 in the Viread arm and
from the baseline mean of 283 to 549 cells/mm3 in the stavudine arm. Grade 3
and 4 adverse events and laboratory abnormalities were similar across
treatment groups. Grade 3 and 4 adverse events were reported in less than
two percent of patients and included rash, bacterial infection, depression,
fever and pneumonia. There was a low discontinuation rate of approximately
15 percent in both arms.
Lipid levels (triglycerides and cholesterol) measured in the fasting state
were significantly different between the Viread and stavudine treatment
groups. Patients receiving Viread experienced a mean increase from baseline
in triglycerides of 5 mg/dL, whereas patients in the stavudine group
experienced an increase of 103 mg/dL (p<0.001). Increases in low-density
lipoprotein cholesterol (LDL or "bad" cholesterol) were 82 percent higher for
patients receiving stavudine, with an increase of 11 mg/dL in the Viread arm
and an increase of 20 mg/dL in the stavudine arm (p<0.001). Significant
differences also were noted in the impact of therapy on high-density
lipoprotein cholesterol (HDL or "good" cholesterol), with patients in the
Viread treatment group experiencing a mean increase of 9 mg/dL in "good"
cholesterol, compared with an increase of 7 mg/dL in the stavudine arm
(p=0.03). In addition, 10 percent of patients in the stavudine arm added a
lipid-lowering drug during the study compared to two percent in the Viread
arm.
Metabolic Changes
The 96-week data from this study further extend the evidence of Viread's
favorable metabolic profile for treatment-naive patients observed at 48
weeks. Physician-reported lipodystrophy was observed in one percent of
patients receiving Viread, compared with 12 percent of patients receiving
stavudine (p<0.001). In a separate sub-study of 250 patients, whole-body
DEXA scans showed significantly more limb fat in the Viread arm than the
stavudine arm at 96 weeks. Loss of limb fat, or peripheral lipoatrophy, is a
crucial component of lipodystrophy - characterized as diverse changes in
metabolism and body shape - which has been associated with long-term
administration of some anti-HIV medications.
Additionally, patients in the Viread arm experienced a favorable weight gain
of 6.1 pounds from baseline versus 0.8 pounds in the stavudine arm (p=0.002).
Weight gain is an important indicator of overall well being for HIV-infected
patients.
Patients who received Viread had significantly fewer adverse events
associated with mitochondrial toxicity, such as peripheral neuropathy, lactic
acidosis and lipodystrophy. After 96 weeks of treatment, the relative risk
of these toxicities was 5.5 fold greater (95 percent confidence interval:
3.0-10.3 fold) in the stavudine-containing arm compared with the
Viread-containing arm.
Study 903 Continues
Gilead designed Study 903 as a three-year trial to gather a wide variety of
data on Viread's efficacy and safety profile in a controlled manner over
time. Study 903 is being conducted in the United States, Europe and South
America. Twenty-six percent of the study participants are women, and 36
percent are people of color. According to the U.S. Centers for Disease
Control, women now account for 30 percent of new HIV infections in the United
States, while nearly three-fourths of new HIV infections affect
non-Caucasians.
About Viread
Viread is the first nucleotide analogue reverse transcriptase inhibitor
(NtRTI) approved for the treatment of HIV in the United States and Europe.
Since approval, approximately 85,000 patients have been prescribed Viread as
part of combination therapy in the United States alone. The U.S. Food and
Drug Administration approved Viread for marketing in October 2001 and the
European Commission granted approval in February 2002. In clinical trials
and expanded access programs, approximately 10,000 patients have been treated
with Viread alone or in combination with other antiretroviral products for
periods up to four years. The drug works by blocking reverse transcriptase,
an enzyme involved in the replication of HIV. The approved dose of Viread
for the treatment of HIV infection is 300 mg once daily taken orally with a
meal.
In the United States, Viread is indicated for use in combination with other
antiretroviral agents for the treatment of HIV-1 infection. This indication
is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a
controlled study of Viread of 24 weeks duration and in a controlled,
dose-ranging study of Viread of 48 weeks duration. Both studies were
conducted in treatment-experienced adults with evidence of HIV-1 viral
replication despite ongoing antiretroviral therapy. Studies in
antiretroviral-naive patients are ongoing; consequently, the risk-benefit
ratio for this population has yet to be determined.
Safety Profile
Assessment of adverse reactions is based on two studies (902 and 907) in
which 653 treatment-experienced patients received treatment with Viread 300
mg (n=443) or placebo (n=210) for 24 weeks followed by extended treatment
with the drug. Adverse event rates in the Viread group were similar to those
in the placebo-treated patients. The most common adverse events in these
patients were mild to moderate gastrointestinal events, such as nausea,
diarrhea, vomiting and flatulence. Laboratory abnormalities observed in
clinical studies occurred with similar frequency in the Viread and
placebo-treated groups.
In clinical practice, a number of adverse events, including renal impairment,
nausea, rash and asthenia (weakness) have been reported. Renal impairment
occurred most often in patients with underlying systemic or renal disease, or
in patients taking concomitant nephrotoxic agents. Lactic acidosis and
severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues alone or in combination with other
antiretrovirals.
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