Gilead Sciences, Inc. (Nasdaq:GILD) today announced 48-week data
from a Phase III clinical trial evaluating virologically-suppressed
patients with HIV who switched from treatment with twice-daily
Combivir(R) (lamivudine/zidovudine) to treatment with Gilead´s
once-daily Truvada(R) (emtricitabine and tenofovir disoproxil
fumarate) as part of their combination drug therapy. In the SWEET
(Simplification With Easier Emtricitabine and Tenofovir) study,
patients who switched from Combivir to Truvada, both in combination
with once-daily Sustiva(R) (efavirenz), experienced improvements in a
number of treatment-related side effects. Patients in both study arms
maintained virological suppression at 48 weeks. The data were
presented at the 11th European AIDS Conference (EACS), held October
24-27 in Madrid, Spain.
"As HIV patients live longer and remain on therapy for extended
periods of time, the long-term side effect profile of treatment is
increasingly more important," said Martin Fisher, MD, Brighton and
Sussex University Hospitals, Brighton, United Kingdom and the
principal investigator for the SWEET study. "Data from this study
indicate that patients on long-term Combivir therapy without clinical
lipoatrophy may benefit from switching to Truvada, as virological
control can be maintained and limb fat loss and recovery may be
improved. These data support the new EACS 2007 guidelines regarding
proactive switching."
New European HIV treatment guidelines issued this week at EACS
list Truvada among the recommended components of a first-line
treatment regimen for antiretroviral naive patients. Combivir,
previously recommended as a first-line treatment option, is now listed
as an alternative treatment option.
In the United States, the components of Truvada and Sustiva are
available in a fixed-dose combination tablet called Atripla(R)
(efavirenz 600mg / emtricitabine 200mg / tenofovir disoproxil fumarate
300 mg). Atripla is currently the first and only once-daily single
tablet regimen approved for the treatment of HIV-1 infection in adults
in the United States for use either as stand-alone therapy or in
combination with other antiretroviral agents. On October 18, 2007, the
Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency (EMEA) recommended that Atripla be approved for use
in the European Union. A final decision on Atripla by the European
Commission is expected by the end of the year.
About The SWEET Study
SWEET was a 48-week, multicenter, prospective, open-label study
evaluating 250 HIV-infected patients. At study entry, patients
received a treatment regimen of Combivir and Sustiva and were
virologically controlled with HIV RNA of less than 50 copies/mL for
the last two consecutive testings and less than 400 copies/mL for more
than three months. Of the 250 patients enrolled in the study, 234
received at least one dose of study drug. Subjects were randomized 1:1
to continue with a regimen of Combivir and Sustiva (n=117) or switch
to a regimen of Truvada and Sustiva (n=117). Baseline characteristics
were well matched between study arms. The median prior use of Combivir
among patients was 36 months. Among patients who switched to Truvada
and Sustiva, 88 percent were suppressed to less than 50 copies/mL at
48 weeks, compared to 85 percent of patients who continued with
Combivir (intent-to-treat, missing = failure analysis; 95% CI: -6% to
+11%; p=0.70). In addition, median CD4 counts remained comparable
between the study arms.
Limb fat was measured using DEXA scans in a subset of 100 study
participants, of whom 74 had both baseline and 48-week data available.
In this sub-study, a median increase in limb fat of 0.21 kg was
observed among patients who switched to Truvada and a median decrease
of 0.14 kg was observed among patients who continued on Combivir
(p=0.025). Differences in limb fat were more pronounced among patients
who had less experience with AZT (zidovudine).
At week 48, a median increase in hemoglobin of 0.5 g/dL was
observed among Truvada patients and a median decrease of 0.1 g/dL was
observed among those taking Combivir (p less than 0.001). Twenty-two
percent of patients who switched to Truvada (n=22) experienced an
increase in hemoglobin greater than 1 g/dL at 48 weeks compared to 2
percent of Combivir patients (n=2). Conversely, 9 percent of patients
who remained on Combivir (n=8) experienced a reduction in hemoglobin
greater than 1 g/dL, compared to 2 percent of patients who switched to
Truvada (n=2).
Truvada patients in the study also experienced improvements across
a number of lipid parameters. After 48 weeks of treatment, fasting
total cholesterol fell by a median of 0.22 mmol/L (8.46 mg/dl) among
Truvada patients, compared to a reduction of 0.06 mmol/L (2.30 mg/dl)
among Combivir patients (p=0.23; Truvada vs. Combivir comparison).
Fasting triglycerides fell by a median of 0.17 mmol/L (15.45 mg/dl)
among Truvada patients, but increased by 0.04 mmol/L (3.63 mg/dl)
among those who continued treatment with Combivir (p=0.11; Truvada vs.
Combivir comparison).
Renal function remained within normal ranges in both treatment
arms after 48 weeks of treatment, as measured by creatinine clearance
(Cockroft-Gault) and estimated glomerular filtration rate (MDRD).
Median creatinine increased by 3 umol/L (less than 0.01 mg/dl) among
Truvada patients (p less than 0.001), and declined by 1 umol/L (less
than 0.01 mg/dl) among patients in the Combivir group (p=0.57).
Five percent of Combivir patients and 3 percent of Truvada
patients discontinued study drug due to adverse events. These included
dizziness, insomnia, nausea, depression and sleep disorder in the
Truvada arm and angiosarcoma, pulmonary embolism, pulmonary
hypertension, weight loss of arms and legs, syncope, worsening of
lipoatrophy and depression in the Combivir arm.
Important Product Safety Information About Truvada and Atripla
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. Truvada and
Atripla are not approved for the treatment of chronic hepatitis B
virus (HBV) infection and their safety and efficacy have not been
established in patients co-infected with HBV and HIV. Severe acute
exacerbations of hepatitis B have been reported in patients who have
discontinued Viread(R) (tenofovir disoproxil fumarate) or Emtriva(R)
(emtricitabine), which are components of Truvada and Atripla. In some
of these patients treated with Emtriva, the exacerbations of hepatitis
B were associated with liver decompensation and liver failure. Hepatic
function should be monitored closely with both clinical and laboratory
follow-up for at least several months in patients who are co-infected
with HIV and HBV and discontinue Truvada or Atripla. If appropriate,
initiation of anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that anti-HIV medicines
including Truvada and Atripla do not cure HIV infection or AIDS and do
not reduce the risk of transmitting HIV to others.
Additional Important Information About Truvada
Truvada is a fixed-dose combination tablet containing 200 mg of
emtricitabine (Emtriva) and 300 mg of tenofovir disoproxil fumarate
(Viread). In the United States, Truvada is indicated in combination
with other antiretroviral agents, such as non-nucleoside reverse
transcriptase inhibitors or protease inhibitors, for the treatment of
HIV-1 infection in adults.
It is not recommended that Truvada be used as a component of a
triple nucleoside regimen. Truvada should not be coadministered with
Atripla, Emtriva, Viread or lamivudine-containing products, including
Combivir (lamivudine/zidovudine), Epivir(R) or Epivir-HBV(R)
(lamivudine), Epzicom(TM) (abacavir sulfate/lamivudine) or Trizivir(R)
(abacavir sulfate/lamivudine/zidovudine). In treatment-experienced
patients, the use of Truvada should be guided by laboratory testing
and treatment history.
Emtricitabine and tenofovir are principally eliminated by the
kidneys. Renal impairment, including cases of acute renal failure and
Fanconi syndrome (renal tubular injury with severe hypophosphatemia),
has been reported in association with the use of Viread, a component
of Truvada. It is recommended that creatinine clearance be calculated
in all patients prior to initiating therapy with Truvada and as
clinically appropriate during therapy. Routine monitoring of
calculated creatinine clearance and serum phosphorous should be
performed in patients at risk for renal impairment. Dosing interval
adjustment and close monitoring of renal function are recommended in
all patients with creatinine clearance of 30-49 ml/min. Truvada should
be avoided with concurrent or recent use of a nephrotoxic agent.
No drug interaction studies have been conducted using Truvada. The
U.S. package insert advises that co-administration of Truvada and
didanosine should be undertaken with caution. Patients should be
monitored closely for didanosine-associated adverse events and
didanosine should be discontinued if these occur. Patients on
atazanavir and lopinavir/ritonavir plus Truvada should be monitored
for Truvada-associated adverse events and Truvada should be
discontinued if these occur. When co-administered with Truvada, it is
recommended that atazanavir be given with ritonavir 100 mg. Atazanavir
without ritonavir should not be co-administered with Truvada.
Decreases in bone mineral density (BMD) at the lumbar spine and
hip have been seen with the use of Viread. The effect on long-term
bone health and future fracture risk is unknown. Cases of osteomalacia
(associated with proximal renal tubulopathy) have been reported in
association with the use of Viread.
Changes in body fat have been observed in patients taking anti-HIV
medicines. The mechanism and long-term health effect of these
conditions are unknown. Immune Reconstitution Syndrome has been
reported in patients treated with combination therapy, including
Viread and Emtriva.
Treatment-emergent adverse events occurring in at least 3 percent
of patients receiving Viread and Emtriva in Study 934 included
dizziness (8%), diarrhea (7%), nausea (8%), fatigue (7%), sinusitis
(4%), upper respiratory tract infections (3%), nasopharyngitis (3%),
somnolence (3%), headache (5%), dizziness (8%), depression (4%),
insomnia (4%), abnormal dreams (4%) and rash (5%).
Skin discoloration has been reported with higher frequency among
Emtriva-treated patients. Skin discoloration, manifested by
hyperpigmentation on the palms and/or soles was generally mild and
asymptomatic. The mechanism and clinical significance are unknown.
The parent compound of Viread was discovered through a
collaborative research effort between Dr. Antonin Holy, Institute for
Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for
Medical Research, Katholic University in Leuven, Belgium. The
inventors of Viread have agreed to waive their right to a royalty on
sales of Viread and Truvada in the Gilead Access Program countries to
ensure the product can be offered at cost in parts of the world where
the epidemic has hit the hardest.
For complete prescribing information for Truvada, visit
www.truvada.com. For full prescribing information outside of the
United States, physicians should consult their local product labeling.
Additional Important Information About Atripla
In the United States, Atripla is indicated for use alone as a
complete regimen or in combination with other antiretroviral agents
for the treatment of HIV-1 infection in adults.
Atripla contains the components Truvada (emtricitabine and
tenofovir disoproxil fumarate) and Sustiva (efavirenz), co-formulated
as a single tablet. As such, the important safety information
appearing in the above Truvada section also applies to Atripla, in
addition to the following important product information.
As a fixed-dose regimen of Viread (tenofovir disoproxil fumarate),
Emtriva (emtricitabine) and Sustiva (efavirenz), Atripla should not be
coadministered with Viread, Emtriva, Truvada (emtricitabine and
tenofovir disoproxil fumarate) or Sustiva. Due to similarities between
Emtriva and lamivudine, Atripla should not be coadministered with
drugs containing lamivudine, including Combivir
(lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom
(abacavir sulfate/lamivudine) or Trizivir (abacavir
sulfate/lamivudine/zidovudine).
Atripla should not be taken with Hismanal(R) (astemizole),
Vascor(R) (bepridil), Propulsid(R) (cisapride), Versed(R) (midazolam),
Orap(R) (pimozide), Halcion(R) (triazolam), ergot medicines (for
example, Wigraine(R) and Cafergot(R)), or Vfend(R) (voriconazole) due
to a contraindication with efavirenz. Use of Atripla with St. John´s
wort (Hypericum perforatum) or St. John´s wort-containing products is
not recommended. This list of medicines is not complete. Patients
should discuss all prescription and non-prescription medicines,
vitamin and herbal supplements, or other health preparations they are
taking or plan to take with their healthcare provider.
Atripla should not be given to patients with creatinine clearance
less than 50 ml/min.
Serious psychiatric adverse experiences, including severe
depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts
(0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%) and
manic reactions (0.2%) have been reported in patients treated with
efavirenz, a component of Atripla. In addition to efavirenz, factors
identified in a clinical study that were associated with an increase
in psychiatric symptoms included a history of injection drug use,
psychiatric history and use of psychiatric medication. There have been
occasional reports of death by suicide, delusions, and psychosis-like
behavior, but it could not be determined if efavirenz was the cause.
Patients with serious psychiatric adverse experiences should be
evaluated immediately to determine whether the risks of continued
therapy outweigh the benefits. Patients should tell their doctor if
they have a history of mental illness or are using drugs or alcohol.
Fifty-three percent of patients in clinical studies have reported
central nervous system symptoms including dizziness (28.1%), insomnia
(16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal
dreams (6.2%) and hallucinations (1.2%) when taking efavirenz compared
to 25 percent of patients receiving control regimens. These symptoms
usually begin during the first or second day of therapy and generally
resolve after the first two to four weeks of therapy. After four weeks
of therapy, the prevalence of central nervous system symptoms of at
least moderate severity ranged from 5 to 9 percent in patients treated
with regimens containing efavirenz. Nervous system symptoms are not
predictive of the less frequent psychiatric symptoms.
Women should not become pregnant or breastfeed while taking
Atripla. Serious birth defects have been seen in children of women
treated with efavirenz during pregnancy. Women must use a reliable
form of barrier contraception, such as a condom, even if they also use
other methods of birth control.
Rash is a common side effect that usually goes away without any
change in treatment. Rash may be a serious problem in some children.
Patients with liver disease may require the healthcare provider to
check liver function or check drug levels in the blood.
Atripla should be used with caution in patients with a history of
seizures. Convulsions have been observed in patients receiving
efavirenz, generally in the presence of a known medical history of
seizures.
Invirase(R) (saquinavir) should not be used as the only protease
inhibitor in combination with Atripla.
The most significant adverse events observed in patients treated
with Sustiva are nervous system symptoms, psychiatric symptoms and
rash. The most common adverse events (at least 5%) observed in
clinical studies with Sustiva include fatigue, pain, dizziness,
headache, insomnia, impaired concentration, nausea, vomiting,
diarrhea, depression, rash, and pruritus.
For complete prescribing information for Atripla, visit
www.atripla.com.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers,
develops and commercializes innovative therapeutics in areas of unmet
medical need. The company´s mission is to advance the care of patients
suffering from life-threatening diseases worldwide. Headquartered in
Foster City, California, Gilead has operations in North America,
Europe and Australia.
Forward-Looking Statement
This press release includes forward-looking statements, within the
meaning of the Private Securities Litigation Reform Act of 1995, that
are subject to risks, uncertainties and other factors, including the
risk that as Truvada and Atripla are used over longer periods of time
by many patients taking numerous other medicines, many of whom have
underlying health problems, we may find new issues such as safety,
resistance or drug interaction issues, which may require us to provide
additional warnings or contraindications on our labels or narrow our
approved indications, each of which could reduce the market acceptance
of these products. These risks, uncertainties and other factors could
cause actual results to differ materially from those referred to in
the forward-looking statements. The reader is cautioned not to rely on
these forward-looking statements. These and other risks are described
in detail in Gilead´s Annual Report on Form 10-K for the year ended
December 31, 2006 and its Quarterly Reports on Form 10-Q for the first
and second quarters of 2007, as filed with the U.S. Securities and
Exchange Commission. All forward-looking statements are based on
information currently available to Gilead, and Gilead assumes no
obligation to update any such forward-looking statements.
U.S. full prescribing information for Truvada, Atripla, Viread and
Emtriva are available at www.gilead.com.
Truvada, Viread and Emtriva are registered trademarks of Gilead
Sciences, Inc. Atripla is a registered trademark of Bristol-Myers
Squibb & Gilead Sciences, LLC.
For more information on Gilead, please call the Gilead Public
Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit
www.gilead.com.
