Gilead Sciences, Inc. (Nasdaq:GILD) today announced the
publication of 96-week data from an ongoing clinical trial, Study 934,
in the Journal of Acquired Immune Deficiency Syndrome (JAIDS). This
study compares a once-daily regimen of Viread(R) (tenofovir disoproxil
fumarate), Emtriva(R) (emtricitabine) and Sustiva(R) (efavirenz) to a
twice-daily regimen of Combivir(R) (lamivudine/zidovudine) with
Sustiva once daily. The study article, "Tenofovir Disoproxil Fumarate,
Emtricitabine, and Efavirenz Versus Fixed-Dose Zidovudine/Lamivudine
and Efavirenz in Antiretroviral-Naive Patients," appears in the
December 15 issue of JAIDS (Vol. 43; issue 5).
"The efficacy, safety and resistance profile of
Viread/Emtriva/Sustiva in this study underscores the importance of
this treatment option for antiretroviral therapy-naive patients," said
lead author Anton Pozniak, MD, of the Chelsea and Westminster
Hospital, London. "Sustiva, Emtriva and Viread were administered as
individual agents in this trial, but a fixed-dose combination of these
drugs is now available, offering more convenient dosing."
Viread and Emtriva are available as once-daily Truvada(R)
(emtricitabine and tenofovir disoproxil fumarate), the most commonly
prescribed backbone for HIV combination therapy. Viread, Emtriva and
Sustiva are available in the United States as ATRIPLA(TM) (efavirenz
600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg),
the only once-daily single tablet regimen for the treatment of HIV-1
infection in adults. ATRIPLA was developed through a U.S. joint
venture between Bristol-Myers Squibb and Gilead Sciences. Together
with Merck & Co., Inc., the companies recently submitted a Marketing
Authorisation Application (MAA) for the product to the European
Medicines Agency (EMEA).
Ninety-six week data from this study were originally presented at
the XVI International AIDS Conference in Toronto, Canada in August,
2006. Data from this analysis have not been reviewed by the U.S. Food
& Drug Administration.
Study 934
Study 934 is a Phase III, open-label, non-inferiority study that
enrolled 517 HIV-infected patients in the United States and Europe.
The study's primary endpoint was at 48 weeks and the study is
continuing through 144 weeks. The prespecified primary efficacy
population included 487 patients. Twenty-four patients (12 from each
arm) who completed week 48 of the study with HIV RNA less than 400
copies/mL did not consent to participate after week 48 and were
excluded from the analysis. Participants were randomized to receive
Viread 300 mg, Emtriva 200 mg and Sustiva 600 mg, all dosed once
daily, or Combivir twice daily and Sustiva 600 mg once daily. At study
entry, patients were treatment-naive and had HIV RNA (viral load)
greater than 10,000 copies/mL.
After 96 weeks of treatment (n=463), 75 percent of
Viread/Emtriva/Sustiva patients compared to 62 percent of
Combivir/Sustiva patients achieved and maintained viral load less than
400 copies/mL using the Time to Loss of Virologic Response algorithm
(TLOVR) (p=0.004; 95% CI, +4% to +21%). Sixty-seven percent of
patients in the Viread/Emtriva/Sustiva arm compared to 61 percent of
patients in the Combivir/Sustiva arm achieved and maintained viral
load less than 50 copies/mL using TLOVR (p=0.16; 95% CI, -2% to +15%).
Patients receiving Viread/Emtriva/Sustiva experienced a significantly
greater increase from baseline in CD4 cell counts at week 96 compared
to those receiving Combivir/Sustiva (270 vs. 237 cells/mm(3);
p=0.036).
There was a significant difference between the two study arms in
terms of virologic rebound at 96 weeks (defined as having a confirmed
viral load of greater than 400 copies/mL after achieving confirmed
viral load of less than 400 copies/mL). Five percent of patients in
the Combivir/Sustiva group experienced rebound compared to less than 1
percent of Viread/Emtriva/Sustiva patients (p=0.007).
Through 96 weeks, 43 patients in the study met criteria for
resistance testing. The K65R mutation, which can be selected by
Viread, did not arise in any patient. There was a significant
difference between study arms in the development of the M184V
mutation, which was observed in 2 patients in the
Viread/Emtriva/Sustiva group compared with 9 patients in the
Combivir/Sustiva group (p=0.036).
After 96 weeks of treatment, discontinuation of study medications
due to adverse events was significantly higher among Combivir/Sustiva
patients compared to the Viread/Emtriva/Sustiva arm (11 vs. 5 percent,
respectively; p=0.008). The most common cause of discontinuation
related to study drug in at least 2 percent of patients in either arm
include anemia (6 percent in the Combivir/Sustiva group vs. 0 percent
in the Viread/Emtriva/Sustiva group), fatigue (2 percent in the
Combivir/Sustiva group vs. 0 percent in the Viread/Emtriva/Sustiva
group), nausea (2 percent in the Combivir/Sustiva group vs. less than
1 percent in the Viread/Emtriva/Sustiva group), and rash (less than 1
percent in the Combivir/Sustiva group vs. 2 percent in the
Viread/Emtriva/Sustiva group).
Patients receiving Viread/Emtriva/Sustiva had a significantly
greater median increase in weight from baseline compared to patients
receiving Combivir/Sustiva (2.7 kg vs. 0.5 kg, respectively; p less
than 0.001). Patients receiving Viread/Emtriva/Sustiva had
significantly greater median limb fat at week 96 compared to patients
receiving Combivir/Sustiva (7.7 kg, n=144 vs. 5.5 kg, n=136,
respectively; p less than 0.001). In addition, in a subset of patients
with 48- and 96-week data, significant differences in median limb fat
were observed (decrease of 0.7 kg in the Combivir/Sustiva arm; n=44;
p=0.001; increase of 0.3 kg in the Viread/Emtriva/Sustiva arm; n=49;
p=0.01).
Renal adverse events were uncommon at 96 weeks, which is
consistent with study data at 48 weeks and results from other
randomized clinical trials involving Viread in treatment-naive and
treatment-experienced patients. Renal safety was similar and renal
function remained stable in the two arms of the study. No patient
discontinued study medication due to renal events.
Important Product Safety Information
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.
ATRIPLA, Viread and Emtriva are not indicated for the treatment of
chronic hepatitis B virus (HBV) infection and the safety and efficacy
of these drugs 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 or Emtriva
(components of ATRIPLA). Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several
months in patients who discontinue ATRIPLA, Viread or Emtriva and are
co-infected with HIV and HBV. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
It is important for patients to be aware that anti-HIV medicines
including ATRIPLA, Viread and Emtriva do not cure HIV infection or
AIDS, nor have they been shown to reduce the risk of transmission of
HIV to others.
Additional Important Information About ATRIPLA
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 is contraindicated for use with astemizole, cisapride,
midazolam, triazolam, ergot derivatives, or voriconazole. Concomitant
use of ATRIPLA and St. John's wort (Hypericum perforatum) or St.
John's wort-containing products is not recommended. Since ATRIPLA
contains efavirenz, emtricitabine and tenofovir disoproxil fumarate,
it should not be coadministered with Sustiva, Emtriva, Viread, or
Truvada (emtricitabine/tenofovir disoproxil fumarate). Due to
similarities between emtricitabine and lamivudine, ATRIPLA should not
be coadministered with drugs containing lamivudine, including Combivir
(lamivudine/zidovudine), Epivir(R) (lamivudine), Epivir-HBV(R),
Epzicom(TM)(abacavir/lamivudine), or Trizivir(R)
(abacavir/lamivudine/zidovudine).
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. 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
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. Fifty-three percent of patients 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%
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% in patients treated with regimens
containing efavirenz. Nervous system symptoms are not predictive of
the less frequent psychiatric symptoms.
ATRIPLA should not be given to patients with creatinine clearance
below 50 mL/min. 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
tenofovir disoproxil fumarate, most often in patients with underlying
systemic or renal disease, or in patients taking concomitant
nephrotoxic agents. Some cases have occurred in patients with no
identified risk factors. ATRIPLA should be avoided with concurrent or
recent use of a nephrotoxic agent.
ATRIPLA may cause fetal harm when administered during the first
trimester to a pregnant woman. Women should not become pregnant or
breastfeed while taking ATRIPLA. Barrier contraception must always be
used in combination with other methods of contraception such as oral
or other hormonal contraceptives. If the patient becomes pregnant
while taking ATRIPLA, she should be apprised of the potential harm to
the fetus.
Mild to moderate rash is a common side effect of efavirenz. In
controlled clinical trials, 26% of patients treated with efavirenz
experienced new-onset skin rash compared with 17% of patients treated
in control groups. Skin discoloration, associated with emtricitabine,
may also occur. ATRIPLA should be discontinued in patients developing
severe rash associated with blistering, desquamation, mucosal
involvement, or fever. Liver enzymes should be monitored in patients
with known or suspected hepatitis B or C and when ATRIPLA is
administered with ritonavir or other medications associated with liver
toxicity. Decreases in bone mineral density (BMD) have been seen with
tenofovir disoproxil fumarate. Use ATRIPLA 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. Redistribution and/or accumulation of body fat
have been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome has been reported in patients treated
with combination antiretroviral therapy, including the components of
ATRIPLA.
Saquinavir should not be used as the only protease inhibitor in
combination with ATRIPLA. Coadministration of ATRIPLA and atazanavir
is not recommended due to concerns regarding decreased atazanavir
concentrations. Patients on lopinavir/ritonavir plus ATRIPLA should be
monitored for tenofovir-associated adverse events. ATRIPLA should be
discontinued in patients who develop tenofovir-associated adverse
events. Coadministration of ATRIPLA and didanosine should be
undertaken with caution. Patients receiving this combination should be
monitored closely for didanosine-associated adverse events. See full
prescribing information for complete list of drug-drug interactions.
In Study 934, adverse events observed in greater than or equal to
5% of patients in the Viread/Emtriva/Sustiva group include dizziness,
nausea, diarrhea, fatigue, headache, and rash.
The dose of ATRIPLA is one tablet once daily taken orally on an
empty stomach. Dosing at bedtime may improve the tolerability of
nervous system symptoms.
About Viread
In the United States, Viread is indicated in combination with
other antiretroviral agents for the treatment of HIV-1 infection.
Viread should not be used in combination with Truvada. Truvada should
not be used in combination with its component drugs, Viread or
Emtriva.
Drug interactions have been observed when didanosine, atazanavir
or lopinavir/ritonavir is co-administered with Viread and dose
adjustments may be necessary. Data are not available to recommend a
dose adjustment of didanosine for patients weighing less than 60 kg.
Patients on atazanavir and lopinavir/ritonavir plus Viread should be
monitored for Viread-associated adverse events, which may require
discontinuation. When co-administered with Viread, it is recommended
that atazanavir 300 mg be given with ritonavir 100 mg. Atazanavir
without ritonavir should not be co-administered with Viread.
Renal impairment, including cases of acute renal failure and
Fanconi syndrome (renal tubular injury with severe hypophosphatemia),
has been reported among patients taking Viread. Renal impairment
occurred most often in patients with underlying systemic or renal
disease or in patients taking concomitant nephrotoxic agents, though
some cases have appeared in patients without identified risk factors.
Decreases in bone mineral density (BMD) at the lumbar spine and hip
have been seen with the use of Viread. The effects of
Viread-associated changes in BMD and biochemical markers on long-term
bone health and future fracture risk are unknown. Redistribution
and/or accumulation of body fat have been observed in patients
receiving antiretroviral therapy. Immune reconstitution syndrome has
been reported in patients treated with combination antiretroviral
therapy including Viread.
The most common adverse events among patients receiving Viread
with other antiretroviral agents in clinical trials were mild to
moderate gastrointestinal events and dizziness. Moderate to severe
adverse events occurring in more than 5 percent of patients receiving
Viread included rash (rash, pruritis, maculopapular rash, urticaria,
vesiculobullous rash and pustular rash), headache, pain, diarrhea,
depression, back pain, fever, nausea, abdominal pain, asthenia and
anxiety (Study 903). Less than 1 percent of patients discontinued
participation because of gastrointestinal events (Study 907).
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.
About Emtriva
In the United States, Emtriva is indicated in combination with
other antiretroviral agents for the treatment of HIV-1 infection in
patients over three months of age. This indication is based on
analyses of plasma HIV-1 RNA levels and CD4 cell counts from
controlled studies of 48 weeks duration in antiretroviral-naive
patients and antiretroviral-treatment-experienced patients who were
virologically suppressed on an HIV treatment regimen. In
antiretroviral-treatment-experienced patients, the use of Emtriva may
be considered for adults with HIV strains that are expected to be
susceptible to Emtriva as assessed by genotypic or phenotypic testing.
Adverse events that occurred in more than 5 percent of patients
receiving Emtriva with other antiretroviral agents in clinical trials
include abdominal pain, asthenia (weakness), headache, diarrhea,
nausea, vomiting, dizziness and rash (rash, pruritis, maculopapular
rash, urticaria, vesiculobullous rash, pustular rash and allergic
reaction). Approximately 1 percent of patients discontinued
participation because of these events. All adverse events were
reported with similar frequency in Emtriva and control treatment
groups with the exception of skin discoloration, which was reported
with higher frequency in the Emtriva-treated group. Skin
discoloration, manifested by hyperpigmentation on the palms and/or
soles, was generally mild and asymptomatic. The mechanism and clinical
significance are unknown.
Redistribution and/or accumulation of body fat have been observed
in patients receiving antiretroviral therapy. Immune reconstitution
syndrome has been reported in patients treated with combination
antiretroviral therapy including Emtriva. For pediatric patients over
three months of age, the adverse event profile observed during
clinical trials was similar to that of adult patients, with the
exception of anemia and a higher frequency of hyperpigmentation.
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. Visit Gilead on the World Wide Web at
www.gilead.com.
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 physicians may not see advantages of ATRIPLA, Viread and
Emtriva over other antiretrovirals and may therefore be reluctant to
prescribe 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 the Gilead Annual Report on Form 10-K for the
year ended December 31, 2005, 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.
Full prescribing information for ATRIPLA is available at
www.atripla.com. Full prescribing information for Viread, Emtriva and
Truvada is available at www.gileadHIV.com.
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences,
LLC. Viread, Emtriva and Truvada are registered trademarks of Gilead
Sciences, Inc.
