Gilead Sciences, Inc. (Nasdaq:GILD) today announced the
presentation of 144-week data from an ongoing clinical trial, Study
934, comparing a once-daily regimen of Truvada(R) (emtricitabine and
tenofovir disoproxil fumarate) and Sustiva(R) (efavirenz) to a
twice-daily regimen of Combivir(R) (lamivudine/zidovudine) with
Sustiva once daily in treatment-naive adults with HIV. Data were
presented by Jose Arribas, MD, of the University Hospital La Paz,
Madrid, Spain at the 4th International AIDS Society Conference on HIV
Pathogenesis, Treatment and Prevention taking place July 22-25 in
Sydney, Australia (Poster #WEPEB029).
Study 934 is an ongoing Phase III, open-label clinical trial in
the United States and Europe. Truvada is a fixed-dose once-daily
tablet containing Gilead's Viread(R) (tenofovir disoproxil fumarate)
and Emtriva(R) (emtricitabine). At study initiation, patients received
Viread and Emtriva with Sustiva. At week 96, which coincided with
commercial availability of Truvada in the United States, all patients
receiving Viread, Emtriva and Sustiva were switched to receive a
simplified regimen of Truvada and Sustiva. Truvada is currently the
most commonly prescribed nucleoside backbone for combination HIV
therapy in the United States.
Truvada and Sustiva are also available in the United States as the
fixed-dose product Atripla(TM) (efavirenz 600 mg/ emtricitabine 200
mg/ tenofovir disoproxil fumarate 300 mg), through a U.S. joint
venture between Bristol-Myers Squibb Company and Gilead Sciences.
Atripla was approved in the United States on July 12, 2006.
"These data demonstrate the safety and efficacy profile of the
components of Atripla over three years," commented Dr. Arribas. "As
the treatment landscape for HIV improves and patients live longer, the
importance of a proven and durable first-line regimen with simple
dosing is critical."
Study 934 Results
Study 934 is a Phase III, open-label, non-inferiority study that
enrolled 517 HIV-infected patients in the United States and Europe.
Two patients were protocol violations and six never received drug,
resulting in an intent to treat population of 509 patients. The
study's primary endpoint was at 48 weeks and the study has continued
through 144 weeks. Twenty-two patients with baseline non-nucleoside
reverse transcriptase inhibitor (NNRTI) mutations and 31 patients who
completed week 48 and week 96 of the study with HIV RNA (viral load)
less than 400 copies/mL but did not consent to participate after week
96 were excluded from the week 144 efficacy population. Participants
were originally 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, had HIV RNA greater than 10,000 copies/mL and any CD4
cell count. At week 96, patients receiving Viread, Emtriva and Sustiva
were switched to a regimen of Truvada/Sustiva.
After 144 weeks of treatment, 71 percent of Truvada/Sustiva
patients compared to 58 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) (n=456, p=0.004; 95% CI,
+4.2% to +21.6%). Sixty-four percent of patients in the
Truvada/Sustiva arm compared to 56 percent of patients in the
Combivir/Sustiva arm achieved and maintained viral load less than 50
copies/mL using TLOVR (n=458, p=0.08; 95% CI, -0.8% to +17%). The mean
increase from baseline in CD4 cell counts at week 144 was 312 and 271
cells/mm(3) in the Truvada/Sustiva and Combivir/Sustiva arms,
respectively (p=0.09).
Genotypic resistance analyses were performed on patients without
pre-existing baseline NNRTI resistance mutations who either had
confirmed plasma HIV RNA greater than 400 copies/mL or discontinued
study drug early. Through 144 weeks, no patients in either arm of the
study developed the K65R mutation, which is associated with reduced
susceptibility to Viread. Fewer Truvada/Sustiva patients developed the
M184V/I mutation, which is associated with resistance to Emtriva and
to the lamivudine component of Combivir (2 vs. 10 patients; p=0.02).
After 144 weeks of treatment, a significantly greater percentage
of patients in the Combivir/Sustiva group experienced adverse events
that resulted in discontinuation of study medications compared to the
Truvada/Sustiva arm (11 vs. 5 percent, respectively; p=0.01). The most
common cause of discontinuation in the Combivir/Sustiva arm was
anemia/hemoglobin decrease (14 vs. 0 patients in the Truvada/Sustiva
arm), and in the Truvada/Sustiva arm was rash (4 patients vs. 1
patient in the Combivir/Sustiva arm).
Renal adverse events were uncommon at 144 weeks, consistent with
study data at weeks 48 and 96. No patient discontinued study
medication due to renal events.
After 144 weeks of treatment, patients in the Combivir/Sustiva arm
experienced greater mean elevations from baseline in fasting total
cholesterol levels (36 vs. 24 mg/dL in the Truvada/Sustiva arm;
p=0.005) and greater mean increases from baseline in fasting
triglycerides (36 vs. 4 mg/dL in the Truvada/Sustiva arm; p=0.047).
Loss of limb fat, a marker for lipodystrophy, was observed among
patients receiving Combivir/Sustiva. Among 269 patients with available
data, median total limb fat was significantly less in patients
receiving Combivir/Sustiva compared to patients receiving
Truvada/Sustiva (5.4 vs 7.9 kg; p less than 0.001) at week 144. Among
patients with data available at 48 and 144 weeks, median total limb
fat decreased significantly in the Combivir/Sustiva arm (from 6.0 kg
to 4.9 kg; n=49, 38) and increased significantly in the
Truvada/Sustiva arm (from 7.4 kg to 8.3 kg; n=51, 48).
Data from this analysis have not been reviewed by the U.S. Food
and Drug Administration.
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 or Emtriva, 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 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.
Coadministration 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.
Adverse events observed with Viread and Emtriva used in
combination in Study 934 were generally consistent with those seen in
other studies in treatment-experienced or treatment-naive patients
receiving Viread and/or 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 a no-profit price in parts of the
world where the epidemic has hit the hardest.
For complete prescribing information for Truvada, visit
www.truvada.com.
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(R) or Epivir-HBV(R) (lamivudine),
Epzicom(TM) (abacavir sulfate/lamivudine) or Trizivir(R) (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 percent), suicidal ideation (0.7 percent), nonfatal
suicide attempts (0.5 percent), aggressive behavior (0.4 percent),
paranoid reactions (0.4 percent) and manic reactions (0.2 percent)
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 percent),
insomnia (16.3 percent), impaired concentration (8.3 percent),
somnolence (7.0 percent), abnormal dreams (6.2 percent) and
hallucinations (1.2 percent) 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 percent) 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. Visit Gilead on the World Wide Web at
www.gilead.com.
Full U.S. prescribing information for Atripla is available at
www.atripla.com.
Full U.S. prescribing information for Truvada, Viread and Emtriva
is available at www.gilead.com.
Full U.S. prescribing information for Sustiva is available at
www.bms.com.
Atripla is a trademark of Bristol-Myers Squibb & Gilead Sciences,
LLC.
Truvada, Viread and Emtriva are registered trademarks of Gilead
Sciences, Inc.
Sustiva is a registered trademark of Bristol-Myers Squibb Pharma
Company.
