Viread for Hepatitis B Maintains Antiviral Suppression with No Development of Resistance Through Four Years of Treatment

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News Article

Viread for Hepatitis B Maintains Antiviral Suppression with No Development of

Resistance Through Four Years of Treatment

From the PharmaLive.com News Archive - Oct. 30, 2010

– New Long-Term Data Also Show Significant “s” Antigen Loss in Key Patient

Population –

BOSTON--(BUSINESS WIRE)--Oct 30, 2010 - Gilead Sciences, Inc. (Nasdaq: GILD)

today announced new data from the open-label phase of two pivotal Phase III

clinical trials (Studies 102 and 103) evaluating the four-year efficacy of

Viread® (tenofovir disoproxil fumarate) for the treatment of chronic hepatitis B

virus (HBV) infection. Significantly, no resistance to Viread emerged over 192

weeks of treatment, and 10.8 percent of patients receiving Viread in Study 103

(HBeAg-positive) for four years experienced surface, or “s”, antigen (HBsAg)

loss, which is a marker of the resolution of chronic HBV infection. Additional

data from these studies and from Study 106 show the durable antiviral efficacy

of Viread among several key patient subpopulations, including patients with high

baseline viral levels, individuals of Asian descent and treatment-experienced

patients. These findings are being presented at the 61st annual meeting of the

American Association for the Study of Liver Diseases (The Liver Meeting 2010) in

Boston.

“The complete absence of Viread-related resistance detected among study

participants shows that this therapy has a high and durable barrier to viral

resistance, which is essential for the long-term success of HBV therapy,” said

Marcellin, MD, of Hôpital Beaujon in Clichy, France, INSERM CRB3 and

University of Paris Denis Diderot, and the principal investigator of Study 102.

“These four-year results underscore the long-term benefits of Viread for diverse

patient populations, including those who are difficult to treat.”

The 192-week data from Studies 102 and 103 evaluate the intent-to-treat

population (with the exception of those who left the study for administrative

reasons). In Studies 102 and 103, the majority of patients who received Viread

for up to 192 weeks experienced sustained suppression of HBV DNA levels in the

blood below 400 copies/mL and normalization of alanine aminotransferase (ALT, an

enzyme that serves as a measure of liver damage). Notably, no HBV pol/RT amino

acid substitutions associated with tenofovir resistance were detected through

192 weeks of Viread.

Among HBeAg-positive patients, 29 percent (based on observed data at week 192)

experienced “e” antigen seroconversion, which is defined as both the

disappearance of the hepatitis B “e” antigen, a marker of HBV replication

(rendering the patient “HBe-antigen negative”), and the appearance of antibodies

to this antigen (making the patient “HBe-antibody positive”). Additionally,

among HBeAg-positive patients receiving Viread through 192 weeks, the cumulative

probability (estimated by Kaplan-Meier) of “s” antigen loss, suggesting that HBV

infections may have cleared completely, was 10.8 percent.

“Over the years, physicians have come to understand the critical role of ˜s'

antigen loss in the cessation of disease activity,” said Heathcote, MD, of

the University of Toronto, Canada, and the principal investigator for Study 103.

“The 10.8 percent ˜s' loss observed in this trial is a significant finding that

makes Viread a highly attractive treatment option for HBV.”

Viread for HBV was approved by the U.S. Food and Drug Administration (FDA) in

2008 and has since become the most-prescribed HBV medicine in the United States.

It is the only recommended first-line therapy for hepatitis B to demonstrate

continuous efficacy and safety through four years in pivotal studies. In October

2010, the FDA expanded Viread's indication to include the treatment of chronic

hepatitis B among patients with decompensated liver disease, the end stage of

hepatitis B in which liver function is marginal and clinical complications

frequently occur. Decompensated liver disease is an indication for consideration

of liver transplantation.

Viread Data at The Liver Meeting

Studies 102 and 103 are both multi-center, randomized, double-blind Phase III

clinical trials comparing Viread to Hepsera® (adefovir dipivoxil) among

HBeAg-negative presumed pre-core mutant (Study 102; n=375) and HBeAg-positive

(Study 103; n=266) chronic hepatitis B patients with compensated liver disease.

Patients had HBV DNA (viral load) above 100,000 copies/mL and elevated levels of

ALT upon study initiation. The majority of patients were treatment-naïve,

although some patients had prior lamivudine treatment experience. Patients

originally randomized to Hepsera in both studies rolled over to open-label

Viread treatment (n=196) at week 48, while patients originally randomized to

Viread continued open-label Viread (n=389). After 72 weeks, patients with

confirmed viremia (HBV DNA levels at or above 400 copies/mL on two consecutive

visits) had the option of adding emtricitabine treatment by substituting

Truvada® (emtricitabine and tenofovir disoproxil fumarate) for Viread. The

number of patients entering year four was 218 (Study 102) and 130 (Study 103)

for those originally randomized to receive Viread and 109 (Study 102) and 71

(Study 103) for those originally randomized to receive Hepsera.

Overall Efficacy and Safety at Week 192 (Abstracts 476 and 477)

In an on-treatment analysis, 99 percent of patients in Study 102 and 96 percent

of patients in Study 103 who were originally randomized to receive Viread

through 192 weeks achieved viral suppression below 400 copies/mL. Among those

who were originally randomized to receive Hepsera, 100 percent of patients in

Study 102 and 99 percent of patients in Study 103 achieved viral suppression

below 400 copies/mL. In an analysis in which the addition of emtricitabine

equals failure, 84 percent and 68 percent of patients (Studies 102 and 103,

respectively) originally randomized to receive Viread and 87 percent and 72

percent of patients (Studies 102 and 103, respectively) originally randomized to

receive Hepsera experienced sustained viral suppression. The majority of

patients with elevated ALT at baseline achieved normalized ALT on treatment

(ranging from 77 percent to 86 percent across both arms in both studies). Viread

was well-tolerated in both studies. During the open-label period (week 48

through week 192), seven patients discontinued treatment due to an adverse

event. Creatinine levels, an indicator of kidney function, remained stable

through 192 weeks.

Patients with High Viral Load (Abstract 137)

In a subgroup analysis pooling data from Studies 102 and 103, 71 percent of

patients who entered the trials with high viral levels (HBV DNA of at least 9

log10 copies/mL) (n=129), achieved sustained viral suppression after 192 weeks

of Viread treatment. Of 29 patients who opted to add emtricitabine treatment

after 72 weeks due to confirmed viremia, 20 had viral suppression at week 192.

At week 192, ALT levels were normalized in 77 percent of patients with high

viral load at baseline. Among HBeAg-positive patients (n=118) in this group, 35

percent achieved HBeAg loss and 23 percent experienced HBeAg seroconversion.

Overall, 15 percent of patients with high viral load experienced HBsAg loss.

Patients of Asian Descent (Abstract 481)

In another subgroup analysis pooling four-year data from Studies 102 and 103, 77

percent of Asian patients achieved sustained viral suppression (163 patients

entered the open-label study phase). Of seven Asian patients who added

emtricitabine treatment during the study, four of six remaining on study had

viral suppression at week 192. ALT levels normalized in 86 percent of Asians

after 192 weeks on treatment. Of 65 HBeAg-positive Asian patients with week 192

serology results, 35 percent achieved HBeAg loss and 26 percent experienced

HBeAg seroconversion. Viread was well tolerated among this group of patients.

During the open-label phase of Viread treatment, serious adverse events occurred

in 6 percent of Asian patients, while grade 3-4 laboratory abnormalities

occurred in 15 percent. During the study, one Asian patient had a confirmed

serum phosphorus level less than 2 mg/dL, which normalized by week 192, and

another had a confirmed increase of at least 0.5 mg/dL in serum creatinine.

Treatment-Experienced Patients (Abstract 136)

In Study 106, Viread showed sustained efficacy in patients with prior Hepsera

treatment experience through 168 weeks. Patients with an incomplete virologic

response after receiving Hepsera for at least six months were randomly assigned

to Viread (n=53) or Truvada (n=52). More than half of all patients also had

prior treatment experience with lamivudine. Sixteen patients in the Viread arm

and nine patients in the Truvada arm remained viremic (HBV DNA greater than 400

copies/mL) after week 24 and initiated open-label Truvada.

The percent of patients achieving viral suppression (HBV DNA below 400

copies/mL) through 168 weeks was the same in both arms of the study at 82

percent. Additionally, 100 percent of patients with baseline resistance

mutations to lamivudine (13/13 patients) and 90 percent of patients with

baseline resistance mutations to adefovir (9/10 patients) achieved viral

suppression. ALT normalization occurred in 68 percent of Viread and 67 percent

of Truvada patients. Both Viread and Truvada were well tolerated, and no

unexpected or clinically important adverse events related to renal function were

reported among these treatment-experienced patients. Notably, no patient

experienced a confirmed increase of at least 0.5 mg/dL in serum creatinine,

calculated creatinine clearance less than 50 mL/min or serum phosphorus less

than 2.0 mg/dL.

Important Information About Viread for Chronic Hepatitis B

Viread (tenofovir disoproxil fumarate) is indicated for the treatment of chronic

hepatitis B in adults. This indication is based primarily on data from the

treatment of nucleoside-treatment-naïve patients, and a smaller number of

patients who had previously received lamivudine or adefovir. Patients were

adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with

compensated liver disease. Viread was evaluated in a limited number of subjects

with chronic hepatitis B and decompensated liver disease. The number of patients

in clinical trials who had lamivudine- or adefovir-associated substitutions at

baseline was too small to reach conclusions of efficacy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,

have been reported with the use of nucleos(t)ide analogs, including Viread, in

combination with other antiretrovirals.

Severe acute exacerbations of hepatitis have been reported in HBV-infected

patients who have discontinued anti-hepatitis B therapy, including Viread.

Hepatic function should be monitored closely with both clinical and laboratory

follow-up for at least several months in patients who discontinue anti-hepatitis

B therapy, including Viread. If appropriate, resumption of anti-hepatitis B

therapy may be warranted.

New onset or worsening of renal impairment including cases of acute renal

failure and Fanconi syndrome has been reported with the use of Viread. It is

recommended to assess creatinine clearance (CrCl) before initiating treatment

with Viread and monitor CrCl and serum phosphorus in patients at risk, including

those who have previously experienced renal events while receiving Hepsera.

Administering Viread with concurrent or recent use of nephrotoxic drugs should

be avoided.

Viread should not be used with other tenofovir-containing products (e.g.

Atripla, Truvada). Viread should not be administered in combination with

Hepsera.

Due to the risk of development of HIV-1 resistance, Viread should only be used

as part of an appropriate antiretroviral combination regimen in HIV-infected

patients with or without HBV coinfection. HIV antibody testing should be offered

to all HBV-infected patients before initiating therapy with Viread.

Decreases in bone mineral density (BMD) have been observed in HIV-infected

patients. It is recommended that BMD monitoring be considered for patients with

a history of pathologic fracture or who are at risk for osteopenia. The bone

effects of Viread have not been studied in patients with chronic HBV infection.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may

contribute to fractures) have been reported in association with the use of

Viread.

Coadministration of Viread with didanosine increases didanosine concentrations.

Use with caution and monitor for evidence of didanosine toxicity (eg,

pancreatitis, neuropathy). Didanosine should be discontinued in patients who

develop didanosine-associated adverse reactions. In adults weighing >60 kg, the

didanosine dose should be reduced to 250 mg when it is coadministered with

Viread. Data are not available to recommend a dose adjustment of didanosine for

patients weighing <60 kg Coadministration of Viread with atazanavir decreases

atazanavir concentrations and increases tenofovir concentrations. Use atazanavir

with Viread only with additional ritonavir; monitor for evidence of tenofovir

toxicity. Coadministration of Viread with lopinavir/ritonavir increases

tenofovir concentrations. Monitor for evidence of tenofovir toxicity.

In controlled clinical trials in patients with chronic hepatitis B with

compensated liver disease, the most common adverse reaction (all grades) was

nausea, observed in 9 percent of patients taking Viread at week 48. Other

adverse reactions observed at week 48 in greater than 5 percent of patients

treated with Viread include abdominal pain, diarrhea, headache, dizziness,

fatigue, nasopharyngitis, back pain and skin rash.

In HBV-infected patients with decompensated liver disease, the most common

adverse reactions (all grades) reported in ‰¥10 percent of patients treated with

Viread were abdominal pain (22 percent), nausea (20 percent), insomnia (18

percent), pruritus (16 percent), vomiting (13 percent), dizziness (13 percent),

and pyrexia (11 percent).

The recommended dose for the treatment of chronic hepatitis B is 300 mg once

daily taken orally without regard to food. The dosing interval of Viread should

be adjusted and renal function closely monitored in patients with moderate and

severe renal impairment.

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.

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 Gilead Access Program countries to

ensure the product can be offered at a no-profit price in parts of the world

where the HIV/AIDS epidemic has hit the hardest.

Important Information about Hepsera (adefovir dipivoxil)

Hepsera (adefovir dipivoxil) is indicated for the treatment of chronic hepatitis

B in patients 12 years of age and older with evidence of active viral

replication and either evidence of persistent elevations in serum

aminotransferases (ALT or AST) or histologically active disease. This indication

is based on histological, virological, biochemical and serological responses in

adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with

compensated liver function, and with clinical evidence of lamivudine-resistant

hepatitis B virus with either compensated or decompensated liver function.

For patients 12 to less than 18 years of age, the indication is based on

virological and biochemical responses in patients with HBeAg-positive chronic

hepatitis B virus infection with compensated liver function.

Severe acute exacerbations of hepatitis have been reported in patients who have

discontinued anti-hepatitis B therapy, including Hepsera. Hepatic function

should be monitored closely with both clinical and laboratory follow-up for at

least several months in patients who discontinue anti-hepatitis B therapy. If

appropriate, resumption of anti-hepatitis B therapy may be warranted.

In patients at risk of or having underlying renal dysfunction, chronic

administration of Hepsera may result in nephrotoxicity. These patients should be

monitored closely for renal function and may require dose adjustment. It is

important to monitor renal function for all patients during treatment with

Hepsera, particularly for those with pre-existing or other risks for renal

impairment and patients taking concomitant nephrotoxic agents. Patients with

renal insufficiency at baseline or during treatment may require dose adjustment.

Caution should be exercised when prescribing Hepsera to adolescents with

underlying renal dysfunction, and renal function in these patients should be

closely monitored.

HIV resistance may emerge in chronic hepatitis B patients with unrecognized or

untreated HIV infection treated with anti-hepatitis B therapies, such as therapy

with Hepsera, which may have activity against HIV. HIV antibody testing should

be offered to all HBV-infected patients before initiating therapy with Hepsera.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,

have been reported with the use of nucleos(t)ide analogs alone or in combination

with other antiretrovirals.

Resistance to adefovir dipivoxil can result in viral load rebound which may

result in exacerbation of hepatitis and, in the setting of diminished hepatic

function, lead to liver decompensation and possible fatal outcomes. To reduce

the risk of resistance in patients with lamivudine resistant HBV, adefovir

dipivoxil should be used in combination with lamivudine and not as adefovir

dipivoxil monotherapy. To reduce the risk of resistance in all patients

receiving adefovir dipivoxil monotherapy, a modification of treatment should be

considered if serum HBV DNA remains above 1000 copies/mL with continued

treatment.

The most common adverse reaction (less than 10 percent) in compensated disease

patients is asthenia and in pre- and post-transplantation lamivudine-resistant

liver disease patients is increased creatinine.

The recommended dose for the treatment of chronic hepatitis B is 10 mg once

daily taken orally without regard to food. The dosing interval of Hepsera should

be adjusted in patients with renal impairment.

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.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,

have been reported with the use of nucleos(t)ide analogs, including Viread, a

component of Truvada.

Truvada is not approved for the treatment of chronic hepatitis B virus (HBV)

infection. Severe acute exacerbations of hepatitis B have been reported in

patients coinfected with HIV-1 and HBV who have discontinued Truvada. Hepatic

function should be monitored closely in these patients. If appropriate,

initiation of anti-hepatitis B therapy may be warranted.

Truvada should not be coadministered with Atripla, Emtriva, Viread or

lamivudine-containing products, including Combivir® (lamivudine/zidovudine),

Epivir® or Epivir-HBV® (lamivudine), Epzicom® (abacavir sulfate/lamivudine) or

Trizivir® (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. 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 including patients

who have previously experienced renal events while receiving Hepsera® (adefovir

dipivoxil).

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. Truvada

should not be administered with Hepsera.

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. Dose reduction of

didanosine should be considered, if warranted. 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 boosted 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. BMD monitoring should be considered in patients with a

history of pathologic fractures or who are at risk for osteopenia. Cases of

osteomalacia (associated with proximal renal tubulopathy and which may

contribute to fractures) have been reported in association with the use of

Viread.

Changes in body fat have been observed in patients taking anti-HIV medicines.

Immune Reconstitution Syndrome has been reported in patients treated with

combination therapy, including Viread and Emtriva, and may necessitate further

evaluation and treatment.

The most common adverse reactions (incidence greater-than or equal to 10

percent) are diarrhea, nausea, fatigue, headache, dizziness, depression,

insomnia, abnormal dreams and rash.

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 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 risks that physicians may not

prescribe Viread over other existing or future HBV medications. In addition, as

Viread is used over longer periods of time by many patients with underlying

health problems, taking numerous other medicines, safety, resistance, drug

interaction or other issues may arise, which could reduce the market acceptance

of Viread. 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 2009

Annual report on Form 10-K and in Quarterly Reports on Form 10-Q for the first

and second quarters of 2010, 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 Viread is available at www.Viread.com.

U.S. full prescribing information for Truvada is available at www.Truvada.com.

U.S. full prescribing information for Hepsera is available at www.Hepsera.com.

Viread, Truvada and Hepsera are registered trademarks of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company's website at

www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or

1-650-574-3000.

Contact: Gilead Sciences, Inc.

O'Brien, 650-522-1936

Investors

or

Cara , 650-522-1616

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