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Pegasys Receives Positive Opinion for HBV in Europe; HBV/HIV Coinfection Medical Management
  Roche issued a Press Release today regarding Pegasys & HBV treatment, announcing that the Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion for Pegasys (peginterferon alfa-2a (40KD)) for the treatment of chronic hepatitis B. The decision is granted for both types of the disease - HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). The recommendation will now go to the EU Commission for final approval. The Roche announcement follows a brief review below covering HBV treatment in HIV+ individuals. It discusses briefly treatment recommendations in HBV/HIV coinfection, the utility of peginterferon & other approved drugs for HBV, adefovir & 3TC; as well as discussion about tenofovir. There is a review of new drugs still in the developmental stages including entecavir, now in phase III. And a discussion of the propspects for combination therapy.
Interferon has a role in HBV therapy in addition to oral agents like 3TC & tenofovir. There are no generally accepted guidelines on treatment for HBV or HBV/HIV coinfection, but some doctors use peginterferon before initiating treatment with oral agents & some prefer not to. The Roche Announcement follows these excerpts on HBV treatment in the HBV/HIV coinfected patient ("HBV/HIV Coinfection Medical Management") written by Chloe Thio, MD (Johns Hopkins University School of Medicine) published Current Hepatitis Reports August, 2004 and in Seminal Liver Disease 2003.
"Hepatitis B Virus Infection in HIV-infected Persons"
Chloe L. Thio, MD. Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Baltimore, MD 21231-1001, USA. Current Hepatitis Reports August, 2004, 3:91-97
The treatment of chronic hepatitis B in the HIV-infected patient is complicated and needs to be individualized. Hepatitis B is transmitted more efficiently than HIV through sexual, vertical, and percutaneous routes. In an HIV-uninfected adult, 90% to 95% of acute HBV infections result in viral recovery, which is detected by the presence of hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs). Of the 5% to 10% of individuals who maintain the hepatitis B surface antigen (HBsAg) (chronic hepatitis B), some eliminate the hepatitis B e antigen (HBeAg), develop antibodies against HBeAg (anti-HBe), and have undetectable levels of HBV DNA (inactive carrier, but still can be transmitted). Those who maintain the HBeAg or develop precore mutant virus (HBeAg negative and detectable HBV DNA) are at risk for developing cirrhosis and hepatocellular carcinoma (HCC). Although HIV clearly accelerates the progression of an HBV infection, the influence of HBV on HIV disease progression remains controversial. HIV also appears to be a risk factor for reactivation of hepatitis B in persons who have developed anti-HBs. Furthermore, mortality from hepatitis B-related liver disease is increased in HIV-infected persons. Thio et al. examined mortality from liver disease in 5293 men, of whom 326 had detectable HBsAg. Those subjects who had HIV and CHB had a mortality rate attributable to liver disease of 14.2 per 1000 person-years, compared with rates of 0.8 and 1.7 per 1000 person-years in men with either HBV or HIV alone, respectively. This study also demonstrated a trend toward more severe liver disease in those with lower CD4 cell counts. In the MACS cohort HBV disease was accelerated by HIV compared to hepatitis B monoinfection. HIV infection is also associated with occult hepatitis B, which is the presence of HBV DNA without HBsAg. The most common serologic pattern for occult hepatitis B is a positive serologic test only for anti-HBc. In the Swiss Cohort Study, of 195 persons with anti-HBc only followed for a median of 31 months, 90% had at least one sample with detectable HBV DNA and 30% had persistently detectable HBV DNA. Prospective studies are needed to determine the clinical significance of occult hepatitis B in the setting of HIV infection.
"...Treatment for CHB should be considered in persons with circulating HBeAg or HBV-DNA levels 104 copies/mL (10,000) and evidence of necroinflammation based on either ALT values or on liver biopsy. However, persons with lower levels of HBV DNA should also be evaluated because the cut-off for treatment in coinfected persons has not been determined. There are many available therapeutic options for CHB in the HIV-HBV-coinfected patient, but HIV complicates these options necessitating individualization of the treatment plan..."
Treatment Goals
Because anti-HBV therapy does not eradicate viral reservoirs (ie, cccDNA), complete elimination of HBV is not possible with current therapy. Thus, the goal in CHB treatment is suppression of viral replication, which stops or decreases the progression of liver disease and risk for HCC. Although sustained loss of HBsAg is considered by some to be a "complete response", other markers of treatment response include the loss of HBeAg with the development of anti-HBe ("HBeAg seroconversion"), normalization of hepatic transaminases, and substantial diminution in HBV DNA. Although a decline in HBV DNA correlates with response, no threshold HBV-DNA goal has been established; however, lowering it below 105 copies/mL (100,000 c/ml) slows the progression of liver disease. As demonstrated in persons waiting for liver transplant, even a partial response can improve liver histology.
When considering treatment of CHB in HIV-HBV-coinfected persons, treatment needs to be individualized with consideration given to the state of both viral infections. Although the optimal therapeutic regimen is not known for the treatment of CHB in this population, some general recommendations based on available data are presented (Table 1). It is important to first determine which virus(es) need treatment. For those in whom only HBV needs treatment, adefovir dipivoxil or pegylated interferon alpha is the preferred options because neither one produces HIV resistance. Adefovir dipivoxil could theoretically lead to HIV resistance; however, this has not been demonstrated thus far. Currently, there is no clear advantage of one of these over the other. For those in whom only HIV needs treatment, one could consider sparing lamivudine/emtricitabine and tenofovir until they are also needed for CHB treatment. Alternatively, if either of these is needed for an optimal HIV regimen, one should try to include both of them to minimize the emergence of drug-resistant HBV. If both viruses need treatment and the patient is naive to lamivudine, then emtricitabine and tenofovir in combination are recommended to try and maximize potency and minimize resistance. If the patient is lamivudine experienced, then tenofovir or adefovir dipivoxil is preferred depending on whether one wants to spare tenofovir for future HIV therapy. Pegylated interferon alpha may be an option, but it has not been studied in lamivudine-resistant virus.
What is the usefulness of interferon in treating HBV?
The frequent side effects of interferon-alfa, including flulike symptoms, psychiatric effects, and bone marrow toxicity, have limited its use. Its advantages are higher HBeAg seroconversion rates and limited treatment duration (16 weeks) in persons who have detectable HBeAg. In HIV-infected individuals it has the additional advantage of not engendering HIV resistance. Interferon-alfa is contraindicated in decompensated liver disease because of an increased risk of death from liver failure or sepsis.
A meta-analysis of randomized trials, which included 837 persons with an ALT > 2 ULN and circulating HBeAg, demonstrated a 33% HBeAg serocon-version rate in persons given 16 weeks of interferon-alfa compared with 12% in untreated controls. A durable response of HBeAg clearance is seen in 80 to 90% of persons; however, HBV DNA and HBsAg often remain detectable. Clearance of HBeAg and not HBV DNA has been correlated with improved clinical outcome.
Studies of interferon alpha therapy in HIV-HBV-coinfected individuals are limited, but collectively suggest a decreased response compared to those without HIV infection. In a meta-analysis of interferon alpha trials, the 55 HIV-infected persons showed a 38% decreased response compared with the 780 HIV-uninfected persons (P = 0.02). Seven small studies (two randomized) involving 98 HIV-HBV-coinfected patients demonstrate a 14.3% HBeAg seroconversion rate to interferon alpha treatment, which is lower than the 33% seen in HIV-uninfected persons. None of these studies have been performed in the highly active antiretroviral therapy era; thus, interferon alpha has not been fairly evaluated in HIV-infected individuals with a reconstituted immune system.
Excerpt from "Treatments for Hepatitis B" published in Clinical Infectious Diseases (Nov 2004) lead author David Asmuth (University of California-Davis Medical center, Sacramento): the use of IFN-alpha therapy for patients with chronic hep B results in sustained response rates in approximately one-third of patients when therapy is given for 16 weeks (to HBeAg-positive patients) or for 52--104 weeks (to HBeAg-negative patients). These virologic and biochemical surrogate markers correlate with the following end points of clinical disease: liver-associated complications, the need for liver transplantation, and, probably, HCC. Pegylated IFN-alpfa formulations appear to be more conveniently dosed and may have higher associated response rates.
Treatments for Hepatitis B
Clinical Infectious Diseases Nov 1, 2004;39:1353-1362
Lamivudine (3TC) for HBV
For Lamivudine (3TC), studies of HIV-HBV coinfected subjects show rates of HBeAg seroconversion of 22 to 28% and appear comparable to the HIV-uninfected patient. In HIV-unifected the HBeAg seroconversion rate in large studies is between 16 and 18% and correlates with ALT levels. In an Asian trial, those with ALT > 5 x ULN had a 64% HBeAg seroconversion rate compared with 26 and 5% among those with an ALT > 2 x and < 2 x the ULN, respectively. The durability of the response in HIV-uninfected patients varies between 63 and 80% and may be more likely if therapy is continued for more than 6 months after HBeAg seroconversion. Lamivudine therapy is limited by the selection of lamivudine-resistant HBV strains. In persons uninfected by HIV, resistance increased from 14% at year 1 to 38, 49, and 66% at years 2, 3, and 4, respectively. The development of resistance in HIV-HBV coinfected persons may be greater and is estimated at 20% per year. Resistance may be predicted by the HBV DNA level 6 months after the initiation of treatment.
The emergence of mutants is usually clinically detected by flares in liver disease, manifested by ALT elevations and reappearance of HBV DNA. In the review article by Chloe Thio she says ---if the mutation appears, lamivudine should be continued in the coinfected patient unless it is detrimental to effective HIV therapy because severe, even fatal, rebound hepatitis may occur on discontinuation of lamivudine in those who have detectable HBV DNA. If lamivudine is discontinued, careful monitoring of ALT and HBV DNA is mandatory. Despite resistance, HBeAg seroconversion has been reported in 25% of patients who continue lamivudine after the appearance of the mutants, but long-term lamivudine for isolated chronic hepatitis B after the development of resistance is a controversial area. Lamivudine is a potent anti-HBV drug, but it should not be used as a single agent in the coinfected patient because of the rapid emergence of HIV and HBV resistance mutations. Its use in the coinfected patient naive to therapy for both viruses will likely be in combination with either adefovir or tenofovir along with a potent antiretroviral regimen. Prior to starting a HIV-infected patient on lamivudine, one must be aware of the patient's HBV status in order to not limit future options for HBV therapy.
Adefovir & Tenofovir for HBV
Adefovir is approved for treatment of HBV, but Gilead Sciences is expeditiously studying tenofovir as a substitute for adefovir since studies suggest that tenofovir is more potent & effective. As you know tenofovir is approved to treat HIV & often used in HAART for HBV+ patients along with FTC or 3TC. It is not yet FDA approved to treat HBV. Adefovir and tenofovir are effective against both lamivudine-resistant and wild-type chronic hepatitis B, and resistance develops slowly. From the review article written by Papatheodoridis & Hadziyannis: In HBeAg-positive chronic hepatitis B, a 12-month course of adefovir dipivoxil, at a daily dose of 10 mg, was found to achieve a loss of HBeAg in 24% of patients, compared with 11% of controls, offering a benefit of 6% in the HBeAg seroconversion rate. Similar to previous observations in HBeAg-positive chronic hepatitis B patients treated with IFN-alpha or lamivudine, higher baseline alanine aminotransferase levels were associated with an improved efficacy of adefovir dipivoxil therapy. Data on the efficacy of long-term adefovir dipivoxil therapy in HBeAg-positive chronic hepatitis B patients have recently been presented. In one phase II extension study, including 28 such patients, adefovir dipivoxil therapy maintained biochemical and virological remission at 2 years without significant toxicity and without any evidence of viral resistance. The extension of the large, phase III trial of adefovir dipivoxil in 85 patients with HBeAg-positive chronic hepatitis B showed that the HBeAg loss rate increased to 44% and the rate of anti-HBe development increased to 23% at 72 weeks of adefovir dipivoxil therapy (Gilead Sciences, data on file, 2003).
Future Therapeutic Directions
Several other agents are in development but appear promising. Entecavir is active against the HBV polymerase and a 48-week course produces a -5.11 log HBV DNA decline against lamivudine-resistant HBV without evidence of resistance mutations. (note from Jules Levin: phase III study results were reported at AASLD and reports are posted & archived in Conferences Section on NATAP website). Emtricitabine (FTC), a fluorinated derivative of lamivudine, has activity against HIV and HBV. A study of 96 weeks of FTC shows HBeAg loss of 51% and anti-HBe seroconversion in 29% of subjects. As expected, resistance develops but at a slower rate than to lamivudine. Telbivudine (L-dT) is an L-nucleoside analogue that is very potent and appears to show greater efficacy in reducing HBV DNA levels than lamivudine does.
Following lessons learned from HIV, combination therapy for treatment of CHB may lead to increased potency and decreased rates of development of resistance. The combination of interferon alpha and lamivudine has been studied in two randomized trials and does not clearly demonstrate an advantage, but the optimal combination regimen of these two drugs may not have been studied. However, it is logical to study other combinations, including pegylated interferon alpha with lamivudine or emtricitabine, tenofovir DF, or adefovir dipivoxil, and also to study the combination of lamivudine or emtricitabine with tenofovir. Combination therapy for CHB is likely to emerge as the preferred treatment for CHB, and studies in this area are urgently needed.
From CID review: From the practical standpoint of the resistance to and toxicity of different therapies, the duration of therapy for nonresponders (i.e., subjects with failure to have seroconversion to HBeAg) becomes problematic. Although lamivudine and adefovir dipivoxil have demonstrated the ability to normalize the ALT level and suppress viral replication, these drugs show a suboptimal rate of viral clearance, as measured by seroconversion to HBeAg. However, if these therapies are not continued indefinitely, hepatic flares can occur as a result of drug withdrawal. In addition, for HBeAg-negative patients, there is no biochemical marker of viral clearance, which makes it even more difficult to determine the duration of therapy. Although there presently are no firm recommendations regarding treatment duration for individuals who currently are receiving therapy, it appears reasonable to continue therapy indefinitely, until resistance develops (i.e., until return of the HBV DNA load to its level at baseline) or until clearance of the virus occurs for patients receiving lamivudine and adefovir dipivoxil. Nucleoside reverse-transcriptase inhibitors appear to be less toxic and easier to administer for a prolonged period, despite lower HBeAg seroconversion response rates, compared with IFN-a. Although most of the data regarding long-term IFN therapy are from early trials in which conventional IFN-a was used, the use of IFN-a is most practical when it is used in its pegylated formulation as salvage therapy.
Roche press release
Pegasys receives positive opinion in the European Union for the treatment of chronic hepatitis B
First pegylated interferon to be indicated for treating chronic hepatitis B

Basel, January 2005
Roche announced today that the Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion for Pegasys (peginterferon alfa-2a (40KD)) for the treatment of chronic hepatitis B. The decision is granted for both types of the disease - HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). The recommendation will now go to the EU Commission for final approval. Hepatitis B is a major public health concern with data suggesting that globally, more than 350 million people are infected with the virus and approximately one million die each year from the disease.
"Today marks another milestone in Pegasys' history as an effective antiviral agent," said Ciro Caravaggio, Head of the Hepatitis Franchise at Roche. "We set out to explore the potential of Pegasys in treating chronic hepatitis B and demonstrated its effectiveness against both forms of the virus and against the two leading medications used to treat it today, lamivudine and conventional interferon," he said. "It's also an achievement for Pegasys in that it becomes the only pegylated interferon indicated for the treatment of chronic hepatitis B."
In contrast to lamivudine, Pegasys works with a dual mode of action: it stimulates the immune system as well as inhibits virus replication. This offers physicians a new option with the advantages of a finite treatment duration and lasting remission from the disease, avoiding the burden of putting their patients on a life-long therapy.
"Studies have shown that Pegasys offers the best chance for a sustained response, in a defined treatment period, for chronic hepatitis B patients," said Professor Patrick Marcellin, Hepatologist at Hôpital Beaujon, Clichy, France and one of the lead investigators of the Phase III global studies. "Pegasys is an effective pegylated interferon, and the only one that has been studied directly against lamivudine. Its response against this agent, as well as interferon, support its use as first line therapy for chronic hepatitis B."
The studies on which the positive opinion has been granted
The CHMP positive opinion was based on one of the largest clinical development programmes in chronic hepatitis B, which included three global studies in more than 1,500 patients from 19 countries.
Pegasys has been proven twice as effective as conventional interferon for the treatment of the most common form of chronic hepatitis B, hepatitis B e antigen (HBeAg) -positive chronic hepatitis B, in a multinational phase II trial. These findings were published in the July 2003 Journal of Viral Hepatitis. Two large-scale multinational phase III trials, in patients with both the HBeAg-positive and HBeAg-negative forms of chronic hepatitis B, demonstrated that after 48 weeks of therapy, more patients achieved a sustained response with Pegasys than with lamivudine. Furthermore, these studies demonstrated that the addition of lamivudine to Pegasys did not improve response rates over Pegasys alone.
The phase III study results in HBeAg-negative chronic hepatitis B, which is particularly prevalent in the Mediterranean areas and is the most difficult-to-treat form of the disease, were published in September 2004 in the New England Journal of Medicine. The results of the phase III study in patients with HBeAg-positive chronic hepatitis B were presented at the 2004 Annual Meeting of the American Association for the Study of Liver Diseases. Both lead investigators have stated that the results of these trials warrant Pegasys becoming the first-line treatment for HBeAg-positive or HBeAg-negative chronic hepatitis B.
About Pegasys
Pegasys, a new generation hepatitis therapy that is different by design, has already become the worldwide market leader in hepatitis C. Pegasys has a dual immunomodulatory and antiviral mode of action. The improved pharmacokinetic profile ensures drug plasma concentrations are maintained at constant levels throughout the one week dosing interval. Pegasys therapy in chronic hepatitis B is given once weekly as a 180 ug subcutaneous injection for a 48-week period.
Pegasys has recently been approved for the treatment of chronic hepatitis B in Switzerland, Taiwan and Thailand. Approval in the US is expected this year.
Roche in Hepatitis
Roche is committed to the viral hepatitis disease area, having introduced Roferon-A for hepatitis B and C, followed by Pegasys in hepatitis C and a full development program in hepatitis B. Roche has its own brand of ribavirin, Copegus, which is used in conjunction with Roferon A or Pegasys for HCV. In addition, Roche manufactures HBV and HCV diagnostic and monitoring systems: The COBAS AMPLICOR Test, and the AMPLICOR MONITOR Test, two testing systems used to detect the presence of, and quantity of, HBV DNA or HCV RNA in a person's blood. Roche has received a positive opinion in the EU for a new indication for Pegasys and COPEGUS as a treatment for patients co-infected with HIV and HCV and it has also been filed in the United States. More than 40,000 patients worldwide continue to participate in trials with Pegasys and COPEGUS as Roche examines the unmet medical needs of hepatitis C patients. Roche's commitment to viral hepatitis also extends to its pursuit of strategic alliances and partnerships to develop new compounds for the future.
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups. Its core businesses are pharmaceuticals and diagnostics. As a supplier of innovative products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2003 the Pharmaceuticals Division generated 19.8 billion Swiss francs in prescription drug sales, while the Diagnostics Division posted sales of 7.4 billion Swiss francs. Roche employs roughly 65,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai.
1 Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003; 10:298-305.
2 Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351:1206-17.
3 Lau GK, et al. Peginterferon alfa-2a (40KD) ( Pegasys®) monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B: results from a large, multinational study. Hepatology, 2004; Vol. 40 (4); Suppl. 1:171A
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