By Jill Stein
BARCELONA, SPAIN -- April 16, 2007 -- More than 99% of patients infected with hepatitis C virus (HCV) who achieve a sustained virological response (SVR) have an outcome that may be considered a cure, according to data presented here at the 42nd Annual Meeting of the European Association for the Study of the Liver (EASL).
Lead investigator Mark G. Swain, MD, professor of medicine, University of Calgary, Calgary, Canada, said that only 8 of 997 patients who achieved an SVR later developed re-infection.
Dr. Swain and colleagues reviewed the long-term outcomes from nine studies and identified patients who had achieved a SVR after treatment with alpha peginterferon alfa-2a (40 KD) (Pegasys(R)) as monotherapy or in combination with ribavirin (Copegus(R)).
"I tell my patients who have had a sustained virological response that they can go home and get on with their lives," Dr. Swain said in a presentation on April 12th. "I tell them that there is less than a 0.5% chance that the disease will ever return."
The study included three trials in which patients were treated with monotherapy and six trials in which the combination treatment was used. The combination therapy is now considered the treatment standard, and as many as 66% of HCV patients who take their antiviral medication as prescribed -- usually for 48 weeks -- are able to achieve the SVR.
A SVR was defined as an undetectable viral load in the blood six months following cessation of treatment.
Dr. Swain noted that statistical analyses on this study were not performed. "We were looking for an absolute number," he said. "There was no comparator group."
Of patients who achieved a SVR, 163 patients who had HCV monoinfection were treated with peginterferon alfa-2a alone; 741 patients with HCV monoinfection were treated with peginterferon alfa-2a plus ribavirin in combination; 93 patients co-infected with HIV and HCV were treated with either monotherapy or combination therapy.
"We found that a sustained virological response is a sustained virological response whether it occurs in an immunosuppressed patient due to disease such as HIV or in a patient who has undergone transplantation and requires immunosuppressive drugs," Dr. Swain said. "There was no falloff in response."
Because of the study's methodology, it will be impossible to determine if patients indeed relapsed or were re-infected, he added.
The study was supported by Roche.
[Presentation title: Durable Sustained Virological Response After Treatment With Peginterferon a-2a (PEGYSUS) or in Combination With Ribavarin (COPEGUS): 5-Year Follow-Up and the Criteria of a Cure. Abstract Number 1]
By Dr Matt Wilkinson
17/04/2007 - Vertex Pharmaceuticals has released early results on its first-in-class hepatitis C drug that show it has the potential to shorten treatment times for those suffering from the hard-to-treat genotype-1.
The results of a Phase II trial of Vertex' protease inhibitor, telaprevir (VX-950), showed the drug, in combination with Roche's pegylated interferon Pegasys (peginterferon alfa-2a; peg-IFN) and ribavirin (RBV) enabled some patients to clear the virus in 12 weeks.
According to the World Health Organisation (WHO), the hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver diseases such as cirrhosis and liver cancer. It is estimated that there are over 170m chronic sufferers worldwide, fuelling the HCV treatment market to over $2.3bn (€1.7bn) in 2004.
The latest results from the trial, dubbed PROVE 1, were released at the Annual Meeting of the European Association for the Study of the Liver (EASL) last week and offer new hope to sufferers of genotype-1 HCV - the most difficult to treat and the most prevalent strain in the US, western Europe and Japan.
While treatments for hepatitis B have met with considerable success, sufferers of HCV have not been so fortunate given the limited effectiveness of the two drugs available to them, peg-IFN and RBV.
HCV has evolved over thousands of years to produce six genotypes and many subgroups, with genotypes 1 and 4 being not as responsive to interferon treatments that can take a year. This is twice as long as typical treatment times for genotypes 2 and 3.
Genotypes 1, 2 and 3 are most commonly found in Europe and the US, whereas genotypes 4 and 5 are most prevalent in Africa.
The company has previously stated its intentions to develop the drug as both a monotherapy and in combination with peg-IFN and RBV as in the current study which showed that the treatment was generally well tolerated and had a high rate of rapid viral response (RVR) and a low rate of on-treatment viral breakthrough.
Many of the current treatment regimens fail and lead to relapse. The treatments are often not well tolerated with patients suffering from severe side effects.
Vertex has also initiated a Phase IIb trial (PROVE 3) to study the effects of the drug on genotype-1 HCV patients who have not achieved a sustained viral response (SVR) with previous interferon-based treatments.
If PROVE 3 is successful the treatment could offer hope to those patients that are unresponsive to peg-INF and RBV as there is currently a lack of alternative treatments with very few sufferers achieving a sustained viral load reduction upon retreatment.
One major problem in stemming HCV transmission is that the virus can go undetected for up to 20 years after the initial infection.
The US National Foundation for Infectious Diseases believes that complications from HCV are now the leading reason for liver transplants and account for nearly 2000 liver transplants a year. Any drug that can help cure the disease would reduce this number significantly.
After a long dearth of potential drugs in companies' pipelines there is now a lot of activity in the area after recent technical advances in cell culture systems and replication assays have led to mechanistic discoveries of HCV infection allowing the discovery of various new potential antiviral targets.
There are two HCV protease inhibitors that are competing with telaprevir to be the first on the market, namely Schering-Plough's SCH503034, which is also in Phase II, and Roche / Intermune's ITMN-191, which is in early clinical trials. Schering-Plough has stated they believe that SCH503034 has the potential to be a multibillion dollar drug.
There are also three polymerase inhibitors currently in Phase II trials: Idenix/Novartis' valopicitabine (NM283), ViroPharma's HCV-796 and Roche's R1626.
Roche/Idenix are also investigating valtorcitabine (val-LdC) - a first strand viral DNA synthesis inhibitor in Phase II HCV trials after initial success as an HBV treatment.
Bristol-Myers Squibb Company announced new results of the Baraclude (entecavir) resistance monitoring programme, which found a continued low incidence of resistance in studies of nucleoside-naive chronic hepatitis B patients through four years of treatment (n=663). In the three nucleoside- naive studies analyzed, two patients, or less than one per cent, experienced virologic breakthrough due to Baraclude resistance through the third year, and no additional patients developed resistance in the fourth year. In lamivudine- refractory patients, virologic breakthrough due to Baraclude resistance occurred in 15 per cent (n=8/53) of patients during year four.
The study results were presented at the 42nd Annual Meeting of the European Association for the Study of Liver Diseases (EASL) in Barcelona, Spain.
Drug resistance occurs when a virus mutates to avoid the effects of the medication. This can make treatment of hepatitis B challenging, because it can decrease the efficacy of the current medication and may compromise future treatment options. To date, studies have shown that multiple mutations are required to develop Baraclude resistance.
"The low incidence of resistance seen in nucleoside-naive patients through four years of treatment reflects Baraclude's high barrier to resistance in this patient population," said Richard Colonno, Ph.D., vice president for virology drug discovery at Bristol-Myers Squibb.
More than 700 patients across six studies initiated therapy on Baraclude (entecavir) and were monitored for treatment response and resistance.
The year four analysis evaluated those patients who received treatment with Baraclude during the fourth year (n=120 for patients in nucleoside-naive studies and n=53 for patients in lamivudine-refractory studies). In this comprehensive analysis, all patients enrolled in Bristol-Myers Squibb clinical trials ETV-014, -015, -022, -027, -026 and -901 who experienced a virologic breakthrough (greater than or equal to one log increase in HBV DNA from nadir as measured by a common assay - polymerase chain reaction or PCR), or whose virus had not yet reached undetectable levels - a measurement of the levels of hepatitis B virus in the blood (HBV DNA levels >300 copies/mL by PCR assay) at weeks 48, 96, 144, 192 or end of dosing were sequenced to determine if any changes occurred in the genetic code of the virus that would result in resistance or loss of effectiveness of Baraclude.
Viral load reduction in chronic hepatitis B patients treated with Baraclude in nucleoside-naive and lamivudine-refractory studies was also evaluated.