Patients 'Shopping' for a Liver Want Only the Best

By Kurt Ullman, Contributing Writer, MedPage Today
Published: December 02, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Organ quality is important to patients, but not well understood, when "shopping" for a liver to transplant, according to a recent survey.

An initial survey of 10 people on the waiting list at a major transplant center found a very poor understanding of the spectrum of organ quality. Most tended to say that livers were either good or bad and that the facility would only offer them the very best available, reported Michael L. Volk, MD, and colleagues from the University of Michigan in Ann Arbor.

Using these findings as a base, a larger group of 95 people was surveyed. The mean risk of acceptable graft failure was 32% at three years after transplantation, the researchers wrote in the December issue of Liver Transplantation.

Despite being told that stringent standards would lower the number of livers available, 58% would accept only livers with graft failure estimates of 25% or less at three years and 18% would only accept those with the lowest possible risk (19% at three years).

The quality of donor livers can vary greatly depending on age, cause of death, steatosis, and ischemia time; those factors can make the difference between 20% and 40% rates of graft failure three years after transplantation, the authors noted in their introduction.

In addition, the quality of donor livers is expected to decrease over time, both because the population is aging and because more people have experienced a stroke as a cause of brain death, the authors noted. As well, a federally funded group is promoting the use of extended criteria donor organs, which will expand the donor pool but also will increase the chance of graft failure.

As a result, discussions of organ quality with patients are more essential than ever, but hard to make time for in a busy clinic. "It is challenging to discuss the use of high-risk organs with patients, in part because of the lack of information on how patients view the topic," wrote the authors.

To find out more about how patients were thinking about these issues, the investigators conducted a two-part study. The first part consisted of a semi-structured interview of 10 patients on the waiting list. The questions at the start were open-ended, but as they continued, they became more focused on finding participants' preferences based on their understanding of organ quality.

The second part consisted of three sections on a computerized survey. They looked at education about the differences in liver quality and what that meant when considering graft failure, patient preferences about the level of risk they would accept, and 10 covariates the researchers thought might influence patients' decision-making.

A bias against lower-quality organs occurred when participants were asked to decide between staying on the list with a 20% chance of dying in three years or accepting a lower-quality organ with a 20% chance of dying but an improved quality of life. Despite having the logically correct answer to accept the liver, 42% still opted to stay on the list.

When the researchers changed the format in which they presented the information, they found a significant impact on patient preferences.

Those who were first presented a graph showing the best possible outcome would accept risk of failure up to 25% on average. Those who saw a graph with the 25% risk of failure (the average for the center) would accept up to a 29% risk on average (P=0.001).

Some participants were presented with a pie-chart pictograph showing graphically what percentage of organs would fail at a given risk level. The initial average failure risk they would accept at three years (28%) increased to 32% once they had seen the pictograph (P=0.003).

Among the 67 who wanted only organs with a 25% or less chance of graft failure, 19% would accept higher risk after the feedback was given. Conversely, only 7% of those who would accept organs with more than 25% failure risk reduced their risk tolerance.

Among the demographic and clinical covariates examined, only sex was associated with risk preference.

After feedback was given, men preferred organs with a lower failure risk than women (29% versus 35%, P=0.04). Only belief in control was significant among the psychological measures, with patients having a more external locus of control more likely to accept higher-risk organs (P=0.04).

Twenty patients were surveyed again after a mean time of 16 months (range 6 to 30 months). As a group, their risk preferences had not changed significantly, with mean acceptable graft failure risk being 34% initially and 33% at the second instance (P=0.3).

But as individuals, the preferences were not stable, with only a modest correlation between initial and re-approached values (Spearman's P=0.24).

"This study of patient decision-making about organ quality has three main findings," the authors concluded. "First, many patients entered discussions about organ quality with an inherent bias against the acceptance of organs with higher risk of graft failure. Second, risk tolerance was highly variable between individuals and not particularly stable over time. Third, an individual patient's risk tolerance was associated with sex and beliefs about his or her control over his or her health, and not with the severity of liver disease."

The work was supported by the Robert Wood Johnson Foundation, the American Gastroenterological Association, and National Institutes of Health. No authors noted conflicts.

Primary source: Liver Transplantation
Source reference:
Volk ML, et al "Patient decision making about organ quality in liver transplantation" Liver Transpl 2011; 17: 1387-1393.

Source

Interferon-Free Treatment Regimens for Hepatitis C: Are We There Yet? Editorial

Download the PDf here

Gastroenterology Dec 2011
Anna Lok, Pratima Sharma

"IFN-free regimens are no longer a dream, but a reality that may be available in the clinic in the next 5 years" (from Jules of NATAP: I think it will be less than 5 yrs)

Combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) was the standard of care for chronic hepatitis C (CHC) for over a decade. Sustained virologic response (SVR) rates vary from 40% to 45% among patients with genotype 1 to 75% to 80% in patients with genotype 2 or 3 infection.1 However, PEG-IFN and RBV treatment are associated with many side effects. In registration trials that enrolled highly selected patients, 13%-15% of patients discontinued treatment early and 25%-42% had dose reductions because of adverse events or laboratory abnormalities.1, 2, 3 Because of the poor tolerability, many patients with CHC have elected not to pursue treatment or were not offered treatment. IFN and RBV are also contraindicated in many conditions, such as autoimmune diseases and severe/uncontrolled psychiatric illnesses.1 Therefore, there is an urgent need for more efficacious and better tolerated therapy for CHC.

Advances in the understanding of the hepatitis C virus (HCV) life cycle have led to the development of many promising direct-acting antiviral agents (DAA) in the last decade (Figure 1).4, 5 Two DAAs-telaprevir and boceprevir-linear inhibitors of NS3/4A serine protease were approved for HCV treatment in the United States in May 2011. Although the approval of boceprevir and telaprevir represents a major breakthrough for the treatment of CHC with SVR rates of 67% and 73%, respectively, in treatment-naïve genotype 1 patients, both drugs require concomitant use of PEG-IFN and RBV to achieve SVR by preventing viral breakthroughs owing to drug resistance.6, 7 Furthermore, both drugs need to be administered every 8 hours and are associated with additional adverse events.

With the development of DAAs directed at multiple targets in the HCV life cycle (Figure 1), the obvious question is, "Are we ready for IFN-free treatment regimens?" Clinical trials involving telaprevir and boceprevir as monotherapy showed a rapid decline in plasma HCV RNA levels within the first day followed by virologic breakthrough as early as day 3.8, 9 HCV circulates as quasispecies, a mixture of viruses with heterogeneous virus sequences. It has been estimated that preexisting drug resistance variants with 1, 2, 3, and even 4 mutations may be present in most HCV-infected patients, and account for the rapid development of drug resistance on exposure to DAAs. The emergence of clinically relevant, drug-resistant variants depends on several factors, such as the potency of the drug, the genetic barrier to resistance, and the replication fitness of the resistance variants.10, 11 Based on modeling experiments, it has been suggested that an IFN-free regimen that can overcome the presence of variants with 4 drug-resistance mutations requires a combination of ≥3 DAAs with a low genetic barrier to resistance, namely, DAAs that select single amino acid resistant variants.12 Each of these drugs should have potent antiviral activity, possess nonoverlapping resistance profiles, and have limited or manageable drug interactions and minimal adverse events. Furthermore, these drugs should be at similar stages of clinical development so that they can be tested in combination.

The first study of combination DAAs, the INFORM-1 study, involved a combination of an NS5B polymerase inhibitor (RG7128) and an NS3/4A inhibitor (danoprevir). This study enrolled treatment-naïve as well as treatment-experienced patients.13 At day 14, 13%-63% of treatment-naïve and 25% of null responders had undetectable HCV RNA (Table 1). None of the patients in any treatment arm experienced virologic breakthrough during the 14-day course of IFN-free regimen suggesting that the addition of RG7128, which has a high barrier to resistance, may have prevented the emergence of resistance to danoprevir.

These promising results have encouraged other studies of combination DAAs. The design and preliminary results of these trials are summarized in Table 1. All the studies reported to date enrolled patients with genotype 1 infection only. Results of 1 phase Ib trial of a combination of an NS3/4A protease inhibitor BI201335, an NS5B polymerase inhibitor BI207127, and RBV are published in the current issue of Gastroenterology.14 In this study, the authors randomized 34 treatment-naïve CHC patients to either 400 or 600 mg TID BI207127, 120 mg once daily BI201335, and weight-based RBV for 4 weeks. All the patients were switched to triple therapy (BI201335 + PEG-IFN + RBV) from day 29 until week 24 or 48, depending on achievement of extended rapid virologic response. The primary endpoint was day 29 virologic response. All 5 genotype 1b but only 6 of 10 genotype 1a patients in the group that received low-dose protease inhibitor achieved day 29 virologic response (Table 1). One genotype 1a patient had virologic breakthrough on day 22, with variants resistant to both drugs (R155K in NS3 and P495L in NS5B) and another patient had an increase in HCV RNA of 0.7 log10 IU/mL from nadir, but sequencing could not be performed because of low HCV RNA level. Both patients had a decrease in HCV RNA to <100 IU/mL after 10 days of BI201335, PEG-IFN, and RBV. All patients (8 genotype 1a and 8 genotype 1b) in the high-dose protease inhibitor group achieved day 29 virologic response. There were no serious adverse events or adverse event-related premature treatment discontinuations, but decreases in hemoglobin, increases in platelet count, and increases in total bilirubin (predominantly indirect) were observed.

These results suggest that an IFN-free regimen comprising 2 DAAs (at the appropriate dose) plus RBV can achieve a very high rate of on-treatment virologic response for up to 4 weeks. However, this study does not address whether IFN-free combination DAAs will result in SVR. It also does not resolve the question of whether RBV contributed to the virologic response and whether RBV reduces relapse with IFN-free regimens. Furthermore, the safety of this combination treatment beyond 4 weeks remains to be determined. Finally, the presence of confirmed a dual drug-resistant variant in 1 patient and a persistent (<1 log) increase in HCV RNA after an initial decline in another patient is concerning, although not surprising, given that both drugs have a low barrier to resistance. Although it has been argued that HCV drug resistance variants are not archived and HCV drug resistance variants become undetectable at a median of 7 months after cessation of telaprevir,15 these data were based on population sequencing, which will not detect variants constituting <20% of the viral population and the real test, that is, response upon retreatment with DAA of the same class, has not been performed.

Another study of combination DAAs involved an NS3 protease inhibitor (GS-9256) and a non-nucleoside NS5B polymerase inhibitor (tegobuvir) with or without PEG-IFN or RBV. The groups that received triple or quadruple therapy achieved higher rates of virologic response at week 4 compared with the group that received dual therapy (Table 1).16 Thirteen of the 16 patients in the dual therapy group, 2 of 15 in the triple therapy group, and none of 15 in the quadruple therapy group experienced virologic breakthrough. Eleven of the patients in the dual therapy arm with breakthrough had variants resistant to both drugs.16 These findings suggest that addition of RBV may accelerate viral clearance, thereby reducing the risk of resistance to DAAs, at least in the short term. The 4th study evaluated a combination of 2 nucleotide RNA-dependent RNA polymerase inhibitors, a purine (PSI-938) and a pyrimidine (PSI-7977) analog. It showed robust and consistent reduction in HCV RNA in the groups that received combination therapy as well as absence of virologic breakthrough up to week 2 (Table 1).17

Collectively, these studies showed that a 14- to 28-day course of the right combination of 2 DAAs dosed appropriately can result in a high rate of virologic response with a low rate of drug resistance, but the likelihood of SVR and risk of drug resistance with longer courses of IFN-free DAA only regimens were not addressed.

To date, SVR data had been reported in only 1 study of combination DAAs (from Jules: at AASLD Nov 2011, Pharmasset reported 100% SVRs in GT2/3 with RBV+PSI-7977, their nucleotide). In this phase II study, genotype-1 null responders were randomized to receive a combination of an NS5A inhibitor (BMS790052) and an NS3 protease inhibitor (BMS650032) alone or together with PEG-IFN and RBV for 24 weeks.18 All 11 patients in the dual therapy arm had a rapid decline in HCV RNA, with 7 achieving undetectable HCV RNA; however, 6 experienced virologic breakthrough and had variants resistant to both DAAs selected (Table 1). Although most of these patients responded to rescue therapy with addition of PEG-IFN and RBV, it is unclear if they will achieve SVR. Four of the 11 patients achieved SVR.12 Responses were more encouraging in the quadruple therapy arm with all 10 patients achieving SVR.12 These data showed that addition of 2 DAAs to PEG-IFN and RBV may result in a greater rate of SVR compared with 1 DAA in nonresponders to PEG-IFN and RBV.19 More important, it provided proof of concept that SVR can be achieved with combination DAAs only.

Similar to Zeuzem et al's study,14 all patients with virologic breakthrough in Lok et al's study had genotype 1a infection.18 Genotypes 1a and 1b HCV may differ in their susceptibility to DAAs. In addition, a larger number of nucleotide changes are required to create a clinically significant protease inhibitor resistance variant for genotype 1b (higher barrier to resistance) than for genotype 1a HCV.10, 11 For example, 2 nucleotide changes are required to generate the resistance mutation R155K for 1b isolates (CGG->AAG), whereas only 1 nucleotide change is required for 1a isolates (AGG->AAG).19 These data indicate that different strategies may be needed for genotype 1a and 1b infection in the era of combination DAAs.

Eight years after the first clinical trial of DAA,20 development of direct-acting HCV treatments is now moving at a rapid pace with many products showing promising results. IFN-free regimens are no longer a dream, but a reality that may be available in the clinic in the next 5 years. It is possible that some of these regimens will also be RBV free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or RBV, or out of concerns about their ability to tolerate these medications. However, caution must be taken in selecting which DAAs to combine and the appropriate dose and duration of therapy for each HCV genotype and subgenotype to prevent multidrug resistance

Source

Alcohol can lead to unsafe sex: It's official

Public release date: 12-Dec-2011

Contact: Jean O'Reilly
jean@addictionjournal.org
44-020-784-80853
Wiley-Blackwell

A new study has found that alcohol consumption directly impacts a person's intention to have unsafe sex. In other words, the more you drink, the stronger becomes your intention to engage in unsafe sex.

Unsafe sex is the most important pathway to HIV infection, and it is a main risk factor for the global burden of disease. Despite this knowledge, and substantial efforts to prevent unsafe sex, HIV incidence in most high income countries (such as the US or the UK) has not changed over the past decade. In some cases, it has even increased. Finding better ways to prevent unsafe sex is thus a major goal of public health efforts for HIV/AIDS prevention.

Alcohol consumption, especially heavy drinking, has long been associated with HIV incidence. However, there have been doubts about the cause-and-effect relationship. Researchers weren't sure if alcohol consumption caused HIV via unsafe sex, or whether certain personality traits in individuals, such as sensation-seeking or a disposition to risky behaviour in general, would lead to both alcohol use and unsafe sex.

The study, published in the January issue of the journal Addiction, summarizes the results of 12 experiments that tested this cause-and-effect relationship in a systematic way. After pooling the results, the researchers found that alcohol consumption affects decision-making, and that this impact rises with the amount of alcohol consumed. The more alcohol that participants consumed, the higher their willingness to engage in unsafe sex.

In these experiments, study participants were randomly allocated to one of two groups in which they either consumed alcohol or did not. Then their intention to engage in unsafe sex was measured. An increase in blood alcohol level of 0.1 mg/mL resulted in an increase of 5.0% (95% CI: 2.8% - 7.1%) in the indicated likelihood of engaging in unprotected sex. This result remained stable in sensitivity analyses aimed to correct for a potential publication bias.

"Drinking has a causal effect on the likelihood to engage in unsafe sex, and thus should be included as a major factor in preventive efforts for HIV", commented Dr. J. Rehm, the Principal Investigator of the study. "This result also helps explain why people at risk often show this behaviour despite better knowledge: alcohol is influencing their decision processes."

Future HIV/AIDS prevention programs should include the results of this study. For instance, efforts to reduce drinking, and especially to reduce heavy drinking occasions, will not only avoid compromising the immune system but will also lower the chance of engaging in unsafe sex, thereby reducing the number of new HIV infections.

###

Full citation: Rehm J., Shield K.D., Joharchi N. and Shuper P.A. Alcohol consumption and the intention to engage in unprotected sex: Systematic review and meta-analysis of experimental studies. Addiction 107, 51-9, doi:10.1111/j.1360-0443.2011.03621.x

Addiction (www.addictionjournal.org) is a monthly international scientific journal publishing more than 2000 pages every year. Owned by the Society for the Study of Addiction, it has been in continuous publication since 1884.

Addiction is the top journal in the field of substance abuse and is number one in the 2010 ISI Journal Citation ReportsC Ranking in the Substance Abuse Category. Addiction publishes peer-reviewed research reports on alcohol, illicit drugs and tobacco, bringing together research conducted within many different disciplines, as well as editorials and other debate pieces.

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The Hepatitis C Market: Biotech’s Version of the Daytona 500

Luke Timmerman    12/12/11

Biotech rivalries are sometimes a bit like boxing matches, where you have two lone fighters vying for the prize. But the hepatitis C market is turning into a battle royal that’s more wide open and unpredictable, with all the competitive maneuvering, surprise crashes, and comebacks you might expect from the Daytona 500.

The medical advances in hepatitis C have been dizzying this year, especially in what it means in terms of multi-billion dollar business implications. The safest thing to say is that there’s plenty of good news for patients this year, but that shareholders in the major hepatitis C drug developers had better hold on tight as a new standard of care gets established.

Some commentators figured that Gilead Sciences (NASDAQ: GILD), the world’s biggest maker of HIV drugs, had essentially locked up the dominant position in this new drug class through its $11 billion acquisition last month of Princeton, NJ-based Pharmasset (NASDAQ: VRUS). But it’s still too soon for anyone to declare victory over the wily and fast-mutating virus that causes hepatitis C. Given the way drug development is going now, it’s possible we could have dueling antiviral drug cocktails that cure almost 100 percent of patients within five years. And before we get there, we’re going to see some fascinating chess moves—and probably a few surprising collaborations—from companies like Vertex Pharmaceuticals, Merck, Roche, Johnson & Johnson, Bristol-Myers Squibb, and Abbott Laboratories, as well as several smaller biotech startups like Alpharetta, GA-based Inhibitex (NASDAQ: INHX).

The Pharmasset compound that prompted Gilead to write such a big check, PSI-7977, is “certainly not a panacea, not the lone answer,” says Kleanthis Xanthopoulos, the CEO of San Diego-based Regulus Therapeutics, and the co-founder of another hepatitis C drug developer, Anadys Pharmaceuticals.

Xanthopoulos says Gilead was “taken to the cleaners,” and that the hepatitis C market is still up for grabs. “It’s going to take some time before people figure out how it plays out,” he says. The Pharmasset drug “is a powerful player, but you will need other direct-acting antivirals. You want to go to a 100 percent cure rate. I can guarantee the Pharmasset compound isn’t going to do it alone.”

Hepatitis C has never really captured big headlines in the U.S., as it has never benefitted from massive awareness boosting campaigns that have supported research for, say, HIV, or breast cancer. But hepatitis C has clearly emerged as one of the biggest opportunities in pharmaceuticals over the past few years. There are more than 3 million people in the U.S., and an estimated 170 million worldwide, with this liver infection that can lead to cirrhosis and liver cancer. Most people have never bothered to get treated, partly because the infection takes years to fully wreak havoc. The other reason is the standard of care with a combination of drugs—pegylated interferon alpha and ribavirin—causes flu-like symptoms that last for almost a year, and usually cures only 30-40 percent of patients. Essentially, most people figure the treatment is worse than the disease.

Vertex Pharmaceuticals changed the equation back in May. The company won FDA approval for a direct antiviral drug, a protease inhibitor called telaprevir (Incivek), that is added to the usual two-drug combo regimen. By adding the Vertex drug, researchers saw the cure rate boom to almost 80 percent of patients, while cutting the treatment time with the other drugs in half. The Vertex drug also significantly raised the cure rate for patients who failed to respond to prior rounds of therapy.

Vertex looked golden for a while, as its stock soared above $55 a share, sending its market value above $10 billion. Analysts were raving about how Vertex smashed sales expectations in its first few months on the market, and started turning profitable in just its second quarter of selling the drug. Waves of patients were suddenly showing up at doctors’ offices to get treatment for hepatitis C, now that the odds of a cure were so much higher.

But important as the Vertex advance has been, researchers have made it clear that this story isn’t over. The ultimate goal is to get rid of interferon, and its side effects, so that physicians can count on some combination of direct antivirals that can be taken as oral pills. That might include Vertex’s drug in combination with others, or might not.

So that’s why Vertex, and other companies, have feverishly been looking to mix and match various hepatitis C drugs. It’s all part of a quest to come up with the ideal combo that can raise the bar on cure rates, minimize side effects, and maximize convenience.

While people on Wall Street like to embrace a simple storyline with clear winners and losers, the hepatitis C virus is one tricky adversary. Like HIV, it has a tendency to mutate and develop resistance capabilities, whenever scientists throw a new antiviral drug against it. So there isn’t likely to be a single magic bullet. The most likely route to success is with a combination of two, three, or maybe four antiviral drugs that attack the virus from different angles, making it much harder for the bug to mutate and escape one drug.

As Steve Worland, the CEO of San Diego-based Anadys Pharmaceuticals, put it in a guest editorial for Xconomy in September, there are at least four important categories of hepatitis C antivirals. There are protease inhibitors on the market like Vertex’s drug and Merck’s boceprevir (Victrelis). There are nucleotide polymerase inhibitors like Pharmasset’s PSI-7977 and a rival drug called mericitabine from Roche. There are non-nucleotide polymerase inhibitors in the works from Abbott Laboratories, Vertex, and Anadys (which Roche acquired this fall for $230 million.) And Bristol-Myers Squibb is betting on another kind of compound, an NS5A inhibitor. (You could also count microRNA therapies, which Santaris Pharma and Regulus are working on at earlier stages of development.)

Just this year, we’ve seen some fascinating jockeying for position. Drug companies often don’t like to test combinations of experimental drugs together in clinical trials, because when side effects emerge, people often like to point the finger at the other guy’s drug. And who wants to divvy up the profits with some other pharma giant when you have the whole thing yourself?

But with hepatitis C, the market opportunity is so big, and the variety of drugs to attack it is so broad, that pharma companies have set aside those concerns just to get a piece of the action. We’ve already seen Merck and Roche form a partnership to co-market Victrelis against the leading drug on the market from Vertex. Gilead just shelled out the breathtaking sum of $11 billion for Pharmasset, even though the smaller company’s lead compound still has to navigate the third and final phase of clinical trials required for FDA approval. Bristol-Myers Squibb and Johnson & Johnson have teamed up in an interesting new collaboration. Roche, through internal efforts and acquisitions, has sought to put all the pieces of the puzzle together under one roof—a protease inhibitor, a nucleotide polymerase inhibitor, a non-nucleotide polymerase inhibitor.

Nobody knows which compounds will match up best together, which ones will be too toxic in combination, or even how many antivirals will be needed to raise the cure rate. But it’s worth noting that Vertex raised the bar very high, by getting cure rates up to around 80 percent. Doctors are certainly eager to get rid of the nasty interferon part of the regimen, but they will only do that when a new regimen can do at least as well on cure rates. And any of these drugs can be derailed by somewhat mild side effects, since the bar on safety is set quite high already.

It might be relatively safe and simple to declare Gilead/Pharmasset the winners in this market, but this race isn’t even close to over. There are 200 laps in the Daytona 500, and in the hepatitis C race, I’d say we’re at about lap 50. There are going to be some fascinating strategic maneuvers, and maybe even a spectacular crash or two, before somebody zooms in under the checkered flag.

Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. E-mail him at ltimmerman@xconomy.com or follow him on Twitter at twitter.com/ldtimmerman.

Source

Carotid atherosclerosis and chronic hepatitis C: A prospective study of risk associations

Hepatology. 2011 Dec 2. doi: 10.1002/hep.25508. [Epub ahead of print]

Petta S, Torres D, Fazio G, Cammà C, Cabibi D, Di Marco V, Licata A, Marchesini G, Mazzola A, Parrinello G, Novo S, Licata G, Craxì A.

Source

Sezione di Gastroenterologia, Di.Bi.M.I.S, Università di Palermo, Italia. petsa@inwind.it.

Abstract

BACKGROUND AND AIMS:

There are contrasting results in studies of cardiovascular risk in patients with genotype 1 chronic hepatitis C (G1 CHC). We evaluated the prevalence of carotid atherosclerosis compared with a control population in order to assess the potential association between atherosclerosis, host and viral factors, and liver histological features.

MATERIALS AND METHODS:

One hundred seventy-four consecutive biopsy-proven G1 CHC patients were evaluated by anthropometric and metabolic measurements. One hundred seventy-four patients attending an outpatient cardiology unit were used as controls. Intima-media thickness (IMT) and carotid plaques, defined as focal thickening of > 1.3 mm at the level of common carotid, were evaluated using ultrasonography. All G1 CHC biopsies were scored by one pathologist for staging and grading, and graded for steatosis.

RESULTS:

Carotid plaques were found in 73 (41.9%) G1 CHC patients compared with 40 (22.9%) control patients (p<0.001). Similarly, G1 CHC patients had a greater IMT compared with control patients (1.04±0.21 versus 0.90±0.16; p<0.001). Multivariate logistic regression analysis showed that older age (OR 1.047, 95%CI 1.014-1.082, p= 0.005), and severe hepatic fibrosis (OR 2.177, 95%CI 1.043-4.542, p=0.03), were independently linked to the presence of carotid plaques. In patients aged ≤55 years, 15/67 cases with F0-F2 fibrosis (22.3%) had carotid plaques, compared with 11/21 (52.3%) with F3-F4 fibrosis (p=0.008). By contrast, in patients >55 years the prevalence of carotid plaques was similar in those with or without severe fibrosis (25/43, 58.1% versus 22/43, 51.1%; p=0.51).

CONCLUSION:

Severe hepatic fibrosis is associated with a high risk of early carotid atherosclerosis in G1 CHC patients. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases

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Economic model of a birth cohort screening program for hepatitis C virus

Hepatology. 2011 Dec 2. doi: 10.1002/hep.25510. [Epub ahead of print]

McGarry LJ, Pawar VS, Parekh HH, Rubin JL, Davis GL, Younossi ZM, Capretta JC, O'Grady MJ, Weinstein MC.

OptumInsight, Medford, MA. lisa.mcgarry@optum.com

Abstract

Recent research has identified high hepatitis C virus (HCV) prevalence among older US residents who contracted HCV decades ago and may no longer be recognized as high-risk. We assessed the cost-effectiveness of screening 100% of US residents born 1946-1970 over 5 years (birth-cohort screening) compared with current risk-based screening, by projecting costs and outcomes of screening over the remaining lifetime of this birth cohort. A Markov model of the natural history of HCV was developed using data synthesized from surveillance data, published literature, expert opinion, and other secondary sources. We assumed eligible patients were treated with pegylated interferon plus ribavirin, with genotype 1 patients receiving a direct-acting antiviral in combination. The target population is US residents born 1946-1970 with no prior HCV diagnosis. Among the estimated 102 million (1.6 million chronically HCV-infected) eligible for screening, birth-cohort screening leads to 84,000 fewer cases of decompensated cirrhosis, 46,000 fewer cases of hepatocellular carcinoma, 10,000 fewer liver transplants and 78,000 fewer HCV-related deaths. Birth-cohort screening led to higher overall costs than risk-based screening ($80.4 billion vs. $53.7 billion), but yielded lower costs related to advanced liver disease ($31.2 billion vs. $39.8 billion); birth-cohort screening produced an incremental cost-effectiveness ratio (ICER) of $37,700 per quality-adjusted life-year gained versus risk-based screening. Sensitivity analyses showed that reducing the time horizon during which health and economic consequences are evaluated increases the ICER, whereas decreasing the treatment rates and efficacy increases the ICER. Model results were relatively insensitive to other inputs. CONCLUSION: Birth-cohort screening for HCV is likely to provide important health benefits by reducing lifetime cases of advanced liver disease and HCV-related deaths, and is cost-effective at conventional willingness-to-pay thresholds. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

Source

Boceprevir: Indication of added benefit for specific patients

December 9, 2011

The active ingredient boceprevir has been available since the middle of 2011 as a treatment for chronic hepatitis C of genotype 1. In an early benefit assessment pursuant to the "Act on the Reform of the Market for Medicinal Products" (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined to establish whether boceprevir offers added benefit in comparison with the previous standard therapy.

According to this assessment, the dossier submitted by the pharmaceutical company provides indications of added benefit for patients who have not yet developed liver cirrhosis. However, the extent of this added benefit cannot be classified.

The pharmaceutical company provided no data - or inadequate data - for two other indications - patients with liver cirrhosis and patients for whom prior treatment was totally ineffective (zero response to prior interferon-based therapy) - and therefore added benefit for these patients is not proven.

An addition to previous standard drug therapy

Hepatitis C viruses attack the liver and can trigger inflammation there. If this becomes chronic, cirrhosis can develop and liver function progressively deteriorates. Moreover, the risk of liver cancer (hepatocellular carcinoma, HCC) increases. Boceprevir (trade name Victrelis®, manufacturer MSD Sharp & Dohme) inhibits the reproduction of hepatitis C viruses. Experts assume that if no viruses are detectable in the blood over a sustained period after treatment (sustained virological response, SVR), the risk of secondary disease is reduced.

Boceprevir is administered in addition to the active ingredients peginterferon alfa and ribavirin, which are already on the market. In accordance with the approval status, different patient groups are treated for different periods, as was allowed for in the assessment. The dual combination of peginterferon alfa and ribavirin has been the standard therapy and this was compared with boceprevir given in a triple combination with the former two drugs.

Reduction in secondary diseases: extent cannot be classified.

For the two indications of pretreated (treatment-experienced) and non-pretreated (treatment-naive) patients without cirrhosis, data from one approval study each (SPRINT-2 and RESPOND-2) were available. With the available studies, it is not possible to assess directly whether the new active ingredient influences secondary diseases, such as the development of liver cancer. This is partly because the studies have not lasted long enough for these patient-relevant outcomes to be recorded.

With respect to SVR, there was a clear advantage for boceprevir, both for pretreated patients and for non-pretreated patients without liver cirrhosis. However, SVR is not itself a patient-relevant outcome and cannot be equated with "cure", and there are no studies in which SVR is validated as a surrogate outcome in accordance with the usual criteria employed by IQWiG. Nevertheless, the Institute accepts SVR in the context of the assessment as a surrogate for the reduced incidence of liver cancer. This is because it is currently accepted that patients with no detectable hepatitis C virus in the blood are at lower risk of liver cancer. However, it is unclear how many cases of liver cancer can in fact be prevented by boceprevir.

For the outcome "secondary diseases", IQWiG recognizes an "indication" of a benefit for boceprevir. The requirements for a "proof" are not fulfilled, one reason being that the data are only derived from a single study each, with a comparatively small number of patients. Moreover, the scientific data do not permit a conclusive assessment of the number of patients in whom liver cancer is actually prevented. It is therefore unclear whether the added benefit is "minor", "considerable" or "major". For such a case, the corresponding legal ordinance specifies the assessment category of "unquantifiable".

Indication of greater harm for patients without prior treatment

The indication of greater benefit is in contrast to the indication of greater harm, but only in previously untreated patients. In these patients, boceprevir more often led to anaemia, although this was rarely serious. IQWiG classified the extent of this greater harm as "considerable". In contrast, in patients with prior treatment, anaemia was no more frequent than with standard treatment.

Effect on mortality unclear

IQWiG established that the approval studies contained inadequate data on quality of life for patients with or without prior treatment. There were no statistically significant differences in mortality between the treatment groups. It thus remains unclear if and how boceprevir influences mortality.

Provided by Institute for Quality and Efficiency in Health Care

Source

Taxes Could Fill AIDS Funding Crunch: U.N.

By Aaron Maasho

ADDIS ABABA (Reuters) Dec 07 - The fight against AIDS risks being set back years by a global financial crisis, the head of the United Nations campaign against the disease warned Wednesday.

Incidence rates of HIV infection have been falling and access to treatment is expanding. However, a decline in donor contributions has caused a funding crisis for the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest body for HIV funding, and is dampening optimism about an eventual end to the disease, UNAIDS director Michel Sidibe told Reuters in an interview.

"It is not the time to stop, to reverse all this achievement. The financial crisis is there ... but when we have a financial crisis we need to be innovative," Sidibe said.

Annual funding for HIV/AIDS programs fell to $15 billion in 2010 from $15.9 billion in 2009, well below the $22-24 billion the U.N. agency says is needed annually by 2015 to pay for a comprehensive, effective global response.

Speaking on the sidelines of an international AIDS conference in the Ethiopian capital, Addis Ababa, Sidibe said donors could raise funds through taxes.

"If we have a global financial transaction tax, say of 0.5%, we will have $226 billion. Ten percent of that resource is enough for financing the fight against HIV/AIDS, stopping the epidemic, because we can reduce by 96% the number of new infections by putting people early on treatment," Sidibe said.

"We can have taxation on cigarettes and alcohol. We can find different ways to mobilize new resources."

With many large international donor countries struggling with looming recession and debt crises, public health experts say it is crucial for countries affected by HIV/AIDS to increase their own funding, especially developing countries.

"Sustainability and particularly reducing dependency, making sure that African leaders are taking responsibility to initiate a new discussion around treatment and (the) AIDS financing crisis in Africa, those for me will be the most important messages to come out from Addis Ababa," Sidibe said.

The Global Fund is already cutting new grants for countries battling HIV. The public-private fund contributes about 70% of the money spent on life-saving antiretroviral drugs in developing nations.

Former President George W. Bush, whose President's Emergency Plan for AIDS Relief (PEPFAR) program committed $15 billion dollars for a five-year period in 2003, urged Americans to contribute despite their own economic woes.

"It's essential our country not retreat from the world, it's essential that we continue to show our compassion by funding programs that work," Bush told reporters ahead of the meeting, which opened Sunday.

The U.S. government provided the Global Fund with its founding contribution and has been its largest single donor since its inception in 2001.

Source

Liver Regeneration Boosted by Blocking Cell-Specific Serotonin Receptor

GEN News Highlights: Nov 28, 2011

Blocking activity of the 5-HT_2B serotonin receptor on fibrogenic hepatic stellate cells (HSCs) in the liver may provide a new approach to boosting liver regeneration in injury and disease, scientists suggest. They report on research demonstrating that scar-causing hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration, and that this negative regulatory activity requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT_2B) on HSCs by serotonin.

The studies, which were led by the Newcastle University’s Institute of Cellular Medicine, showed that selective antagonism of 5-HT_2B on HSCs enhanced hepatocyte growth in rodent models of acute and chronic liver injury. Similar effects were also seen in mice lacking 5-HT_2B. The findings are reported in Nature Medicine in a paper titled “Stimulating healthy tissue regeneration by targeting the 5-HT_2B receptor in chronic liver disease.”

Liver disease is characterized by reduced hepatocyte regeneration, which is accompanied by fibrogenesis and the development of liver cirrhosis and cancer, the authors explain. Unfortunately, the complexity of pathways that regulate hepatocyte proliferation, including the contribution of fibrogenic HSCs, is not well understood.

What has been shown, however, is that in the diseased liver HSCs transdifferentiate into activated myofibroblasts that drive fibrogenesis and secrete soluble factors such as hepatocyte growth factor, TGF-β1, and interleukin-6 (IL-6), which might impact on hepatocyte proliferation.

To investigate the role of HSCs in hepatocyte regeneration the team first evaluated the effects of triggering selective apoptosis-mediated depletion of HSCs on hepatocyte proliferation in bile duct-ligated (BDL) mice, a well-established rodent model of extrahepatic cholestasis. To effect selective apoptosis, HSCs were targeted using a single-chain antibody, C1-3, conjugated to gliotoxin. This mycotoxin is specific to synaptophysin, an antigen expressed on myofibroblasts positive for α-smooth muscle actin (α-SMA+ myofibroblasts), which are specifically derived from the transdifferentation of HSCs.

Treatment of BDL mice using C1–3 gliotoxin resulted in marked but not complete, deletion of hepatic α-SMA+ cells in mice ( α-SMA+ myofibroblasts derived from other cell types weren’t affected) and the stimulation of hepatocyte proliferation. Importantly, there was no accompanying change in the expression of the hedgehog target gene Gli2, which indicated that stimulation of hepatocyte growth after HSC depletion wasn’t due to activation of the hedgehog pathway, the authors note.

The team’s previous work had identified functional 5-HT_2B serotonin receptors on activated HSCs in liver disease. Hence, they next looked at whether paracrine signaling between HSCs and hepatocytes might explain the antiregenerative properties of HSCs. To investigate the influence of 5-HT_2B on hepatocyte regeneration during liver injury the researchers used a drug called SB-204741, which is a highly specific 5-HT_2B antagonist but has negligible effects on the 5-HT_2A and 5-HT_2C receptor subtypes.

Studies in the experimental mice showed that administration of SB-204741 stimulated hepatocyte proliferation in progressive BDL-induced liver injury and in liver damage induced by acute carbon tetrachloride (CCl₄) administration. These results indicated a specific antiregenerative role for 5-HT_2B signal, a notion supported by studies in 5-HT_2B knockout mice (Htr2b^-/-).

Partial hepatectomy (PHX) in these knockout animals led to elevated hepatocyte proliferation. Levels of IL-6 and TNF-α, which are primers of hepatocyte regeneration and expressed transiently shortly after surgery, were modestly increased in 5-HT_2B knockout mice at four hours of PHX. Crucially, though, the production of TGF-β1, which is induced in the end stage of liver regeneration and acts to repress hepatocyte proliferation, was evident in the livers of wild-type mice at 36 hours after PHX but not in the livers of 5-HT_2B knockout animals.

Interestingly, the investigators report, the liver-to-bodyweight ratios of wild-type mice treated using SB-204741 increased after PHX, indicating that selective antagonism of 5-HT_2B results in sustained stimulation of liver regeneration.

5-HT_2B is expressed on HSCs in diseased liver but at lower levels on cholangiocytes and Kupffer cells, the researchers continue. Studies indicated that 5-HT_2B was induced in HSCs after PHX, but its expression was reduced in hepatocytes. Treatment with C1-3-gliotoxin increased hepatocyte proliferation after PHX, and this was associated with reduced hepatic expression of TGF-β1.

Thus far, it appeared that HSC depletion and 5-HT_2B antagonism had similar effects on hepatocyte proliferation in models of liver damage, but what wasn’t known was whether they acted through independent mechanisms. If so, then additive effects should be observed when combining HSC depletion with 5-HT_2B antagonism. However, while the combination of HSC depletion and SB-204741 treatment in CCl₄-injured mice enhanced hepatocyte proliferation and inhibited TGF-β1 expression, there were no additive effects.

The investigators next designed chromatin immunoprecipitation studies to identify the intracellular signaling pathways through which serotonin and 5-HT_2B exert their antiregenerative effects. They found that either antagonism of 5-HT_2B or treatment using the ERK inhibitor PD98059 suppressed serotonin-induced recruitment of JunD, which is one half of the heterodimer making up the AP-1 transcription factor that controls transcription of TGFβ1. Likewise serotonin-induced phosphorylation of JunD was also suppressed on administration of PD98059 or SB-204741.

“On the basis of these data, we propose that phosphorylation and activation of JunD by ERK mediates the stimulation of TGF-β1 transcription by serotonin and 5-HT_2B in HSCs,” the authors conclude. “If this pathway operates in the context of the injured liver, then JunD would be predicted to function as a transcriptional repressor of hepatocyte proliferation.”

In confirmation of this, the team found that compared with wild-type mice, JunD-knockout mice recovering from CCl₄ injury demonstrated higher numbers of mitotic hepatocytes, which was associated with reduced TGF-β1 expression.

The researchers finally moved on to evaluate whether 5-HT_2B antagonism would have an antifibrogenic effect in mouse models of progressive liver disease in which both fibrogenesis and regeneration result in remodeling of the hepatic architecture. Experimental animals were given CCl₄ injections over three weeks to establish fibrotic disease, and then CCl₄ treatment was continued either with or without treatment with SB-204741.

“Treatment with SB-204741 significantly reduced the number of hepatic α-SMA+ fibrogenic cells, fibrotic matrix, hepatic expression of TGF-β1, and expression of the fibrogenic genes encoding TIMP-1 and pro-collagen I, confirming an antifibrogenic effect at the molecular level,” they write.

Moreover, SB-20741 administration was linked with a higher rate of cellular apoptosis in the fibrotic matrix. Administration of SB-20471 in the model of progressive BDL-induced liver disease also resulted in a protective antifibrotic effect as well as improvements in liver function.

The overall results demonstrate that the negative regulation of hepatocyte regeneration by HSCs in the liver requires stimulation of the 5-HT_2B receptor on HSCs by serotonin, which activates expression of TGF-β1 through signaling by ERK1 and the transcription factor JunD, the authors conclude.

“5-HT_2B is selectively expressed by activated human HSCs and the signaling pathway we describe here is conserved in human HSCs. Potent and selective antagonists of 5-HT_2B are already available and have been reported as being safe for clinical use in humans. This class of drug may therefore have therapeutic potential in liver disease, both as stimulants of hepatocyte regeneration and as anti-fibrotic agents.”

Source

Notes from the Field: Risk Factors for Hepatitis C Virus Infections Among Young Adults

From Morbidity & Mortality Weekly Report

Massachusetts, 2010

Daniel Church, MPH; Kerri Barton, MPH; Franny Elson, MS; Alfred DeMaria, MD; Kevin Cranston, MDiv; Norma Harris, PhD; Stephen Liu, MPH; Dale Hu, MD; Deborah Holtzman, PhD; Scott Holmberg,

Posted: 12/08/2011; Morbidity & Mortality Weekly Report. 2011;60(42):1457-1458. © 2011 Centers for Disease Control and Prevention (CDC)MD; Rania A. Tohme, MD

Abstract and Introduction

Introduction

During 2002–2009, rates of newly diagnosed hepatitis C virus (HCV) infection increased from 65 to 113 cases per 100,000 population among persons aged 15–24 years in Massachusetts.^[1] Accordingly, the Massachusetts Department of Public Health (MDPH) and CDC interviewed persons aged 18–24 years with HCV infection reported to MDPH during July 1–December 31, 2010, to elicit detailed information regarding demographic, clinical, and risk characteristics.

Of the 394 patients indentified, 193 (49%) had a valid telephone number; of those 193 patients, 101 (52%) did not answer after three call attempts, 19 (10%) were either in a drug treatment facility or incarcerated, 19 (10%) refused to participate, 31 (16%) agreed to participate but did not come on the scheduled interview day, and 23 (12%) completed the interview. An additional five persons aged 18–24 years with diagnosed HCV infection during July 1– December 31, 2010, but not reported to MDPH, were interviewed in a correctional facility, where they were incarcerated.

Mean age of the 28 respondents was 21.9 years (range: 19–24 years); 15 (54%) patients were female, 23 (82%) were white, nine (32%) did not finish high school, nine (32%) were unemployed, and 25 (89%) had health insurance. Twenty-six (93%) had used drugs; of these, 100% reported marijuana use, with a median age of initiation of 13 years (range: 9–17 years); 92% reported opioid analgesic abuse (oxycodone and/or Oxycontin), with a median age of initiation of 17 years (range: 12–23 years); and 89% reported heroin use, with a median age of initiation of 18 years (range: 14–21 years). Nearly all respondents (95%) used opioid analgesics before switching to heroin. During the preceding 6 months, the most frequently injected drugs among respondents were heroin (50%) and opioid analgesics (30%).

Medical record reviews showed that five respondents had visited emergency departments on multiple occasions complaining of pain and were prescribed opioid analgesics. Most respondents (70%) reported sharing syringes and drug paraphernalia within networks of injection drug users that included persons with known HCV infection (43%). One in four respondents reported never being informed of their HCV infection by their health-care provider, and 11 (39%) were tested for HCV in a drug treatment program or during incarceration.

The findings in this report are subject to at least three limitations. First, only a small number of persons agreed to be interviewed, which limits the ability to generalize these findings. The low response rate might be attributed, in part, to the characteristics of the targeted population (young injection drug users) coupled with lack of provision of incentives. Second, comparison of the demographic and clinical characteristics of persons who were interviewed with those who could not be interviewed was not possible because information was lacking for nearly 60% of the 394 hepatitis C cases reported during July 1–December 31, 2010. However, of those cases with available information, 229 (58%) occurred among females and approximately 80% occurred among whites, which is consistent with the demographic characteristics of interviewed respondents. Finally, persons with HCV infection who were in drug rehabilitation centers could not be interviewed because of federal confidentiality regulations specific to these centers.

Consistent with other studies, most respondents reported opioid analgesics abuse before switching to heroin (which is less expensive).^[2,3] Health-care providers should routinely ask about prescription and illicit drug use and screen all persons with risk factors for HCV infection, regardless of age.^[4] They also need to be aware of warning signs of prescription opioid and drug abuse, such as frequent complaints of pain and request for opioids. Drug treatment programs and prisons are potential venues for education regarding the risk for hepatitis C from sharing needles and other injection paraphernalia and for providing vaccination against hepatitis A and B. School and community-based education programs also are needed to prevent initiation of illicit and prescription drug use.^[5] Several harm reduction interventions have been conducted to assess the effectiveness of reducing incidence of both human immunodeficiency virus and HCV infection. Overall results from a recent meta-analysis did not indicate a statistically significant decrease in incident HCV infection from a single programmatic strategy; however, the results did indicate that combined interventions were effective.^[6] Thus, combining current interventions and identifying new evidence-based approaches to preventing drug use and unsafe injection practices in young adults are needed to control and prevent HCV infections.

References

1. CDC. Hepatitis C virus infection among adolescents and young adults—Massachusetts, 2002—2009. MMWR 2011;60:537–41.
2. Lankenau SE, Teti M, Silva K, Bloom JJ, Harocopos A, Treese M. Initiation into prescription opioid misuse amongst young injection drug users. Int J Drug Policy 2011; June 19 [Epub ahead of print].
3. Grau LE, Dasgupta N, Harvey AP, et al. Illicit use of opioids: is OxyContin a "gateway drug"? Am J Addict 2007;16:166–73
4. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).
5. National Institute on Drug Abuse. Preventing drug use among children and adolescents: a research-based guide for parents, educators, and community leaders. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 2003. Available at http://www.drugabuse.gov/prevention/index.html. Accessed October 25, 2011.
6. Hagan H, Pouget ER, Des Jarlais DC. A systematic review and meta-analysis of interventions to prevent hepatitis C virus infection in people who inject drugs. J Infect Dis 2011;204:74–83.

Source

Resonance Health begins licensing discussions for fatty liver test, lodges patent application

Friday, December 09, 2011 by Angela Kean

Resonance Health (ASX: RHT) is moving to protect the intellectual property associated with its diagnostic test for the assessment of fatty liver, HepaFat Scan, through the lodgement of a Provisional Patent Application.

The company has also registered the HepaFat Scan trademark and, importantly, begun discussions with interested parties on its potential use and licence.

Results of a clinical study conducted earlier in the year demonstrate that the MRI-based diagnostic product can accurately assess the severity of fatty liver disease, replacing the need for an invasive liver biopsy.

According to Resonance, nearly one in three Americans have fatty liver, and non-alcoholic fatty liver disease is the most common liver disease in the U.S. and Europe.

An accurate diagnosis of early stage fatty liver disease provides a better outcome for patients, to address the condition before the onset of liver damage.

Meanwhile, Resonance has also recorded substantial growth in the sales volumes of its non-invasive, MRI-based service for the measurement of liver iron overload, FerriScan, in the 2012 financial year.

From July to November 2011 there has been a 30% month-on-month increase in the numbers of FerriScans sold, compared to the same period in 2010.

Resonance announced earlier this week it has expanded the distribution of FerriScan into the Middle East with the appointment of Gulf Drug Establishment as a distributor.

Gulf Drug Establishment will distribute the FerriScan service in the United Arab Emirates, Saudi Arabia and Egypt where there is a high number of patients with iron overload caused by regular blood transfusions to treat an underlying condition.

FerriScan is currently available through over 120 centres in more than 20 countries. Resonance witnessed strong growth in new FerriScan users in Brazil, Japan, Italy and China in 2010-11.

Source

AHF Targets Merck Over AIDS Drug Pricing

Dec. 8, 2011, 3:10 p.m. EST

AIDS group launches advocacy campaign pressuring the drug giant to heed President Obama's call for drug companies to "do their part" to help Americans get access to life-saving AIDS treatments

LOS ANGELES, Dec 08, 2011 (BUSINESS WIRE) -- As part of its ongoing campaign to lower AIDS drug prices and increase access, AIDS Healthcare Foundation (AHF) today announced that it is launching a new advocacy campaign calling for the drug company Merck to lower its prices for cash-strapped AIDS Drug Assistance Programs (ADAPs). ADAPs, a network of federal and state funded programs that provide life-saving HIV treatments to low income, uninsured, and underinsured individuals living with HIV/AIDS nationwide, are facing a severe financial crisis that has left as many as 10,000 people with AIDS without access to treatment.

The campaign comes days after Gilead Sciences, Inc., the largest manufacturer of AIDS drugs in the U.S., announced it has agreed to provide additional discounts to the programs. Gilead is the second company, following Boehringer Ingelheim, to agree to additional discounts for ADAPs.

On December 1st -- World AIDS Day -- President Obama proclaimed the need for all stakeholders to do more to help the struggling ADAP programs, saying: "The federal government can't do this alone, so I'm also calling on state governments, and pharmaceutical companies, and private foundations to do their part to help Americans get access to all the life-saving treatments."

"We want to state loud and clear that Merck's refusal to lower its prices for ADAPs is a death sentence for people with AIDS," said Michael Weinstein, AIDS Healthcare Foundation President. "Our campaign will feature a series of actions near Merck headquarters in New Jersey, including print and television advertisements, protests at Merck's main campus, direct mail, and contact with Merck investors," said Weinstein. Weinstein added: "At a cost to ADAPs of roughly $8,000-$9,000 per person per year, Merck's Isentress is one the highest priced AIDS drugs in the US today. Merck employees and the public should know about the company's shameful pricing and policies on AIDS."

"Gilead and other companies have agreed to provide additional discounts to ADAPs, and the President has asked the companies to do more to help these programs. There's no reason for Merck to refuse other than greed," said Tom Myers, Chief of Public Affairs for AIDS Healthcare Foundation.

The first ad in AHF's campaign will be a "Merck: Breaking the Bank" direct mail postcard sent to the communities surrounding Merck's headquarters in Whitehouse Station, NJ. The postcard highlights that Merck has made billions of dollars on AIDS drugs, lending to a nearly $100 billion market capitalization for the company, yet it refuses to lower prices for the publicly funded ADAPs.

As part of its strategy to raise the pricing issues with Merck investors, in October AHF testified before the board of CalPERS (California Public Employees Retirement System) about the pricing policies of Merck and other drug companies. At that meeting the CalPERS board agreed to contact Merck and others about their pricing policies in light of the financial difficulties experienced by ADAPs. The CalPERS action followed the move by California State Treasurer Bill Lockyer, and state Treasurer John Chiang, to write to Merck and other companies and urge them to provide additional discounts to ADAPs.

AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and services to more than 124,000 individuals in 23 countries worldwide in the US, Africa, Latin America/Caribbean the Asia/Pacific region and Eastern Europe. www.aidshealth.org

SOURCE: AIDS Healthcare Foundation

Source

Boehringer Ingelheim completes patient entry for Phase III trial programme in Hepatitis C

BusinessWire · Dec. 9, 2011 | Last Updated: Dec. 9, 2011 3:00 AM ET

For media outside of the U.S.A. only

Boehringer Ingelheim today announced that the final patient has been randomised to treatment in the large-scale Phase III clinical trial programme for BI 201335, its investigational, oral protease inhibitor for the treatment of chronic hepatitis C virus (HCV).

The extensive study programme is underway at more than 350 sites in 15 countries and together encompasses nearly 2,000 treatment-experienced as well as treatment-naïve patients. Key regions in the programme include the European Union, Japan, U.S., Canada, Taiwan, Korea and Russia.

The programme consists of three Phase III trials, that will be conducted to evaluate BI 201335 plus the standard backbone treatment, pegylated interferon (pegIFN) and ribavirin (RBV) in patients with chronic genotype-1 HCV. Most HCV patients are infected with genotype-1 virus and belong to the most challenging HCV group to treat. The study programme evaluates “sustained viral response” (SVR) as the primary clinical endpoint, which is considered viral cure. Results from the Phase III studies are expected in the first half of 2013.

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the entire BI 201335 programme. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important new drugs to patients earlier.

“We are progressing our BI 201335 programme with a high priority to leverage its potential to improve cure rates in HCV treatment,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. “We believe our HCV-pipeline may become an important tool to fight a chronic disease that affects over 170 million people worldwide.”

Phase IIb results presented last month showed that the interferon-free combination of BI 201335, with Boehringer Ingelheim’s polymerase inhibitor BI 207127 (SOUND-C2), led to 76% of patients achieving a virological response at week 12, with 63% achieving SVR12 (undetectable virus, 12 weeks post-treatment) with 16 weeks treatment. These results were presented at the American Association for the Study of Liver Diseases (AASLD) 2011 Liver Meeting in San Francisco, USA, alongside SILEN-C1 and SILEN-C3 study results which showed the potential for BI 201335/ PegIFN/RBV to shorten treatment duration and improve the likelihood of viral cure (SVR). These Phase IIb results provide a strong basis for further development as BI 201335 progresses through Phase III.

NOTES TO EDITORS

SOUND-C2

SOUND-C2 is an open-label, randomised, Phase IIb study where 362 treatment-naïve GT1 HCV patients were randomised into five interferon-free treatment groups, each with 120mg BI 201335 once daily but with different dosing of BI 207127 and treatment durations as follows:

• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 16 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 28 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 40 weeks;
• BI 201335 120mg QD + BI 207127 600mg BID + RBV for 28 weeks; or
• BI 201335 120mg QD + BI 207127 600mg TID without RBV for 28 weeks.

SILEN-C1

SILEN-C1 is a double-blind, placebo-controlled trial, that randomised 429 treatment-naïve GT1 HCV patients (1:1:2:2) to receive either placebo or BI 201335 120 mg with three days Lead-in (LI) of PegIFN/RBV, BI 201335 240 mg QD with three days LI or BI 201335 mg 240mg QD without LI. In each treatment group, BI 201335 was given for 24 weeks together with PegIFN/RBV for 24 or 48 weeks. Patients were evaluated for SVR according to various baseline characteristics.

SILEN-C3

In this open-label Phase II trial, 159 treatment-naïve GT1 HCV patients were randomised to receive 120 mg QD BI 201335 for 12 or 24 weeks, each after three days lead-in (LI) with pegylated interferon and ribavirin (PegIFN/RBV). In both groups, PegIFN/RBV was given for 24 weeks. Patients who did not achieve an eRVR, continued PegIFN/RBV to week 48. eRVR was defined as viral load less than 25 IU/mL at week 4 and undetectable at weeks 8-18.

About Hepatitis C Virus (HCV)

HCV is an infectious disease of the liver and is a leading cause of chronic liver disease and liver transplant. The number of individuals chronically infected with HCV globally has been estimated at 170 million, with 3–4 million new infections occurring each year. Only about 20–45% of patients clear the virus in the acute phase. Of the remaining chronically infected patients, 20% will develop cirrhosis within a mean of 20 years. The mortality rate after cirrhosis has developed is 2-5% per year. End-stage liver disease due to HCV infection currently represents the major cause for liver transplantation in the Western world.

About Boehringer Ingelheim in Virology

Boehringer Ingelheim has more than 7,500 scientists working in cross disciplinary teams within our global R&D network in six large therapeutic areas, including virology. In addition to its ongoing research program for HCV, Boehringer Ingelheim has a longstanding history in virology drug development, including compounds for the treatment of HIV (VIRAMUNE® (nevirapine) tablets/oral suspension, the first approved HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) and Aptivus®, an HIV protease inhibitor). The company has a well established research centre in Laval, Canada, dedicated to virology research since the early 1990’s, and is committed to developing new therapies for virological diseases with a high unmet medical need.

Boehringer Ingelheim in Hepatitis C Virus (HCV)

Boehringer Ingelheim has a dedicated HCV treatment development programme, called HCVerso^TM, which at its core, aims to reverse the existing HCV paradigm. The ultimate aim of this programme is to deliver improved HCV treatment outcomes for patients whilst breaking down the barriers of current treatment regimens.

BI 201335 is an investigational oral HCV NS3/4A protease inhibitor, discovered from Boehringer Ingelheim’s own research and development, which has completed clinical trials through Phase IIb (SILEN-C studies). This Phase II programme supports the investigation of BI 201335 in Phase III trials currently ongoing. Boehringer Ingelheim is also developing BI 207127, an NS5B RNA-dependent polymerase inhibitor that has completed Phase I clinical trials. Phase II trials evaluating BI 207127 with BI 201335 in interferon-sparing regimens, both with and without ribavirin, are currently underway.

Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

For more information please visit www.boehringer-ingelheim.com

http://www.twitter.com/boehringer

Contacts

Boehringer Ingelheim
Corporate Communications
Media + PR
Julia Meyer-Kleinmann, +49 6132 – 77 8271
55216 Ingelheim/Germany
Fax: +49 6132 – 77 6601
press@boehringer-ingelheim.com
More information
www.boehringer-ingelheim.com

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Vertex and Alios BioPharma Begin Clinical Studies of Nucleotide Drug Candidates ALS-2200 and ALS-2158 for the Treatment of Hepatitis C

December 9, 2011

-Studies to evaluate safety and effects on viral kinetics in people with chronic genotype-1 hepatitis C-

-Data expected in second quarter of 2012 could enable initiation of interferon-free, nucleotide-based combination studies in the second half of 2012-

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Alios BioPharma, Inc. today announced the initiation of two clinical studies for the nucleotide analogues ALS-2200 and ALS-2158, which are inhibitors of the hepatitis C NS5B polymerase. The studies will evaluate the safety and tolerability of ALS-2200 and ALS-2158 in healthy volunteers followed by a seven-day evaluation to observe the effects on viral kinetics in people with chronic genotype-1 hepatitis C. Data are expected in the second quarter of 2012, which could enable the initiation of studies to evaluate multiple all-oral, interferon-free combination regimens for chronic hepatitis C in the second half of 2012. Vertex has worldwide development and commercialization rights for ALS-2200 and ALS-2158, which were discovered by Alios BioPharma. Alios and Vertex are jointly conducting the Phase 1 studies announced today.

"These studies are an important step in our ongoing efforts to strengthen our leadership position in hepatitis C by developing all-oral regimens that could further improve the future treatment of this disease," said Peter Mueller, Ph.D., Executive Vice President, Global Research and Development, and Chief Scientific Officer for Vertex. "The studies of ALS-2200 and ALS-2158 announced today are designed to generate data that may provide the opportunity to rapidly advance into Phase 2 development where we could evaluate a number of nucleotide-based regimens beginning in the second half of next year, including regimens with INCIVEK or VX-222."

Study Design

The two Phase 1 studies announced today will be randomized, double-blind, placebo-controlled studies. The primary goals are to evaluate the safety and tolerability of single ascending doses of ALS-2200 and ALS-2158 in healthy volunteers and of multiple ascending doses in people with chronic genotype-1 hepatitis C. A secondary objective will be to evaluate the effects on viral kinetics of ALS-2200 and ALS-2158 during seven days of dosing in people with hepatitis C.

Dosing is now underway for the study of ALS-2200, and dosing is expected to begin next week for the study of ALS-2158. Vertex and Alios BioPharma expect to have complete data, including seven-day viral kinetic data, from each trial in the second quarter of 2012, which could enable the initiation of all-oral, interferon-free Phase 2 combination studies in the second half of 2012. These Phase 2 studies are expected to evaluate combination regimens of ALS-2200 or ALS-2158 with INCIVEK (telaprevir) or VX-222, potential dual nucleotide regimens and other interferon-free combination regimens that may also include ribavirin. INCIVEK is Vertex's FDA-approved protease inhibitor for chronic genotype-1 hepatitis C, and VX-222 is Vertex's investigational hepatitis C non-nucleoside polymerase inhibitor. The combination studies will be designed to generate sustained viral response (SVR or viral cure) data.

About ALS-2200 and ALS-2158

ALS-2200 and ALS-2158 are highly potent pan-genotypic nucleotide analogues that appear in in vitro and non-clinical studies to have a high barrier to drug resistance and the potential to be dosed orally once-daily. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound is structurally distinct and has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens, including regimens with INCIVEK^TM (telaprevir) and VX-222. Data from in vitro studies showed that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with INCIVEK and VX-222. Additionally, in those in vitro studies, both compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 and ALS-2158 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK™ (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.² However, approximately 60 percent of people do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8

More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.⁹ Hepatitis C is four times more prevalent in the United States compared to HIV.⁹ The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.¹⁰ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.^11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.⁹

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 1,900 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including, hepatotropic and respiratory viruses and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability. Alios is the recipient of the 2011 BayBio Pantheon Outstanding Partnering Award.

Special Note Regarding Forward-Looking Statements:

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Mueller's statements in the second paragraph of this press release and statements regarding (i) the expectation that Vertex will receive data from two Phase 1 studies in the second quarter of 2012 that could enable initiation of interferon-free, nucleotide-based combination studies in the second half of 2012; (ii) the design, goals, objectives and expected timing of receiving data from the Phase 1 studies; (iii) the possible combination regimens that could be evaluated in Phase 2 studies and the potential design of such studies; and (iv) the potential for developing ALS-2200 and ALS-2158 together as a dual nucleotide regimen and as part of other combination therapy regimens. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, the possibilities that the outcomes from the Phase 1 studies may not be favorable, that the Company may not be able to successfully develop ALS-2200 or ALS-2158, and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.

References:

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.

² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

⁹ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.

¹⁰ Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.

¹¹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

¹² Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

(VRTX-GEN)

Vertex Pharmaceuticals Incorporated
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Media:
Zachry Barber, 617-444-6992
mediainfo@vrtx.com

Source: Vertex Pharmaceuticals Incorporated

Source

A sprint to increase response to HCV treatment: expectancies but caution

J Hepatol. 2011 Nov;55(5):1154-8. Epub 2011 Jul 1

Asselah T.

Source

Service d'Hépatologie, Hôpital Beaujon, Clichy, France. tarik.asselah@bjn.aphp.fr

Abstract

BACKGROUND:

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

METHODS:

We conducted a double-blind study in which previouslyuntreated adults with HCV genotype 1 infection were randomly assigned to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

RESULTS:

A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (p < 0.001), and in 213 of the 311 patients (68%) in group 3 (p < 0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (p = 0.04), and in 29 of the 55 patients (53%) in group 3 (p = 0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

CONCLUSIONS:

The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared to standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

BACKGROUND:

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

METHODS:

To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

RESULTS:

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, p < 0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10)IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41-46% of boceprevir-treated patients and 21% of controls.

CONCLUSIONS:

The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared to peginterferon-ribavirin alone.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Comment on

N Engl J Med. 2011 Mar 31;364(13):1195-206.

Source