December 12, 2011

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.

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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.

NS.gif

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

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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.

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