Hepatitis Digest;Patients with cirrhosis present decreased brain density in many areas of the grey and white matter

Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy
"patients with cirrhosis present decreased brain density in many areas of the grey and white matter......showed a clear relationship between the extension and size of decreased brain density areas and the severity of cerebral dysfunction......similarities with the lesions observed in Alzheimer Disease suggest that it may represent organic lesions".........

Immunopathologic differences of Sjogren's syndrome versus sicca syndrome in hepatitis C virus and human immunodeficiency virus infection
A clinical picture of dry eye and dry mouth, with the histological counterpart of focal lymphocytic sialoadenitis, usually detected in minor salivary glands (MSGs), is considered the hallmark of Sjogren's syndrome (SS). The association of sicca complaints and focal sialoadenitis can be also found in a number of other diseases, including some systemic viral infections.

Among these conditions, chronic hepatitis C virus (HCV) infection, associated with mixed cryoglobulinaemia and extra-hepatic manifestations, and human immunodeficiency virus (HIV) infection, particularly in the phase of diffuse interstitial lymphocytic infiltration (DILS), may mimic the clinical and histological aspects of SS.

However, each disorder is characterised by specific, disease-related immuno-pathological aspects.Besides sicca complaints, the various disorders may also share a number of systemic extraglandular features and the possible development of mucosa-associated lymphoid tissue (MALT) lymphomas. This latter event represents in all of these diseases the final result of an antigen-driven chronic stimulation of B lymphocytes.

Author: Claudio VitaliCredits/Source: Arthritis Research &Therapy 2011, 13:233
Published on: 2011-08-19

Chronic hepatitis C genotype 2 and 3: Are we ready for personalized medicine?
Volume 55, Issue 3, Pages 505-506 (September 2011)

Refers to article:
Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C , 14 January 2011 Michael Manns, Stefan Zeuzem, Ajit Sood, Yoav Lurie, Markus Cornberg, Hartwig Klinker, Peter Buggisch, Martin Rössle, Holger Hinrichsen, Ismail Merican, Yaron Ilan, Stefan Mauss, Saif Abu-Mouch, Andryes Horban, Thomas H. Müller, Christoph Welsch, Rongdean Chen, Rab Faruqi, Lisa D. Pedicone, Heiner Wedemeyer Journal of Hepatology September 2011 (Vol. 55, Issue 3, Pages 554-563)
Abstract Full Text

Over the last several years, efforts have been made in patients with genotypes 2 and 3 chronic hepatitis C (CHC) to assess whether shortening the duration of therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) might preserve the efficacy of the standard 24week treatment duration while decreasing side-effects and improving tolerability. Data on viral kinetics have shown that both the effectiveness of IFN in blocking production of the virus in the first phase of viral decline (rapid decline) and the rate of decline in the second phase (slower decline) differ in patients with hepatitis C virus (HCV) genotype 1 and in those with genotypes 2 or 3 [1], [2]. This led several investigators to the hypothesis that in patients with CHC genotype 2 or 3 and rapid virologic response (RVR, i.e. HCV RNA undetectable after 4weeks of therapy), 12–16weeks of treatment with PEG-IFN and RBV may be as effective as a course of 24weeks [3], [4], which induces sustained virologic response (SVR) in about 80% of patients [5], [6].
While several European studies [3], [7], [8], [9] and a study from Taiwan [10] appeared to support this hypothesis, the results were somewhat different in the ACCELERATE [11] and NORTH-C [12] trials. The conflicting results may have been due to differences in the study design, prevalence of advanced fibrosis and cirrhosis, baseline viral counts, predominant genotype, ethnic background of the study population, and different RBV dosing schedules. The earlier trials by Dalgard et al. [7] and VonWagner et al. [8] included a relatively young HCV population with mostly early-stage fibrosis, while almost 25% of patients in ACCELERATE (a large prospective randomized, multinational non-inferiority trial) had bridging fibrosis or cirrhosis [11]. The absence of bridging fibrosis/cirrhosis was shown to be an independent predictor of SVR among genotype 2 and 3 patients by both Dalgard et al. [7] and Shiffman et al. [11], although this has not been reported by others [3], [8], [13].

Unlike most prior studies which evaluated truncation of treatment duration to less than 24weeks in genotype 2 and 3 patients, ACCELERATE used a fixed dose RBV (800mg/d). Since the mean body weight of ACCELERATE patients with genotype 2, for example, was about 84kg [11], that resulted in a mean daily dose of RBV of 9.52mg/kg, in contrast to 15.3mg/kg in the study of genotype 2 patients by Yu et al. (mean body weight about 66kg) [10]. Although Hadziyannis et al. [14] previously showed that a combination of PEG-IFN alfa-2a and RBV 800mg/d was as effective as a combination of PEG-IFN alfa-2a and RBV 1000–1200mg/d in patients with genotypes 2 and 3 using a 24-week treatment regimen, the prevailing literature as of the publication of the ACCELERATE study left open the question of whether a higher weight-based dose of RBV might still permit a shorter-duration of treatment of genotype 2 and 3 patients with RVR without increasing the risk of relapse.

The notion that the impairment in SVR with truncated therapy in RVR patients in ACCELERATE was due to the low, flat RBV dose (800mg daily) used in that study was challenged by results of the NORTH-C trial [12]. Using PEG-IFN alfa-2b 1.5ug/kg/wk and RBV 800–1400mg daily in patients (n=298) with genotype 2 and 3, the authors were unable to show non-inferiority of the 14-week regimen (as compared to a 24-week regimen) in patients with RVR, with lower SVR (81% vs. 91%) and higher relapse rates (11% vs. 5%) in those treated for 14weeks. Despite the inferiority of the 14-week regimen, Dalgard et al. suggested that a 26–32% reduction of drug exposure and cost with 14weeks of treatment in patients with RVR – recognizing that this would entail a 24-week course of retreatment for the minority with relapse – justified truncation of therapy in such patients (as long as the relapse rate is less than 35%) [12].

Given the intense motivation among most physicians and patients to optimize the chance of success with the initial course of therapy for CHC, the non-uniformity of the data on truncation of therapy in patients with genotypes 2 and 3 who attain RVR has led many clinicians to continue to treat these patients for 24weeks. The study by Manns et al. [15], as reported in the current issue of the Journal, provides the opportunity to glean further insights into this question, along with other aspects of therapy for patients with genotypes 2 and 3, within the context of a large study evaluating both a lower dose of PEG-IFN alfa-2b and a reduced treatment duration. In this study, treatment-naïve patients with CHC genotype 2 and 3 infection were derived from two cohorts: the Hep-Net cohort enrolled in Germany and an international cohort enrolled throughout Europe and Asia. Patients were randomized to receive PEG-IFN alfa-2b (1.5μg/kg/wk) for 24weeks (group A), PEG-IFN alfa-2b (1.0μg/kg/wk) for 24weeks (group B) or PEG-IFN alfa-2b (1.5μg/kg/wk) for 16weeks (group C); all in combination with weight-based RBV (800–1200mg/day). Treatment duration in group C, as well as in groups A and B, was independent of RVR; patients were not randomized to 16 vs. 24weeks of therapy based on RVR. Moreover, data on week 4 HCV RNA were assessed only in the International cohort.

Of the 682 patients enrolled in the study 80% were of genotype 3, which potentially constrains the ability to draw comparably robust conclusions about both of the evaluated genotypes. SVR rates were 66.5%, 64.3%, and 56.6% for groups A, B, and C, respectively, with groups B and C failing to show non-inferiority relative to group A. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Among those who achieved an RVR in the International cohort, SVR rates were consistently high across all treatment arms: 75.3%, 75.9%, and 72.4%, respectively. The relapse rates in the RVR patients were not provided. Among genotype 3 patients, SVR was similar in groups A and B but lower in group C. While in group A SVR rates were highest in patients with genotype 2 infection and low baseline viral load, even among genotype 2 patients with low baseline viral load, SVR rates were lower in group C compared with group A. Treatment-related serious adverse events were highest in group A and predictably, lowest in group C. However, adverse events leading to discontinuation of therapy were similar across the arms.

The current study by Manns et al. [15] adds support to the growing body of literature, including two recent meta-analyses [16], [17], suggesting that 24weeks of therapy should remain the standard of care for genotype 2 and 3 patients. It does demonstrate, however, that the dose of Peg-IFN alfa-2b can be reduced to 1.0μg/kg/wk in those with safety concerns without substantial decline in efficacy. It reaffirms that genotype 3 patients should not be treated routinely for less than 24weeks, as well as those patients with either genotype 2 and 3 without RVR. It again brings up the question whether, based on the low SVR rate of about 50% in these non-RVR populations, treatment of over 24weeks duration might be indicated and randomized controlled trials, such as one currently in progress, are needed to address that issue.

While supporting 24 weeks as the overall standard of care, Manns et al. lend credence to the concept of truncation of therapy in patients with genotype 2 or 3 who achieve an RVR with weight-based ribavirin. The data in the overall literature, however, remain inconclusive as to whether this can be done routinely without jeopardizing the chance of SVR to any significant extent even among “favorable” patient populations with characteristics such as younger age [7], [10], [11], [18], no or minimal fibrosis [7], [9], [11], [19], BMI30kg/m2 [11], [19], [20], low viral load [7], [8], [9], [11], [19], genotype 2 [8], [11], or platelet count140,000 [20]. Despite the potential merit of a cost-effectiveness argument in support of shorter treatment, or a modest improvement in tolerability, many clinicians would find it problematic to routinely administer a regimen that had failed to demonstrate non-inferiority to patients who wish to maximize their prospects of success during the initial treatment course without incurring any incremental chance of having to undergo a repeat therapy. Based on the available data, truncated therapy with PEG-IFN and RBV should be reserved – after individualized discussion about benefit-risk considerations – for genotype 2 or 3 patients with favorable treatment characteristics who have attained RVR if they have significant tolerability issues after 12–16weeks of therapy.

Conflict of interest
Dr. Jacobson received support from: Schering/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome, Sciences, Pfizer Bristol Myers Squibb, and Zymogenetics.
Is a speaker for: Schring/Merck, Gilead, Bristol Myers Squibb, and Roche/Genentech.
Acts as a Consultant/Advisor for: Bristol Myers Squibb, Novartis, Gilead, Schering/Merck, Pfizer, Vertex, GlobeImmune, Human Genome Sciences, Boehringer Ingelheim, Pharmasset, Zymogenetics, Tibotec, Roche/Genentech, Achillion, Glaxo Smithkline, and Biolex.
References

HIV

Pediatric HIV — A Neglected Disease?
Marc Lallemant, M.D., Shing Chang, Ph.D., Rachel Cohen, M.P.P., and Bernard Pecoul, M.D., M.P.H.N Engl J Med 2011; 365:581-583
August 18, 2011
The results of the HIV Prevention Trials Network 052 (ClinicalTrials.gov number, NCT00074581) study were released this past May, 30 years after the first publication about U.S. cases of what would come to be called AIDS. The new study's stunning results — earlier treatment of human immunodeficiency virus (HIV) infection leads to a 96% reduction in the risk of HIV transmission within sero-discordant couples — will influence guidelines in the direction of even earlier initiation of antiretroviral therapy.1 The notions of “test and treat” and “treatment as prevention” come as no surprise to anyone who has been involved in the fields of prevention of mother-to-child transmission of HIV and pediatric HIV care.

What the Rubberman Wrote: Chronicles from the International AIDS Society Conference
Michael Harney, The Rubberman, is an HIV/AIDS/STD/Hepatitis prevention educator and street outreach worker at the Western North Carolina AIDS Project , and separately operates the Needle Exchange Program of Asheville .

Pharmaceutical

Launch trends for Incivek and Victrelis in hepatitis C sector
Article 9 August 2011

Results from a survey fielded one month after the launch of Vertex’ Incivek (telaprevir) and Merck & Co’s Victrelis (boceprevir) indicate that there is a high demand for triple therapy with the new protease inhibitors in patients with hepatitis C (HCV).

Both drugs gained US approval earlier this year, and Victrelis has been cleared in Europe with Incivek gaining a positive opinion (The Pharma Letters passim).

In a new report titled LaunchTrends Incivek and Victrelis, BioTrends, a Decision Resources unit, surveyed a total of 80 physicians (gastroenterologists, hepatologists and infectious disease specialists) about their current perceptions, early experience and anticipated future use of these products. In addition, feedback around patient type, product satisfaction, obstacles to use and promotional activities by Merck and partner Roche and Vertex is captured.

More than half of physicians have initiated trials
Not surprisingly, with the long-awaited anticipation of the new protease inhibitors, unaided awareness and familiarity is extremely high at one month post launch and more than half of surveyed participants have already initiated trial with Incivek or Victrelis. Trial rates do vary by physician specialty, but among those who have prescribed these agents, most are experimenting with both brands.

About 80% of surveyed physicians report seeing either a Victrelis or Incivek medical representative. Among those who have not seen a representative, the majority indicate that they would like to be called on, indicating the desire by practitioners for more information about these products.

Physicians report a high number of eligible patients for the new protease inhibitors, both in newly diagnosed patients and for a large base of patients that have been awaiting the approval of Incivek and Victrelis. Market share projections in the next six months suggest that Incivek will claim a significant share advantage over Victrelis

Media

Operation closed; piercing clients urged tested
ithin days of an Alberta Health Services media release, the release had been reported in numerous media outlets, which spread the possible virus concern across Canada.


FYI

CDC: Flu Vaccine for All, Again
By Todd Neale, Senior Staff Writer, MedPage TodayPublished: August 18, 2011

Although the influenza strains included in the upcoming season's trivalent vaccine are unchanged from last season, the CDC is still recommending that everyone older than 6 months get vaccinated this year.

This season's vaccines, which have already begun to ship, protect against the pandemic H1N1 virus, as well as an H3N2 and a B strain, the same as last season, according to new recommendations from the Advisory Committee on Immunization Practices (ACIP) published in Morbidity and Mortality Weekly Report.

Even so, because studies have shown that protection can wane in the year after receiving the vaccine, everybody who is eligible should be vaccinated again this season, said Carolyn Bridges, MD, of the CDC's National Center for Immunization and Respiratory Disease, on a conference call with reporters.

One group of individuals who might not need as much vaccine as in years past are children younger than 9. Normally, these children would need two doses to provide sufficient protection against the flu. But because the strains are the same as last season, any children who received at least one dose of vaccine last season only need to get one for the upcoming season, according to the recommendations.

Although the guidance is largely similar to that from previous seasons, additional updates include the availability of the intradermal formulation of Fluzone -- which was approved by the FDA in May -- and new recommendations regarding vaccination in individuals with egg allergy -- which were discussed at one of ACIP's meetings in June.

Included in the recommendations for vaccination in the presence of egg allergy:
Those with a history of hives only after exposure to egg can receive influenza vaccine, but should receive the trivalent inactivated vaccine (TIV) rather than the live attenuated influenza vaccine (LAIV), should be vaccinated by a healthcare provider who is familiar with potential manifestations of egg allergy, and should be observed for at least 30 minutes following administration.

People who have had more severe allergic reactions to egg should be referred to a physician with expertise in the management of allergies for further risk assessment.
The vaccine should be administered in settings equipped for the rapid recognition and treatment of anaphylaxis.

The authors noted that a previous severe allergic reaction to influenza vaccine, regardless of the component causing the reaction, is a contraindication to getting the vaccine.
Although the CDC recommends that everyone get an influenza vaccine every year -- barring a contraindication -- certain groups have been identified as high priorities for vaccination.

Two such groups -- healthcare personnel and pregnant women -- were the subject of MMWR reports this week.

Both included comparisons based on Internet surveys of vaccination rates in the 2010-2011 season with those in the 2009-2010 season -- which included the H1N1 pandemic.
For healthcare personnel, in whom vaccination protects both the individual workers and any patients they encounter, receipt of the trivalent seasonal vaccine changed little, from 61.9% in 2009-2010 to 63.5% in 2010-2011. The vaccination rates in 2009-2010 were higher than in the previous decade, attributed to the H1N1 pandemic.

Nearly all of those who worked at a facility that required vaccination (98.1%) were vaccinated, compared with just 58.3% of those without such a requirement.

Among healthcare personnel who worked at a facility that did not have mandatory vaccination but offered vaccine on site, factors associated with a greater likelihood of receiving flu vaccine were a personal reminder from the employer to get immunized (OR 1.6, 95% CI 1.1 to 2.3) and the availability of free vaccine for more than one day (OR 2.8, 95% CI 1.7 to 4.5).
The coverage rate for pregnant women also showed little change from 2009-2010 to the most recent season.

Historically, the vaccination rate has hovered around 15%, although that spiked to about 50% during the H1N1 pandemic.

Nearly half of respondents (49%) reported receiving flu vaccine during the peak of the 2010-2011 season, still well below the Healthy People 2020 goal of 80%.

The advice of a healthcare provider appeared to be influential in a pregnant woman's decision to get vaccinated, as the coverage rate was dramatically higher among women who were offered the vaccine by their doctor (71% versus 14%).

"The study underscores the fact that continuing efforts are needed to encourage providers to strongly recommend and to offer vaccination to their pregnant patients," Bridges said.
http://www.medpagetoday.com/InfectiousDisease/URItheFlu/28107

Trends in Infectious Diseases
In ambulatory care settings, 24.2 and 3.9 million visits to office-based physicians and hospital outpatient departments, respectively, were made in 2008 for the treatment of infectious and parasitic diseases, according to the CDC.....
Somnath Pal, BS , MBA, PhD Professor of Pharmacy Administration College of Pharmacy & Allied Health Professions St.

Marijuana

Cannabis Genetic Code Unlocked Paving Way To New Global Innovations
19 August 2011
Sequencing of the entire genomes of the cannabis species Cannabis sativa and Cannabis indica, equating to some 131 billion base pairs of genetic data have been published this week. This data will supposedly lead to innovations that will accelerate ongoing and new research into the therapeutic benefit of Cannabis, help identify nonpsychoactive therapeutic compounds made by the plant and elucidate biochemical and enzyme pathways that could make Cannabis derived compounds easier to produce. For starters, GW Pharm, one of the most well-recognized names in cannabinoid therapeutics research has produced an oromucosal cannabinoid spray the has been approved in countries including the U.K., Canada, New Zealand, and Spain as an add-on treatment for improving the symptoms of spasticity in multiple sclerosis patients who have not responded adequately to other antispasticity medications. Over the last few months the drug has also been approved and/or launched in the Czech Republic, Germany, and Denmark........

Medical marijuana probe flags 8 Arizona physicians
Updated 01:41 p.m., Saturday, August 20, 2011
PHOENIX (AP) — State health officials have filed complaints against eight physicians who have recommended nearly half of the 10,000 Arizonans certified to use medical marijuana.They say the physicians have failed to check patients' prescription-drug histories, as required.State rules regulating the voter-approved medical-marijuana law require people to obtain a written recommendation from a licensed physician.

The doctor must perform a physical exam, review a year's worth of medical records, discuss the risks and benefits of medical marijuana, and review a state database that tracks prescription-drug use.

The Arizona Republic (http://bit.ly/pM1Ln4 ) reports that physicians can face a variety of consequences, from a letter of reprimand to suspension of their license, if their regulatory boards find they falsified medical records or are otherwise guilty of unprofessional conduct.In one case, a naturopathic physician issued recommendations to about 1,000 people but checked the state Board of Pharmacy's controlled-substances database just 56 times, said Will Humble, director of the state Department of Health Services.

Because she indicated that she had checked the database on all the patients, Humble wonders what else she was lying about."It's obvious that these physicians are not acting on the up and up," Humble said. "To me, it's an indicator of, 'What else aren't you doing?' "
A review of the patient's drug-prescription history can help physicians determine whether medical marijuana is the best option or whether the patient is just looking to get high. The database tracks the log-in for every patient as well as searches for patients who aren't in the system.

In an effort to prevent doctors from encouraging recreational-marijuana use, Humble asked his staff to pull the names of doctors who had written more than 200 recommendations since the law took effect in mid-April. Ten came up.When patient records were compared with the state pharmacy database, it showed that eight of those 10 physicians — three allopathic doctors and five naturopaths — failed to review drug histories on many of their patients.
Three doctors had never logged on, although they had checked the box on hundreds of medical-marijuana applications saying they had reviewed the patient's drug history.The eight physicians account for nearly half of the 10,000 doctor recommendations in Arizona. The number recommended by each doctor ranged from slightly more than 200 to about 1,300.Humble has no authority over Arizona physicians, but he reported the doctors to their regulatory boards this week. State law prohibits him from releasing their names, but they will become public if the boards agree to investigate.

Lisa Wynn, executive director of the Arizona Board of Medical Examiners, said a record-keeping violation would be relatively simple to review. A clinical investigation involving patient care, however, would involve hiring an expert in medical-marijuana use to evaluate whether physicians were acting appropriately.
If the board decides to investigate, a review committee will determine what discipline, if any, to recommend. The board can take that recommendation or issue its own, including dismissal of the complaint.

Proposition 203, approved by voters in November, legalized medical-marijuana use for people with certain debilitating conditions and allowed them to designate someone as a "caregiver" to grow or otherwise obtain marijuana for them.About 80 percent of those issued state ID cards to use medical marijuana also are authorized to grow it.
The state was to begin licensing dispensaries in June, but a federal lawsuit filed by Gov. Jan Brewer put that process on hold, sparking a new round of legal action. Because there are not yet any licensed dispensaries, caregivers and patients are allowed to grow their own pot, up to 12 plants per person.___
Information from: The Arizona Republic, http://www.azcentral.com