Bristol Myers-Squibb recalls Viaspan over potential Bacillus contamination

The bacterium, Bacillus cereus as cultivated on sheep blood agar 

Credits: CDC/ Courtesy of Larry Stauffer, Oregon State Public Health Laboratory

March 30, 2012

Pharmaceutical giant, Bristol Myers-Squibb (BMS) announced Thursday a global recall of the sterile organ storage fluid, Viaspan after bacterial contamination was discovered on the production line at a manufacturing facility in Austria.

The bacterium, Bacillus cereus was found in fluid used to test the sterility of the Viaspan production line. Batches of Viaspan are now being tested for contamination.

Viaspan is a fluid used to preserve organs, primarily the liver, pancreas and bowel, after removal from the donor until transplant into the organ recipient.

The recall applies to 10 countries where there are alternative storage solutions: Australia, Italy, Estonia, Slovenia, Argentina, Chile, Germany, France, Ireland, and the United Kingdom.

BMS is also working with health officials in 11 other European countries and New Zealand that use Viaspan but do not have alternative solutions.

Viaspan is not sold in the United States or Asia.

The Belfast Telegraph reports that BMS is performing tests to determine where the leak in the production line is located. A faulty pressure gauge is thought to be the problem.

In the UK, where there are about 800 liver, 250 pancreas and 30 to 40 bowel transplants each year, they will continue to use Viaspan as there is currently no evidence of any problems in patients who have recently had transplants where Viaspan has been used according to Chief Medical Officer Professor Dame Sally Davies.

Patients that did present with an infection with Bacillus cereus could be treated with antibiotics.

Bacillus cereus is an aerobic, spore-forming bacterium found in the soil and the environment worldwide.

The organism is a well-recognized and common cause of food poisoning worldwide.

Bacillus cereus made the news last year when alcohol pads produced by the Triad Group were found to be contaminated with the spore-forming bacteria. The contaminated pads were implicated in the death of a 2-year-old boy.

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ICVH 2012: Boceprevir, Interferon Alfa-2a, Ribavirin Effective in HCV

From Medscape Medical News > Conference News

Neil Canavan

March 30, 2012 (New York, New York) — Peginterferon alfa-2a, in combination with the protease inhibitor boceprevir and ribavirin (R), was shown to have efficacy equivalent or superior to that seen with historical use of the same regimen with peginterferon alfa-2a — the standard of care — for treating hepatitis C virus (HVC) infection, according to data reported here at the International Conference on Viral Hepatitis (ICVH) 2012.

These results provide a definitive rationale for the inclusion of the alfa-2a interferon variant in the treatment regimen, allowing for greater ease of administration by the patient infected with HCV.

"This is the first trial in which peginterferon alfa-2a was used as a backbone instead of alfa-2b," said study investigator John Howe, PhD, senior principal scientist, Merck & Co., Inc, Whitehouse, New Jersey.

In a previous study of the combination with alfa-2b, the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) trial, patients who were previously nonresponders or had relapsed after treatment with ribavirin and interferon alfa-2b showed significant improvement in sustained viral response (SVR) with the addition of boceprevir (66% vs 21% for controls).

The current investigation was a double-blind, placebo-controlled study that randomly assigned 201 HCV genotype-1 relapsers and nonresponders in a 1:2 fashion to 1 of 2 treatment groups. Treatment group 1 received 4 weeks of peginterferon alfa-2a and ribavirin followed by 44 weeks of placebo plus ribavirin plus peginterferon alfa-2a (standard of care). Treatment group 2 received 4 weeks of ribavirin plus peginterferon alfa-2a followed by boceprevir plus ribavirin plus peginterferon alfa-2a for 44 weeks.

Therapy was discontinued in both treatment groups if HCV RNA was undetectable at week 12 (defined as HCV RNA level of 9.3 IU/mL).

Results showed a superior efficacy for the boceprevir combination; 64% of patients achieved an SVR as compared with 21% in the control group (P < .0001).

The rate of relapse with the protease inhibitor combination, 12%, was lower than that with the standard of care, 33% (P value not reported).

"These results are consistent with RESPOND-2," said Dr. Howe.

Reasons for a non-SRV outcome in the boceprevir/peginterferon alfa-2a/ribavirin treatment group for a total of 44 patients were as follows: viral breakthrough on treatment after initially being undetectable for 1 patient; incomplete virologic response for 4 patients; relapse after treatment for 11 patients; and nonresponse for the remaining 28 non-SVR patients (this figure includes patients who discontinued treatment for any reason).

Samples from 33 of 44 patients who received boceprevir/peginterferon alfa-2a/ribavirin who did not achieve SVR were subjected to sequence analysis of postbaseline resistance-associated variants (RAVs). This analysis revealed that 8 of the 33 patients had RAVs; the total included 1 patient with viral breakthrough, 3 patients who had incomplete responses, 2 patients who relapsed, and 2 nonresponders.

By resistance locus, overall RAV profiles were similar to those in all other studies in which peginterferon alfa-2b was used as part of an HCV treatment combination. "The resistance data collected in this trial are consistent with results reported in SPRINT-2 and RESPOND-2," said Dr. Howe.

Treatment Choices With HCV

"I believe that these two interferons [alfa-2a, alfa-2b] are similar," commented Ayse Aytaman, MD, chief of gastroenterology and hepatology, Veterans Affairs New York Harbor Health Care System, Brooklyn, New York. "But we use the alfa-2a more commonly because it's easier for the patient. It is a prepared syringe, you don't have to give weight-based dosing, and it comes in different dosages. It is much simpler. It's particularly good for patients who have trouble understanding instructions."

As for choosing between the 2 new protease inhibitors now at her disposal (boceprevir and telaprevir), "We are trying to learn how to deal with them," she said. "Yes, they are very potent, but they have a lot of side effects."

Before adding interferon on top of a protease inhibitor, Dr. Aytaman cautioned that there are some patients for whom the physician may want to wait for better pharmacologic options before treating.

"When I look at a patient who is 60 years old, I have to consider that I'm going to take a year out of this person's life with them coming to me weekly, or biweekly, injecting himself, being miserable with flu-like symptoms… Why?" Even if the patient has early-stage cirrhotic disease, Dr. Aytaman is willing to wait for an all-oral HCV treatment combination with fewer side effects.

If she has to choose between the protease inhibitors available now, side effect profile is one consideration; cost is another.

"There is a huge cost difference. Telaprevir, even though it's only [given] for 3 months, is much more expensive than boceprevir. If it wasn't for that, every hepatologist I know would go for telaprevir because it's so much simpler, with a much shorter duration of treatment."

"The reality is, I'm given a budget to treat patients. If I can treat more patients for fewer dollars, I will," said Dr. Aytaman, "That said, I do use both. Most of my patients get boceprevir, but for previous null responders, or if I'm anticipating significant anemia or cytopenia, I go for telaprevir."

Dr. Howe is an employee of Merck & Co. Dr. Aytaman has disclosed no relevant financial relationships, and her opinions are expressed as a physician, not as an employee of the US government.

International Conference on Viral Hepatitis (ICVH) 2012. Abstract # 79317. Presented March 26, 2012.

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Increasing Routine Viral Hepatitis Testing

March 30, 2012

By Ronald Valdiserri, M.D., M.P.H., Deputy Assistant Secretary for Health, Infectious Diseases, and Director, Office of HIV/AIDS and Infectious Disease Policy, U.S. Department of Health and Human Services

Dr. Ronald Valdiserri

The Viral Hepatitis Action Plan spells out the importance of identifying persons infected with viral hepatitis early in the course of their disease as an important component of national efforts to improve diagnosis, care and treatment to prevent liver disease and liver cancer. As awareness of viral hepatitis increases and treatment options become more effective and better tolerated, it is vital that we implement best practices to improve the frequency, availability, and acceptability of viral hepatitis testing.

To inform and advance these efforts, my office hosted a day-long consultation last month. Sharing their perspectives with us were representatives from state and local health departments, community health centers, drug treatment and correctional health programs, local and national advocacy organizations, the American Association for the Study of Liver Disease, the National Medical Association and other partners. Also participating in the discussion were experts from various federal agencies including the Centers for Disease Control, Agency for Healthcare Research and Quality, Centers for Medicaid and Medicare Services, HRSA’s Bureau of Primary Health Care and HIV/AIDS Bureau, Indian Health Service, National Institutes of Health, Office of Minority Health, and Substance Abuse and Mental Health Services Administration, as well as Federal Bureau of Prisons and the Department of Veterans Affairs.

Among the many examples of promising practices shared from diverse settings were:

• Targeting patient education and outreach – Tamara Brickham, M.P.H., Houston Department of Health and Human Services, shared details of a successful community partnership model the agency used to increase hepatitis B awareness, screening, testing and vaccination among Asian Americans. To more effectively reach the communities with a higher prevalence of HBV infection, the health department partnered with numerous community-based organizations already working with the Vietnamese, Chinese, Korean, and Asian Indian communities. Ms. Brickham noted that this enabled the health department to take the education, screening, vaccination and testing activities directly to higher risk adults in community settings rather than waiting for them to come to the health department or a healthcare provider. As a result of the first year of this population-specific outreach, more than 1,000 people were screened. Three percent were identified as having chronic HBV infection and were referred for care. One-third of those screened were vaccinated.

• Using rapid testing – Several participants highlighted the challenge of getting those who do ultimately get tested to return for their results. Colleen Flanigan, R.N., M.S., Director of the Viral Hepatitis Section at the New York State Department of Health, discussed how a 12-site state-supported demonstration project will use rapid HCV testing to overcome this hurdle. The demonstration project will target higher risk populations and use rapid HCV tests to eliminate the need for clients to return for a second visit for test results. Clients with a reactive test result will receive a written referral to a provider that can perform a confirmatory PCR test. Through the demonstration project, they will study how this approach improves diagnosis and linkage to care for chronic HCV.

• Adapting systems to support viral hepatitis testing – A number of participants noted that inadequate fiscal resources are an impediment in many settings but that even when resources are available, improving viral hepatitis screening and testing requires the development of processes and systems that make it easier for providers to implement the recommended protocols. Kenneth Tai, M.D., discussed the efforts he led at North East Medical Services (NEMS) in San Francisco to address high rates of HBV among its patient population who are primarily people of Asian heritage. NEMS started by setting a goal to increase HBV testing and vaccination among patients from 60% to 70% in one year. In addition to enhancing patient education, the community health center undertook critical systems changes including: adding an HBV module to the electronic health record (EHR) used at the clinic, improving the workflow in the clinic to make testing and vaccination more efficient, and mining EHR data to generate a list of patients being seen each day who need an HBV test. Finally, the health center also added HBV testing as a measure to its physician report card. Janet Durfee, R.N., M.S.N, A.P.R.N., Deputy Chief Consultant, Clinical Public Health at the Department of Veterans Affairs (VA) noted that systems changes have also helped the VA health system to improve and enhance their HCV screening efforts. Among the changes implemented in recent years has been adding a clinical reminder to the electronic health record prompting healthcare providers to screen and test if indicated. VA has distributed responsibility for screening among nurses and other personnel, so this does not fall to physicians alone. To address both provider and patient discomfort with discussing risks, VA revised its approach so that providers ask the patient whether he/she has any of a list of risks, thereby avoiding the need to admit to any particular stigmatizing risk factor and increasing the likelihood of candid responses.

“The promising practices shared by consultation participants and the lively discussion that followed underscored that it is possible to improve the frequency, availability, and acceptability of viral hepatitis testing in a variety settings, in some cases by only making minor changes to processes, in others through partnerships and coordination of services,” observed my colleague Corinna Dan, R.N., M.P.H., Viral Hepatitis Policy Advisor, Office of HIV/AIDS and Infectious Disease Policy, who organized the consultation.

As Corinna notes, the consultation clearly illustrated that numerous successful approaches to improving viral hepatitis testing exist in very diverse settings. A key to our success in scaling up these efforts will be better documenting, disseminating and encouraging the adoption of these model programs.

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Treatment of Hepatitis C Virus in Liver Transplant Recipients

Hepatology - Hepatitis C Management in Special Populations

Authors: Mark S. Sulkowski, MD (More Info)

Last Reviewed: 3/1/12

The decision to initiate hepatitis C virus (HCV) therapy must weigh the benefits of achieving a sustained virologic response (SVR) vs the risks of triggering graft rejection and the side effects associated with immunosuppressive therapy. Although a preemptive antiviral approach intuitively seems to offer the best chance for liver transplant recipients, several reasons prevent the American Association for the Study of Liver Diseases (Management Guidelines)^{[Ghany 2009]} and the European Association for the Study of the Liver (Management Guidelines) from recommending this approach:^{[EASL 2011]}

• Postoperative increases in human leukocyte antigen and major histocompatibility complex elevate the risk of acute rejection in the presence of immunomodulators such as interferon-based therapy
• Patients have a reduced clinical status while recovering from surgery
• Between 30% and 50% of patients will not develop chronic liver disease
• 40% to 60% of patients are not candidates for this therapy because of cytopenias, renal disease, or other underlying conditions
• Early therapy has been associated with high rates of adverse effects, an increased risk of graft rejection, and higher proportions of patients requiring dose reductions

Thus, the recommended standard of care is the treatment of histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out.^{[Ghany 2009; Ponziani 2011]}

Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.^{[EASL 2011; Ghany 2009]} However, severe adverse effects, including anemia, thrombocytopenia, and leukopenia, contribute to the low adherence to the recommended dose of ribavirin, which may lead to the low response rates of transplant recipients (Figure), even when hematopoietic growth factors are administered.^{[Ponziani 2011]}

Figure. Response rates with peginterferon plus ribavirin for the treatment of recurrent HCV postliver transplantation.

The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in patients with liver transplants. However, a study of telaprevir plus peginterferon alfa-2a and ribavirin is planned for stable liver transplant patients (Clinical Trial: NCT01467505). Because this and other studies are completed with HCV protease inhibitors in the transplantation setting, drug-drug interactions will become an important consideration. Indeed, since both boceprevir and telaprevir inhibit CYP3A4, coadministration with any medication that is known to be metabolized by CYP3A4 should be done under close clinical supervision and monitoring.^{[Ghany 2011]} Unfortunately, 2 drugs commonly used to prevent allograft rejection, cyclosporine and tacrolimus, are metabolized via the CYP3A4 pathway. In a phase I, nonrandomized pharmacokinetic study involving 10 healthy volunteers, coadministration of cyclosporine and telaprevir increased the elimination half-life of cyclosporine from 12 ± 1.67 hours to 42.1 ± 11.3 hours; tacrolimus and telaprevir coadministration increased the half-life of tacrolimus from 40.7 ± 5.85 hours to 196 ± 159 hours.^{[Garg 2011]} A comparable study of the impact of boceprevir on the pharmacokinetics of cyclosporine and tacrolimus was also conducted.^{[Hulskotte 2011]} In contrast to telaprevir, boceprevir is primarily metabolized by aldo-keto reductase with a lesser contribution from CYP3A4. In a study of 10 healthy volunteers, coadministration of boceprevir with cyclosporine induced a 2.01-fold increase in C_max and a 2.70-fold increase in the area under the concentration time curve (AUC) from time 0 to infinity after single dosing (AUC_inf) of cyclosporine. By contrast, coadministration of boceprevir and tacrolimus caused a 9.9-fold increase in C_max and a 17.1-fold increase in AUC_inf of tacrolimus. These data indicate that coadministration of boceprevir with either cyclosporine or tacrolimus would require significant dose adjustments of the calcineurin inhibitors and attentive monitoring of their trough concentrations, of renal function, and of potential adverse effects; in particular, coadministration with tacrolimus would likely require significant dose reduction and/or prolonged dosing. When considering the results of these studies, it is important to emphasize that the populations assessed involved healthy participants. In the context of liver transplant recipients with HCV recurrence, the pharmacokinetic effects of boceprevir or telaprevir on elimination of these immunosuppressive agents may be greater.^{[Charlton 2011]} Thus, these protease inhibitors should not be used in combination with the calcineurin inhibitors cyclosporine and tacrolimus until the appropriate dose reductions are understood.^{[Garg 2011]} Finally, many other agents that require cytochrome P450 enzymes for their metabolism are often administered in the transplantation setting, including mycophenolate mofetil, macrolides, calcium channel blockers, and others.^{[Charlton 2011]} As a result, pharmacokinetic interactions with cyclosporine or tacrolimus provide only a partial view of potential protease inhibitor effects that may be relevant to liver transplant recipients.

A summary of recommendations for the management of recurrent HCV in liver transplant recipients is shown in Table 10.

Table 10. Summary of Recommendations for the Management of Recurrent HCV in Liver Transplant Recipients

• Prophylactic HCV therapy in liver graft recipients is not recommended.
• Histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out, should be treated.
• Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.
• The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in liver transplant patients.

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Also See: An Open Label Study of the Effect of Telaprevir in Combination With Ribavirin and Peginterferon on HCV Infection in Stable Liver Transplant Patients

An Open Label Study of the Effect of Telaprevir in Combination With Ribavirin and Peginterferon on HCV Infection in Stable Liver Transplant Patients

Conditions: Hepatitis C

Interventions: Drug: Telaprevir
1125 mg bid for 12 weeks
Drug: ribavirin
Initial dose of 600 mg total daily dose with goal of up to 1000mg-1200mg total daily dose based on body weight for 48 weeks
Drug: peginterferon alfa-2a
180 mcg/week for 48 weeks

Study Phase: Phase 2

Status: Recruiting

Study IDs: VX11-950-117 NCT01467505

To assess efficacy of telaprevir, peginterferon alfa-2a (Peg-IFN), and ribavirin (RBV) for HCV in a 48-week total treatment duration regimen following liver transplantation.

Study Description | Recruitment Information | Tracking Information | Administrative Information

ClinicalTrials.gov processed this record on 3/30/2012

Source: U.S. National Library of Medicine (NLM) and ClinicalTrials.gov.