Hepatitis C infection identified as leading risk factor for HCC

Posted on HemOncToday.com January 19, 2012

Yang JD. Mayo Clin Proc. 2012;87:9-16.

Liver-scarring diseases such as cirrhosis from alcohol consumption continue to present a high risk for the development hepatocellular carcinoma, but hepatitis C infection has been identified as the leading risk factor, according study results published in Mayo Clinic Proceedings.

Researchers analyzed trends in incidence, etiology and treatment of liver cancer among residents in Olmsted County, Minn. Using medical records from a community-wide medical record linkage system, they identified 104 residents aged older than 20 years diagnosed with hepatocellular carcinoma (HCC) from 1976 to 2008.

Divided into three eras based on time of diagnosis, the analysis demonstrated that the age- and sex-adjusted incidence rate for HCC in Olmsted County was 3.5/100,000 person-years for the first era (1976-1990), 3.8/100,000 for the second era (1991-2000) and 6.9/100,000 for the third era (2001-2008).

In the first era, alcohol use was identified as the most common cause of HCC, with no diagnoses of hepatitis C virus (HCV). In the second era, however, the percentage of HCCs attributable to HCV had risen to 25%, including 7.1% who were observed to have joint HCV and alcohol use as causes of HCC. In the third era, 21 of 47 patients diagnosed with HCC had evidence of chronic HCV infection.

The increase in the proportion of HCV most significantly affected patients aged 50 to 59 years — seven of eight exhibited HCV in the most recent era. Additionally, coexisting alcoholic liver disease was common in HCV patients who developed HCC at an age younger than 60 years: Six of eight HCV patients aged younger than 60 years had coexisting alcoholic liver disease, whereas only one (6.3%) of 16 patients aged 60 years or older had this coexisting disease (P,.01).

“The liver scarring from hepatitis C can take 20 to 30 years to develop into cancer,” W. Ray Kim, MD, principal investigator in the study, said in a press release. “We’re now seeing cancer patients in their 50s and 60s who contracted hepatitis C 30 years ago and didn’t even know they were infected.”

Disclosure: Study researcher Lewis R. Roberts, MBChB, PhD, reports receiving research grants from Bristol-Myers Squibb and MDS Nordion.

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American Red Cross Fined Millions for “Shoddy” Blood Collection—Again

January 20, 2012
Ruth McCambridge

January 19, 2012; Source: Care2 | The American Red Cross has been fined $9.6 million after the U.S. Food and Drug Administration (FDA) found hundreds of violations in its blood collection procedures. The fines have been levied against half of the blood collection centers nationwide. The violations—which include having donated blood infected with HIV, Hepatitis C and the West Nile Virus—were detailed in a 32-page Adverse Determination Letter (ADL) written by Evelyn Bonnin, the FDA Director of the Baltimore District and issued by the FDA. The letter details problems including poorly trained staff and inadequate record keeping where donated blood was mishandled or misplaced. In some cases, potentially infected blood was transfused into patients.

The Red Cross has responded that they are disappointed in the FDA for relying on the results of an inspection carried out 15 months ago. They say that they have cleaned up their procedures in the meantime and that their blood supply is “safer than ever.” But this argument may be difficult to sell since this is not the first time the Red Cross has been fined for such infractions. In fact, they have apparently been fined $47 million for similar violations since 2003. The FDA letter states, “many of the violations recounted in this letter are virtually identical to violations charged in previous ADLs. [The Red Cross] has known of these continuing problems and has failed to take adequate steps to correct them.” –Ruth McCambridge

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Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

From Clinical Gastroenterology and Hepatology

Ju Dong Yang; W. Ray Kim

Posted: 01/19/2012; Clin Gastroenterol Hepatol. 2012;10:16-21. © 2012 AGA Institute

Clinical Scenario

A59-year-old man was referred to liver transplantation clinic for the evaluation of enlarging abdominal girth and swelling of feet during the preceding 2 months. The patient was a Cambodian native who immigrated to the United States 5 years ago. The patient was first diagnosed with chronic hepatitis B virus (HBV) infection shortly after his entry into the United States. However, he was not further evaluated, treated, or followed. He had no personal or family history of liver disease or liver cancer. Physical examination of the abdomen showed mild hepatosplenomegaly with positive shifting dullness from a moderate amount of ascites. There was no abdominal tenderness. Laboratory results included platelet count, 95,000/μL; aspartate aminotransferase, 100 U/L; alanine aminotransferase, 45 U/L; and Model for End-Stage Liver Disease score, 13. Viral serology showed hepatitis B surface antigen–positive and eantigen– positive and HBV DNA of 5 million IU/mL. Serum alpha-fetoprotein (AFP) was normal at 4 ng/mL. An abdominal ultrasound (US) showed cirrhotic liver contour and evidence of portal hypertension. An esophagogastroduodenoscopy showed large esophageal varices. The patient was started on the following medications: spironolactone and furosemide for the ascites, propranolol for the varices, and entecavir for HBV. Patient was further assessed and then listed for liver transplantation.

During the ensuing 12 months, the patient had substantial clinical improvement including resolution of ascites as well as hepatitis B e seroconversion. He also underwent abdominal US and serum AFP measurement on a 6-month interval. An abdominal US performed 18 months after his presentation showed a new 2.1-cm hyperechoic nodule in the right lobe of the liver along with mild elevation of serum AFP at 22 ng/mL. A subsequent triphasic abdominal computed tomography (CT) scan showed a 2.2-cm well-circumscribed vascular mass that had arterial enhancement and venous washout, thus meeting the radiographic diagnosis criteria for hepatocellular carcinoma (HCC) of the American Association for the Study of Liver Disease (AASLD). The patient underwent transarterial chemoembolization and subsequently received a liver transplant. Four years later, the patient is doing well with satisfactory liver function with no evidence of recurrent HBV or HCC.

The Problem

Our patient represents a case in which implementation of HCC surveillance likely improved his ultimate outcome. HCC is a major global health problem because it is the third leading cause of cancer-related death in the world. GloboCan reported that the incidence and mortality of HCC continued to increase as of 2008. In general, HCCs tend to be asymptomatic until the tumor is in an advanced stage. Although there has been substantial progress in the treatment of HCC, long-term survival is only achievable in a small proportion of patients— those presenting in an early stage where potentially curative modalities such as liver transplantation and surgical resection are feasible. Therefore, it is widely held and recommended that early detection of HCC is imperative in improving the prognosis.

Screening is defined as application of diagnostic tests in patients at risk for a condition (eg, HCC) without a high index of suspicion that the condition is already present. Surveillance is conducted by repeated application of screening tests. In the case of HCC, the stated goal of surveillance is to decrease HCC mortality or at least to increase the meaningful duration of life through the early detection of HCC in asymptomatic patients. Existing evidence indicates that HCCs detected by surveillance are more likely to be amenable to curative treatment. Because long-term survival can be achieved in a majority of patients eligible for liver transplantation or resection, surveillance might decrease HCC mortality. This is a main rationale for which HCC surveillance is recommended in high-risk individuals.

There have been 2 randomized controlled trials that investigated the efficacy of surveillance. Both studies were conducted in China in patients with HBV infection. The first study, involving 19,000 patients, showed that surveillance is efficacious in reducing HCC mortality. Patients assigned to semiannual surveillance with serum AFP and abdominal US had a 37% decrease in HCC mortality compared with patients not under surveillance. Although the study was limited by a high dropout rate of study participants and suboptimal randomization and concealment schemes, it provides the best evidence to date that has shown the benefit of surveillance on "hard end points" in HCC. The other study was performed with 5581 HBV patients. In contrast to the first study, it used serum AFP as the primary tool for surveillance. This study showed that surveillance increased the detection of early-stage tumors but did not affect overall survival and liver cancer mortality. Besides these trials, a number of observational studies have suggested that surveillance improves survival in HCC patients (Table 1).

Although HCC surveillance is generally accepted, its implementation is suboptimal in real-life practices. In the United States, a study that used the Surveillance Epidemiology and End Results-Medicare database showed that only 17% of cirrhotic patients were under regular surveillance 3 years before the diagnosis of HCC. In a more recent study involving 13,000 cirrhotic hepatitis C virus patients at Veterans Administration health care facilities throughout the United States, only 12% received routine HCC surveillance.

Management Strategies and Supporting Evidence

Who Are the Candidates for Hepatocellular Carcinoma Surveillance?

Hepatocellular carcinoma surveillance should be performed in a group of patients whose risk for HCC development is sufficiently high to make it cost-effective (Table 2). Surveillance is considered effective if it increases life expectancy by more than 3 months and considered cost-effective if less than $50,000 is needed to increase 1 quality-adjusted life-year. Under this concept, the incidence of HCC is the primary determinant of the cost-effectiveness of surveillance.

The first category of candidates for surveillance is patients with cirrhosis. Cirrhosis is the single most important risk factor for HCC, and most patients with HCC have underlying liver cirrhosis. According to a guideline from AASLD, surveillance is recommended when the HCC incidence is higher than 1.5% in a patient with cirrhosis. This category of patients includes those with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis, and thus these patients should be under a surveillance program. In addition, experts recommend patients with other types of cirrhosis to receive surveillance, although firm data about the incidence of HCC in this group of patients are lacking.

In implementing surveillance, one of the common challenges is to identify patients with cirrhosis. Because viral hepatitis is easily recognizable, patients at risk for chronic viral hepatitis infection need to be screened for HBV and/or hepatitis C virus according to the established guidelines. It is also important to have a high index of suspicion of chronic liver disease in patients with abnormal liver function test, significant alcohol history, or metabolic syndrome.

The diagnosis of cirrhosis is straightforward in patients with hepatic decompensation, on the basis of the characteristic symptoms of portal hypertension and liver failure. Hepatocellular carcinoma surveillance in this group of patients would be most meaningful if liver transplantation is available. Under the current allocation system, an early-stage HCC within the socalled Milan criteria increases the priority of receiving a liver transplant from a deceased donor. In contrast, if liver transplantation is not available, surveillance in patients with hepatic decompensation severe enough to disallow meaningful therapy is unlikely to be beneficial.

Diagnosing patients with compensated liver cirrhosis might present a challenge because patients are usually asymptomatic without an overt sign of portal hypertension. Although histology is considered the gold standard for the diagnosis of cirrhosis, a liver biopsy is invasive and subject to sampling variability. Various laboratory data and mathematical models have been proposed to noninvasively identify patients with cirrhosis. Transient elastographic techniques with magnetic resonance imaging (MRI) or US measure the stiffness of the liver, which correlates with hepatic fibrosis. As data accumulate in support of accuracy of these techniques in identifying asymptomatic cirrhotic patients, they are gaining wider acceptance in clinical practice.

The other category of candidates for surveillance is HBV carriers who might develop HCC without cirrhosis. In those subjects, surveillance is warranted when the HCC incidence is higher than 0.2%/year. These high-risk hepatitis B carriers include Asian men older than 40 years and Asian women older than 50 years. Although the annual incidence of HCC in individuals of African race or those with family history of HCC cannot be firmly established, they are also recommended to undergo surveillance starting at an earlier age (Table 2).

What Modality is to be Used for Surveillance?

Most guidelines advocate abdominal US as the standard surveillance test for HCC. It has sensitivity greater than 60% and specificity greater than 90% as a screening test for HCC. It is widely available and less expensive than CT or MRI. It does not expose patients with repeated radiation. However, there are several weaknesses of US as a surveillance test for HCC. Abdominal US is highly dependent on the operator. Because small HCC often presents with a nonspecific appearance, detecting an early HCC nodule can be challenging, particularly in a patient with a nodular cirrhotic liver. Sensitivity of US is further decreased in obese subjects. Because of the high prevalence of obesity in the United States, the utility of US as an HCC surveillance test in those patients has been questioned.

These limitations of US have prompted some clinicians to use abdominal CT or MRI in select patient groups, eg, those waiting for liver transplantation. However, the risk of repeated radiation and contrast exposure and high cost are obvious limitations that prevent its routine use in the broader population at risk. Finally, serum AFP is commonly used as an adjunct to abdominal US, although its use as a surveillance test for HCC remains controversial.

What is the Next Step if a Suspicious Lesion is Found by a Surveillance Test? (Recall Policy)

Once a suspicious lesion is found on US, a systematic algorithm, also known as the recall policy, can be followed to appropriately and expeditiously diagnose an HCC (Figure 1). If the nodule is smaller than 1 cm, a close follow-up with a repeat US at 3 months is recommended. If the lesion is found to enlarge to a size larger than 1 cm, a dynamic imaging study (CT or MRI) should be performed. If the size of the lesion remains the same for more than 2 years, the original 6-month follow-up might be resumed.

Figure 1. Lesions on surveillance US: recall policy.

For lesions that appear larger than 1 cm on US, a contrastenhanced dynamic CT or MRI must be performed. If characteristic vascular features (arterial enhancement and venous washout) are seen, a diagnosis of HCC is established. If the imaging characteristics are not typical, a second dynamic scan should be performed (if the first modality was CT, then MRI, and vice versa). If it shows the characteristic vascular features, a diagnosis of HCC might be made. If not, a percutaneous biopsy of the lesion should be considered, although the biopsy might not always be diagnostic. Finally, if there is considerable increase in serum AFP in the absence of a demonstrable lesion on US, a contrast-enhanced dynamic CT or MRI should be performed.

Areas of Uncertainty

Is Serum Alpha-Fetoprotein Beneficial?

There is broad agreement that serum AFP alone is inadequate as an independent tool for HCC surveillance and must not be used. For example, investigators of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial serially measured the serum AFP every 3 months before the diagnosis of HCC and reported that serum AFP has inadequate efficacy as a surveillance test. Many other studies investigating the performance of AFP were in the setting of diagnosis rather than surveillance, where pretest probabilities are higher and the performance of the test is overestimated. The biggest limitation of serum AFP, when used alone, is its low sensitivity. Whereas the test might be made sufficiently specific if a high cutoff value is used, modest elevations might be seen in patients with viral hepatitis especially hepatitis C, pregnant women, and in those with tumors other than HCC, most notably gonadal tumors. Thus, depending on the cutoff value, serum AFP has suboptimal sensitivity and/or specificity. More recent serum markers such as des-carboxy prothrombin and the ratio of lecithinbound AFP to total AFP are even less sensitive than AFP for the detection of early-stage HCCs and have not been shown to be useful for surveillance.

Compared with US alone, the combination of US and serum AFP might slightly enhance the sensitivity to detect an HCC lesion. A study from China showed that the combination of US and serum AFP increases the liver cancer detection rate by 9%. However, the combination was associated with a 2.4-fold increase in false positivity and a 2.2-fold decrease in the positive predictive value. A cost-effectiveness analysis performed in the United States showed abdominal US is most cost-effective, and addition of AFP to US in HCC surveillance provides a small gain at a significant increase in cost. This increase in cost stems not only from adding the cost of AFP testing but also from the expenses needed to investigate false-positive results. For this reason, the AASLD guideline recommends the use of US alone for the surveillance of HCC.

Despite these limitations of serum AFP, a recent study that used the Surveillance Epidemiology and End Results-Medicare database reported that the combination of serum AFP and US, followed by serum AFP alone, is most commonly used for HCC surveillance in the United States. The reality in practice is that AFP is widely available and inexpensive. Proponents point out that given the poor adherence to US-based surveillance, even a suboptimal test might still be better than complete lack of any surveillance. This might be more relevant in settings with limited health care access and resources, such as in Alaskan natives with chronic HBV infection in whom serum AFP was found to be beneficial.

How Often Should Tests be Repeated?

Most guidelines recommend surveillance to be conducted every 6 months. The principle for determining the interval for surveillance is that it should not be based on the anticipated incidence of HCC, but on the rate of tumor growth. Even if the incidence is high, if all of the tumors grow slowly, infrequent surveillance would be sufficient. On the other hand, if many tumors grow fast, frequent surveillance is needed for any hope of early diagnosis to exist. Thus, the absolute risk (incidence) of HCC determines whether surveillance should be performed, whereas the rate of tumor growth dictates the interval for surveillance.

It is currently uncertain whether surveillance every 6 months is superior to every 12 months in decreasing HCC mortality and improving patient survival (Table 3). Several retrospective studies showed that there is no difference in survival between 6-month and 12-month surveillance intervals. However, the most recent study showed that surveillance every 6 months improved patient survival compared with that every 12 months. In short, to date, there is no robust evidence from a randomized controlled trial to determine the optimal surveillance interval. Most hepatologists tend to err on being more conservative with frequent (ie, semiannual) surveillance.

Published Guidelines and Summary

Most practice guidelines suggest that patients at risk of HCC undergo surveillance. Published guidelines for HCC surveillance are summarized in Table 4. Although not ideal, US is the preferred modality for surveillance. The AASLD guideline recommends patients with cirrhosis from any cause to undergo HCC surveillance by using abdominal US at 6-month intervals. AFP is inadequate as a surveillance test. The European Association for the Study of the Liver recommends that the ideal target population is Child–Pugh class A cirrhotic patients without severe comorbid conditions. Patients not suitable for curative therapy might be excluded from surveillance. The Asian Pacific Association for the Study of the Liver specifies cirrhotic patients with HBV and HCV as candidates for surveillance in whom the combination of US and AFP is to be used every 6 months. In contrast to these liver societies, the National Cancer Institute calls for additional data before HCC surveillance is routinely recommended, even in high-risk patients. They note that data to date suffer from several methodological flaws and limited generalizability and thus have not proved that surveillance decreases HCC mortality.

Against the backdrop of these recommendations, in the particular case of our patient, we have little doubt that he benefited from the surveillance because it led to detection of an early HCC lesion, followed by successful liver transplantation. He was "fortunate" to have experienced hepatic decompensation that drew close medical attention to his liver disease, which resulted in institution of surveillance for HCC. Because he had not been followed for his HBV, he could very well have presented with advanced HCC, if his liver disease had remained compensated. Although our patient would have been a candidate for surveillance according to most guidelines, he belonged in the majority of patients in whom surveillance is not practiced as a result of patient preference, lack of socioeconomic or health insurance support, or poor awareness of or adherence to guideline recommendations by the physician.

Among human malignancies, HCC is unique in that cirrhosis or advanced fibrosis is essentially a prerequisite condition, which makes it relatively straightforward to identify subjects who should be subjected to surveillance. However, it is obvious that not all patients with cirrhosis develop HCC, and the best informed surveillance strategy should include accurate risk stratification. As of today, we lack detailed knowledge for individualized risk stratification, which prevents formulation of an optimal surveillance program. Clearly, more high-quality data are needed to improve the outcome of patients with HCC, whose incidence is rising in the United States and globally. In the meantime, the clinician is encouraged by cases like ours that careful adherence to surveillance in at-risk individuals provides opportunities to make a meaningful difference in the patient's outcome.

References

1. Bruix J, Aasld SM. AASLD practice guideline, management of hepatocellular carcinoma: an update. Available at: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf. Accessed August 02, 2010.
2. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
3. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL Conference—European Association for the Study of the Liver. J Hepatol 2001;35:421–430.
4. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
5. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010;52:132–141.
6. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110–118.
7. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010;138:493–502.
8. Santi V, Trevisani F, Gramenzi A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291–297.
9. Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 2003;10:204–209.
10. Davila JA, Henderson L, Kramer JR, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med 2011;154:85–93.

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GAO asked to review VA quality-of-care policies

By Patricia Kime - Staff writer
Posted : Thursday Jan 19, 2012 17:57:33 EST

The top Democrats on the House and Senate Veterans’ Affairs committees are seeking an investigation of the Veterans Affairs Department’s handling of several incidents involving improper sterilization of reusable medical equipment.

The lawmakers say those problems could be an indication that VA leaders are not following their own guidelines for investigating such incidents or disciplining those responsible.

In a Jan. 19 letter to Government Accountability Office Comptroller Gene Dodaro, Sen. Patty Murray, D-Wash., and Rep. Bob Filner, D-Calif., asked for a GAO review of VA’s procedures and policies.

“We continue to hear about the same types of quality-of-care incidents at VA medical facilities and we are concerned this is an indication that VA is not effectively learning from these incidents and subsequently translating these lessons into system-wide improvements,” Murray and Filner wrote.

In the past seven years, more than 13,000 veterans treated at VA health facilities have been placed at risk for exposure to infectious disease such as hepatitis and HIV after undergoing procedures with improperly sterilized equipment.

From 2004 to 2009, 11,000 veterans at the Murfreesboro, Tenn., Augusta, Ga., and Miami VA medical centers were notified of their risk after they underwent colonoscopies with improperly prepared endoscopes.

At least 25 veterans contracted Hepatitis C, eight developed Hepatitis B and five tested positive for HIV.

In January 2011, surgeries at the St. Louis VA Medical Center were halted after VA found 1,812 vets were placed at risk from improperly sterilized surgical equipment.

And in Dayton, Ohio, VA offered to test 500 veterans for possible exposure after leaders determined a dentist didn’t change his latex gloves between patients.

“On numerous occasions, VA has reported to Congress about the various investigations it has conducted and the problems these investigations have identified, which they claim to have led to the development of new processes and procedures to reduce risk,” the lawmakers wrote.

In October, members of the House Veterans’ Affairs Committee were surprised to learn that Miami VA Medical Center Chief Mary Berrocal still had her job.

Berrocal received a letter of admonition in 2009 after the colonoscopy scandal surfaced but remained as chief until November, roughly a month after she testified that conditions at the facility were improving.

Her testimony came a week after a Miami VA employee was arrested for selling the names and personal information of 18 patients and compromising the personal data of 3,000 veterans, and three months after a veteran was allowed to leave the medical center when she should have been placed on suicide watch.

Veteran Catawba Howard was shot by police just hours after she left the medical center.

“This raises concerns as to whether VA’s leadership is taking appropriate actions, including appropriate disciplinary actions, to effectively address the problems across the system,” the lawmakers wrote.

VA spokesman Josh Taylor said Thursday that the department is committed to providing safe, high-quality care.

He said VA agrees with Murray and Filner that “every health care provider must ensure they follow good infection-control practices and that they send equipment for proper reprocessing. Failure to do so is unacceptable.”

Taylor added that VA has been recognized by the New England Journal of Medicine for its patient disclosure policy, what he called a “reflection of VA’s commitment to transparency.”

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Mobile Outreach Strategies for Screening Hepatitis and HIV in High-Risk Populations

Public Health Nurs. 2012 Jan;29(1):27-35. doi: 10.1111/j.1525-1446.2011.00970.x. Epub 2011 Oct 3.

Zucker DM, Choi J, Gallagher ER.

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School of Nursing, University of Massachusetts Amherst, Amherst, MassachusettsMassachusetts General Hospital, Boston, Massachusetts.

Abstract

ABSTRACT Objectives: To screen, counsel and offer hepatitis A and B vaccination for subjects at high risk for hepatitis C virus (HCV) and HIV, and determine any relationship between risk factors and HCV positivity. Design and Sample: A descriptive correlational design. We correlated risk factors and HCV positivity and measured vaccination completion rates. Two hundred and two unduplicated subjects in 4 locations in Western Massachusetts: a walk in substance abuse clinic, a homeless shelter, a county jail, and a community corrections facility. Measures: Demographic data and a standard HCV risk- screening survey were used. Results: Significantly higher rates of HCV were found in subjects who were currently using injection drugs (83.3% HCV positive, χ(2) (1)=20.85, p<.001), who had a history of sharing needles for drug use (75% HCV positive χ(2) (1)=83.20, p<.001), or a history of receiving treatment for drug abuse/alcoholism (38.4% HCV positive χ(2) (1)=12.14, p<.001). Vaccination completion ranged by setting between 18% and 38%. Conclusions: Targeted outreach to hard to reach groups is effective in providing access for those at high risk for HIV and HCV infection. A mobile outreach strategy can focus needed resources for a variety of groups in a community.

© 2011 Wiley Periodicals, Inc.

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Combination of oral drugs suppresses common type of hepatitis C

Public release date: 18-Jan-2012

Contact: Mary F. Masson
mfmasson@umich.edu
734-764-2220
University of Michigan Health System

Researchers targeted the type of hepatitis C most common in the United States, results reported in New England Journal of Medicine

Ann Arbor, Mich. – A new combination of investigational drugs successfully suppressed hepatitis C genotype 1 infection in a high percent of patients who had not responded to previous treatment in a study led by a University of Michigan hepatologist.

The study, which will be published Jan. 19 in the New England Journal of Medicine, focused on hepatitis C genotype 1, which is predominant in the United States and the most difficult to treat. Hepatitis C is a virus that infects the liver and can cause liver cancer and liver cirrhosis. It is transmitted through direct contact with infected blood and blood products.

In this pilot study, patients with hepatitis C genotype 1 infection, who had not responded to previous treatment with PEG-interferon alfa and ribavirin, were given a combination of two investigational direct-acting antiviral agents (daclatasvir and asunaprevir) alone, or were given these two antiviral agents along with PEG-interferon alfa-2a and ribavirin. All the patients saw their hepatitis C viral load drop rapidly, says Anna S. Lok, M.D., professor of Internal Medicine, Division of Gastroenterology at the University of Michigan Medical School and lead author of the study.

All 10 patients given the four drug treatment -- two direct-acting antiviral agents (daclastasvir and asunaprevir) that block the NS3 and NS5A regions of the hepatitis C virus plus PEG-interferon alfa and ribavirin -- had sustained virologic response with undetectable virus at the end of treatment and at 12 weeks after stopping treatment. Four of the 11 patients given the two direct-acting antiviral agents only also achieved sustained virologic response.

A sustained virologic response or SVR means there is no detectable Hepatitis C virus in a patient's blood after treatment is stopped. Achieving sustained virologic response is important, because research has shown that late relapse is rare.

"The two recently approved hepatitis C drugs – telaprevir or boceprevir -- combined with PEG-interferon alfa and ribavirin have limited success in patients who have not responded to previous treatment with PEG-interferon alfa and ribavirin. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in that population," says Lok, who also is Director of Clinical Hepatology at U-M. "The high rate of sustained virologic response in patients who received the four drug regimen is very exciting. Although only four of 11 patients given the two direct-acting antiviral agents only achieved sustained virologic response, this is the first study to show that sustained virologic response can be achieved without the use of interferon or ribavirin. These data are very encouraging because PEG-interferon alfaand ribavirin are associated with many side effects and many patients with hepatitis C choose not to receive treatment for fear that they cannot tolerate those drugs."

An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 80 percent of those infected with hepatitis C will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

In the Phase II clinical trial, Lok, along with a team of researchers including scientists from Bristol-Myers Squibb, studied patients with Hepatitis C genotype 1, who had not responded to prior therapy with PEG-interferon alfa and ribavirin. The study was funded by Bristol-Myers Squibb.

"Overall, these results suggest that further research into combinations of direct-acting antiviral agents, with or without PEG-interferon and ribavirin, should be encouraged," Lok says. "Caution must be exercised in selecting the right combination of direct-acting antiviral agents in studies of interferon-free regimens because in this study, all 7 patients who received only two direct-acting antiviral agents that did not achieve sustained virologic response had emergence of drug resistance variants to both drugs."

In this study there were no serious adverse events on treatment or discontinuations due to adverse events. Diarrhea was the most common adverse event in both groups, but it was mild or moderate in all cases.

###

Journal citation: N Engl J Med 2012;366:216-24

Funding: Bristol Myers Squibb.

Additional authors: David F. Gardiner, M.D., Kurt Zhu, Ph.D., Dessislava I. Dimitrova, M.D., Timothy Eley, Ph.D., Dennis M. Grasela, Pharm.D., Ph.D., Claudio Pasquinelli, M.D., Ph.D., Fiona McPhee, Ph.D., Tong Guo, Ph.D., Megan Wind-Rotolo, Ph.D., Anna Persson, Ph.D., all of Bristol Myers Squibb; Eric Lawitz, M.D., of Alamo Medical Research, San Antonio, Texas; Claudia Martorell, M.D., of The Research Institute, Springfield, Mass.; Gregory T. Everson, M.D., of the University of Colorado-Denver; Reem Ghalib, M.D., of the Texas Clinical Research Institute; Robert Reindollar, M.D., of the Carolinas Center for Liver Disease; and Vinod Rustgi, M.D., of Metropolitan Research, Fairfax, Va.

About U-M's Division of Gastroenterology: U-M is one of the largest gastroenterology practices in the country and is a leader in the prevention, diagnosis, and treatment of diseases of the gastrointestinal tract and liver. Our 50-plus physicians are experts in the diagnosis and treatment of all diseases of the gastrointestinal system, from simple to complex, including those of the esophagus, stomach, small intestine, colon, rectum, liver, gallbladder, pancreas and biliary tract.

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Also See:

1. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published
2. Hepatitis C treatment with antivirals is effective: study
3. Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon
4. New Combo KOs HCV Without Interferon, Ribavirin

Achillion's Hep C Pipeline Likely Can't Compete

By Adam Gefvert, Contributor

Thursday, 19 January 2012 08:16

Hepatitus C drug developers have been drinking champagne and eating caviar lately. Companies in this space that have shown little to no revenues for years have been getting acquired at huge premiums to their share price and for billions of dollars.

Pharmasset (VRUS) was offered $11 billion by Gilead Pharmaceuticals (GILD) in November 2011, for an over 100% premium to the share price. Gilead bought it for its PSI-7797 anti-HCV (Hepatitis C Virus) nucleoside. Bristol-Meyers Squibb (BMY) made a tender offer for Inhibitex over the January 7^th weekend for $2.5 billion, a 160% premium over its share price. Also for its anti-HCV nucleoside.

With the recent heavy M&A action in the Hepatitis C space, drug development company stocks that are focusing on Hepatitis C drugs have taken off. Since the Inhibitex buyout on Jan 9, Achillion (ACHN) has gone from $7.92 to $12.95, for a 64% gain. It has since settled down to about $11.

However, Inhibitex and Pharmasset HCV drugs: INX-189, and PSI-7977, respectively, are nucleosides which are a different type of anti-viral drug than those currently used to fight HCV. Nucleosides are believed to be the next generation drug to fight HCV because they have shown in clinical trials to be able to destroy the HCV virus on their own without the aid of other drugs.

Achillion is at a disadvantage to its competitors because none of its HPV drugs in development are nucleosides.

The type of drugs currently used to fight HCV are protease inhibitors which are not able to fight the HCV alone. HCV’s mutations are able to resist protease inhibitors, so they must be used along with the standard of care treatment of pegylated interferon and ribavirin (PR) in order to cure patients. Use of a protease inhibitor along with PR gives a 75% chance to cure HCV, while treatment of only PR, the old method of fighting HCV, gives only a 50% chance to cure it.

The problem is, the side effects of interferon are so bad, that many patients would rather have the disease or wait for a better solution than deal with the treatment. Many patients say the side effects are worse than the disease itself.

The fact that big pharmaceutical companies paid so high a price for Pharmasset and Inhibitex nucleosides is a testament to the thesis that the future of HCV treatment is going to be done without interferon.

“We believe the interferon free era will come late 2015 and early 2016 and we would anticipate, from a time perspective, being competitive with that," said Inhibitex's chief executive Russell Plumb.

In the following picture, Pharmasset illustrates the contrast between the present and future of Hepatitis C treatment.

Achillion’s most advanced HPV drug that is currently going through phase II trials, is ACH-1625, which is a protease inhibitor. It has been going through preclinical trials since 2008 before it was discovered that nucleosides can efficiently fight the HCV. If ACH-1625 won’t work without the help of interferon, then it will pretty much be worthless. By the time it gets to market in 2015 or 2016, if it gets approved, there won’t be any HCV patients willing to do a treatment with interferon.

There is a glimmer of hope for protease inhibitors though. In October 2011, Abbott Laboratories and partner Enanta Pharmaceuticals announced positive results from a phase 2 study of ABT-450, their oral protease inhibitor against HCV, without the use of interferon.

“In the trials, 44 previously untreated patients with hepatitis C were given ritonavir with Abbott's ABT-450 and one of two Abbott polymerase inhibitors, ABT-333 or ABT-072, and ribavirin for 12 weeks. All patients who remained in the studies achieved an early virologic response at 12 weeks, and of the 10 patients to date who were tested 24 weeks after completing the treatment course, nine had achieved a sustained virologic response”, the company said.

Abbott said it could have this shorter duration combination therapy for hepatitis C on the market in 2015 with annual sales potential of about $2 billion.

Early virologic response is a reduction of 2 or greater log in HCV RNA (hepatitis C ribonucleic acid) at week 12 of therapy, and this predicts sustained virologic response, which is an undetectable level of HCV RNA, at further treatments.

"We are seeing there is another way of achieving a regimen without interferon that looks like it will be competitive, it will eventually all boil down to who has the better data,” said Leerink Swann analyst Howard Liang.

However, Brean Murray Carret & Co. analyst Brian Skorney noted that "I continue to believe Pharmasset's [therapy] will be better." (FYI - this was stated before Gilead made the offer to acquire Pharmasset).

Merck is also working on an interferon-free regimen with their protease inhibitor MK-5172. From the company website: “MK-5172 suppressed HCV in patients infected with HCV genotypes 1 and 3. In addition, new in vitro data shows antiviral activity against a wide range of resistant mutant HCV types. The company is actively pursuing the use of MK-5172 in an interferon-free regimen for HCV.”

Achillion’s ACH-1625 drug hasn’t been proven to work without the help of PR. The drug has quite a few obstacles to climb to be worth anything. It would not only have to show effectiveness against HCV without interferon, but it would also have to compete with the nucleosides’ data when they come to market, as well as Abbott’s ABT-450 if it becomes successful, and Merck’s protease inhibitor and those of other big pharma companies. Then there’s all the resources and expenses necessary to get it through the trials. Phase III trials alone would likely cost over $100 million.

Besides ACH-1625, all its other drugs in the pipeline are in the preclinical stage or are starting phase 1 trials. It wouldn’t make any sense for a big pharmaceutical company to acquire Achillion at its current elevated price. Most of them are already working on their own HCV drugs. For example, Vertex and Alios BioPharma have teamed up to do clinical trials of their nucleoside drugs ALS-2200 and ALS-2158.

As shown in the Q3 2011 report, Gilead Sciences had entered into a research collaboration and license agreement with Achillion in 2004, and is continuing to do a minimal amount of collaborative research with the company, only paying $64K last quarter. Then Gilead went ahead and acquired Pharmasset for $11 billion totally snubbing Achillion. If any big pharma was going to buy Achillion, it would seem that Gilead would’ve been a good candidate since they have worked together for awhile. Achillion’s market cap was only about $400 million in late November when Gilead bought Pharmasset.

It’s unlikely that Achillion will be able to find an interferon-free treatment for HPV with ACH-1625 because when the drug was first designed, it didn’t have that goal in mind. Now, going through its phase 2 trials, with all the competition, I’m giving it a 15% chance that it will be able to develop an interferon-free regimen and become a top HPV drug with $2 billion a year in revenues like Abbott predicts its ABT-450 drug will peak at.

Achillion’s other two HCV inhibitors, ACH-2684 and ACH-2928, are going through phase 1 trials, so I’m giving them a 10% chance to succeed and reach the $2 billion annual sales number. I’m not including in the value calculation Achillion’s drugs still going through preclinical trials.

Even if Achillion managed to develop and commercialize a $2 billion a year in sales drug, it would need help to market it as it doesn’t have any experience selling drugs. That’s why the company is looking for an acquirer, or a big pharma to continue with the trials from here, take on the expenses, and give Achillion royalty payments once the drug hits the market. The latter is the scenario I use in my discounted cash flows analysis.

Continue Reading …

New Combo KOs HCV Without Interferon, Ribavirin

By Michael Smith, North American Correspondent, MedPage Today
Published: January 18, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

A combination of direct-acting antiviral agents aimed at hepatitis C -- and given without standard therapy -- can lead to sustained virologic response in patients with a difficult-to-treat strain of the virus.

In an "exploratory" phase II study, four of 11 patients treated with the two agents daclatasvir and asunaprevir had undetectable levels of the virus 12 and 24 weeks after the end of treatment, according to Anna Lok, MD, of the University of Michigan Ann Arbor, and colleagues.

All of the patients had previously failed standard therapy with pegylated interferon and ribavirin, Lok and colleagues reported in the Jan. 19 issue of the New England Journal of Medicine.

The finding is a "proof-of-concept" that combining agents that directly target the virus through different mechanisms can yield good outcomes even without the standard therapy, the researchers argued.

On the other hand, results were even better in the second arm of the study, in which 10 patients were given all four drugs: all had a sustained virologic response 12 weeks after stopping treatment and nine still had undetectable levels of hepatitis C RNA after 24 weeks.

Sustained virologic response – defined as a plasma level of viral RNA of less than 10 IU per milliliter 12 weeks after treatment ends – is regarded as the functional equivalent of a cure, since the virus rarely rebounds after that.

In clinical trials, standard therapy with pegylated interferon and ribavirin yields sustained virologic responses in no more than half of patients with the difficult to treat genotype 1 and in no more than 80% of those with genotypes 2 or 3.

Adding either of the approved direct-acting agents – telaprevir (Incivek) and boceprevir (Victrelis) – improves those outcomes markedly.

But regimens including pegylated interferon and ribavirin are difficult to take and real-world effectiveness is much lower, leading to a growing interest in other agents that attack viral replication directly and may be used without interferon and ribavirin.

That's why the current study is a "watershed moment" in hepatitis C therapy, according to Raymond Chung, MD, of Massachusetts General Hospital in Boston.

In an accompanying editorial, Chung said that researchers can "certainly" do even better than Lok and colleagues by adding other direct-acting agents into the mix.

With other classes in development – such as nucleotide polymerase inhibitors – "we are on the threshold of a treatment revolution," Chung argued.

"There has never been a more exciting time for patients and providers who grapple with this silent killer," he concluded.

The two drugs under study both attack the viruses' ability to replicate inside cells. Daclatasvir inhibits the NS5A replication complex, while asunaprevir blocks the activity of the NS3 protease enzyme.

For this study, Lok and colleagues enrolled 21 patients with genotype one hepatitis C who had not responded to previous therapy and assigned them randomly to get the two drugs alone or in combination with standard therapy for 24 weeks.

The primary endpoint was a sustained virologic response 12 weeks after therapy ended.

Lok and colleagues reported:

• Four patients in the two-drug group (36%) met the primary endpoint, including two of the nine with viral genotype 1a and both of those with genotype 1b.
• Six patients -- all with genotype 1a -- had viral breakthrough while receiving therapy, and in all of them the researchers found resistance mutations to both antiviral agents.
• All 10 patients in the four-drug group had a sustained virologic response 12 weeks after treatment, and nine maintained that for another 12 weeks.

The most common adverse event in both groups was diarrhea, and six patients had transient elevations of alanine aminotransferase levels to more than three times the upper limit of the normal range.

The study is not the first to find such a result; Japanese researchers have also shown that the two drugs in combination – but without interferon -- can lead to promising outcomes.

But in that open-label, single-arm study, all the patients had genotype 1b virus, which appears to respond better to therapy than genotype 1a.

The study was supported by Bristol-Myers Squibb.

Lok reported financial links with Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough, and Roche. Other authors also reported financial links with industry and several are either employees of or hold stock in Bristol-Myers Squibb.

Chung reported financial links with Merck, Gilead, Pfizer, Roche, and Schering.

Primary source: New England Journal of Medicine
Source reference:
Lok AS, et al "Preliminary study of two antiviral agents for hepatitis C genotype 1" N Engl J Med 2012; 366: 216-224.

Additional source: New England Journal of Medicine
Source reference:
Chung RT "A watershed moment in the treatment of hepatitis C" N Engl J Med 2012; 366: 273-275.

Source

Also See:

1. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published
2. Hepatitis C treatment with antivirals is effective: study
3. Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon

Where Drug Names Come From

Naming Convention Drugmakers propose generic names for new drugs by starting with stems that describe structure, function, and targets, then tacking on syllables of their choice.

Chemical & Engineering News Volume 90 Issue 3 | January 16, 2012 | pp. 36-37

Behind every generic name lies a specific process

By Carmen Drahl

It isn’t every day that a molecular moniker is on the docket at Illinois’ Cook County Circuit Court. But then, the 2002 case of cis-8-methyl-N-vanillyl-6-nonenamide was most unusual.

The trouble wasn’t with the compound’s International Union of Pure & Applied Chemistry-approved name. It was that cis-8-methyl-N-vanillyl-6-nonenamide also happens to be a medication. Drug molecules get an additional, simpler name called a nonproprietary name or generic name. Winston Pharmaceuticals, a company that develops products based on cis-8-methyl-N-vanillyl-6-nonenamide, sought to change that molecule’s generic name, which an independent body had chosen in-line with decades of drug-naming conventions. If the case went Winston’s way, more than a name on a box would have been at stake.

Drug naming rarely involves drama. But this example illuminates a little-talked-about layer in drug development, one that affects doctors, pharmacists, and patients.

Unlike IUPAC-sanctioned chemical names, generic names usually describe a drug’s physiological function rather than its chemical structure. Today’s regimented generic-naming process got its start in the 1960s, a time when drugs had grown complex in structure and IUPAC names had grown to unwieldy lengths. In 1961, the American Medical Association, the U.S. Pharmacopeial Convention, and the American Pharmacists Association created the U.S. Adopted Names (USAN) Council to select concise generic names. The Food & Drug Administration joined the effort in 1967.

Today, the USAN Council names the active ingredients in drugs, biologics, vaccines, and even contact lenses and sunscreens. The council recommends names to the World Health Organization’s (WHO) International Nonproprietary Names (INN) program, which ultimately chooses a single name for each new drug that’s acceptable worldwide. For drugmakers, obtaining a generic name is a required part of bringing new products to market. Choosing a brand, or trade, name is an entirely separate process.

USAN Council members believe it’s important to develop drug names that are free for anyone to use, says Ruta Freimanis, who served as associate executive secretary and then as executive secretary of the USAN Council between 1978 and 2000. Brand names might be handy at first, “but eventually drugs do go off patent,” she says. A generic name “can go in the literature, on package labels, or even in educational materials” without copyright issues related to brand names, she explains.

The naming process itself “is an evolving type of science,” says Stephanie C. Shubat, the current director and secretary to the USAN Council. Generic names have evolved from being truncated versions of chemical terminology to being largely independent of it, she explains.

A list of naming rules, some of them quirky, has evolved as well. The letters h, j, k, and w are off-limits because they lead to pronunciation problems in other languages. Drugmakers can suggest names to the USAN Council, but any name with an implication that a drug is better, newer, or more effective than the competition heads straight for the reject pile, Shubat says. When a prospective name reaches the WHO stage, international connotations come into play. A name that sounds perfectly fine in English might have bad or even obscene connotations elsewhere. No one wants to sell the Chevy Nova of the drug world.

The crux of the generic-naming system is a collection of short name fragments called stems. Each stem has a meaning connected to a particular drug class or mode of action. The official list of USAN and INN stems and substems has grown and changed over time as companies come up with new classes of drugs, Shubat explains.

Understanding drug names through stems is a lot like learning English vocabulary by studying Greek and Latin roots. Learn what the stems mean, and you’re most of the way to figuring out what a drug does. Take top-selling drug Nexium, which has a generic name of esomeprazole. The stem in that name is -prazole, which means the drug is a benzimidazole antiulcer agent. The drug’s es- prefix describes the nature of the drug’s chirality—esomeprazole is dextrorotatory and contains a chiral center in the S configuration.

A prefix, in fact, was a player in the Winston case. The generic name Winston wanted to change, zucapsaicin, contains the prefix “zu,” which comes from German chemical nomenclature and indicates a cis isomer. Zucapsaicin is the cis isomer of capsaicin, a compound in chili peppers. The molecule targets a specific ion channel and can be used to treat pain, inflammation, or itch, says Joel E. Bernstein, a physician and Winston’s chief executive officer. Winston requested a name change from zucapsaicin to civamide, which according to the company was commonly used in hospitals and pharmacies.

It’s possible to change generic names, but only on rare occasions, and usually only for safety reasons. In 2009, for instance, the entire family of botulinum toxin drugs, which includes the popular cosmetic Botox, got a generic-name makeover in light of reports of serious side effects and deaths from dosage mix-ups.

Winston did not win its court case. A 2004 petition to FDA to change the name didn’t work out either. The name zucapsaicin was found to be in-line with established naming precedents. As for name confusion among physicians and pharmacists, the USAN Council concluded Winston was partly to blame.

The name zucapsaicin had been on the books since 1994. The council negotiated the name with a company called GenDerm, which owned the rights to the drug at the time. Civamide was a generic name GenDerm suggested. After that name was rejected, GenDerm continued to use the name civamide in the literature and its documentation. Winston continued the practice when it acquired the rights to the drug in 1999.

Most of the documents Winston cited to support its claim are dated after 1994, wrote then-USAN program director Sophia V. Fuerst in a letter to Winston. It’s both Winston and GenDerm’s “use of the name civamide after the name zucapsaicin was adopted that has caused the confusion,” she wrote.

Bernstein disputes that idea. Still, he says, “we weren’t able to get USAN to change their mind, nor FDA, so we have zucapsaicin.”

Most of the time, a simple back-and-forth between a company and the USAN Council is enough to settle any name disputes, says John E. Kasik, professor emeritus at the University of Iowa Carver College of Medicine and a longtime member of USAN’s review board, which settles naming spats. In fact, the review board has only had to step in to resolve five disputes throughout its decades-long existence.

Sometimes small disagreements occur when a manufacturer asks for a new stem to be created, Shubat says. It’s the council’s job to keep naming as streamlined as possible, which means being conservative when it comes to adding new stems, she explains.

“Manufacturers have to supply concrete arguments as to what differentiates their compound to qualify for a new stem,” Freimanis says. Drugs within the same category are different, she says, “otherwise manufacturers wouldn’t be selling them.”

Once the council builds in stems, prefixes, and other conventions, “a lot of times a name is three-quarters predetermined,” Shubat says. Once in a while, though, companies get to do something special with the syllable or two they supply. Onyx Pharmaceuticals’ experimental multiple myeloma treatment carfilzomib is named after molecular biologist Philip Whitcome and his wife, Carla, who both succumbed to cancer. (The ph in Philip was changed to an f to make the name compatible with multiple languages.) Philip Whitcome was a founder of the company Proteolix, which first developed carfilzomib, says Onyx spokeswoman Lori Melançon. With the name, the company “wanted to celebrate both Phil and Carla’s legacy,” she says.

Bristol-Myers Squibb’s experimental hepatitis C drug asunaprevir gets part of its name from Li-Qiang Sun, the chemist who first made it, says Joel C. Barrish, BMS’s vice president of medicinal chemistry.

And dasatinib, a chronic myelogenous leukemia medication BMS markets under the brand name Sprycel, is named for research fellow Jagabandhu Das. Das, or Jag, as he’s known around the labs, didn’t discover dasatinib. “What Jag did was challenge dogma,” Barrish explains. On two separate occasions, Das’s discoveries pulled his teammates out of medicinal chemistry ruts.

Long after a drug’s patent expires, “it’s the generic name that will always be remembered,” Barrish says. “Being able to recognize Jag that way for his accomplishments made the whole team feel good.”

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2012 American Chemical Society

Source

A Glucose Meter That Detects Viruses

Virus Meter? By making glucose a signal for viral DNA, researchers repurposed a glucose meter into a virus detector. Credit: Shutterstock

January 18, 2012

Medical Diagnostics: Researchers convert device for monitoring diabetes into one that can spot hepatitis B

By Erika Gebel

Although scientists have developed a variety of cheap, portable instruments for doctors to use in the field to pinpoint viruses, none have hit the market. To speed things along, researchers have now converted a commercially available device—a glucose meter—into one that can spot viral DNA (Anal. Chem., DOI: 10.1021/ac203014s).

“Our idea was to start with a technology that is already mature,” says Yi Lu of the University of Illinois, Urbana-Champaign. He and his team repurposed glucose meters, which people with diabetes commonly use to monitor their blood sugar, into virus meters by using glucose as a proxy for viral DNA. The scientists designed a chain of biomolecular interactions to link the two.

With hepatitis B as the virus they chose to detect, they first made two DNA probes that each would recognize half of the virus’s DNA sequence. The researchers then attached one probe to a tiny magnetic bead and the other to invertase, an enzyme that turns sucrose into glucose.

They tested their system by adding both probes to a solution of hepatitis B DNA at a known concentration. As the mixture incubated for a couple of hours, each strand of viral DNA bound both probes, thereby linking the enzymes to the beads. The researchers then isolated the beads with a magnet and placed them in a sucrose solution, where the enzymes slowly produced glucose. After three hours, the scientists removed the beads and measured the solution’s glucose concentration with a glucose meter.

Based on the measurement, they could determine how much invertase was present and, in turn, the amount of viral DNA in the original solution. Their system could detect hepatitis B DNA down to 40 pM, a level adequate to diagnose the disease at some stages, but not all. To improve the method’s sensitivity, Lu wants to increase incubation times and possibly engineer an enzyme that produces more glucose.

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2012 American Chemical Society

Source

Effort Improves Outcomes for Liver Transplants

Written by Elizabeth Witherspoon

Nationally there are 17,000 people on the waiting list for a liver transplant. Yet according to A. Sidney Barritt, IV, M.D., M.S.C.R., surgeons are able to perform only about 6,000 transplants annually. And, unfortunately, the obesity and diabetes epidemics in this country may be reducing the number of viable organs for transplantation each year. Thus, science which advances the understanding of how best to treat patients and prevent mortality while they wait for transplants is vital.

Barritt and colleagues from UNC-Chapel Hill funded, in part, by an NIH KL2 grant through the North Carolina Translational and Clinical Sciences (NC TraCS) Institute studied one of the factors that may affect mortality of patients awaiting transplant – the density of gastroenterology (GI) specialists in their home communities. He presented his findings at the annual Liver Meeting of the American Association of the Study of Liver Disease and received an AASLD Presidential Poster of Distinction award in November.

Previous studies have looked at patients’ geographic distance from the transplant center, hypothesizing that the greater the distance, the lower the transplant rate. Instead, Barritt and his team considered the density of GI subspecialists in communities and found a correlation: the more GI subspecialists patients have in their home communities, regardless of how far they lived from the transplant center, the better the outcome.

This study showed that among patients referred for liver transplant, the number of gastroenterologists in their home hospital service area independently increases the odds of receiving a liver transplant by 16% for each additional gastroenterologist per 100,000 population. Increasing Model for End-stage Liver Disease (MELD) score and hepatocellular carcinoma also increase the odds of receiving a transplant. Medicaid and Medicare insurance coverage are detrimental to a patient’s odds of receiving a liver transplant, but are better than no insurance coverage at all.

“We were not looking at referral patterns. We were not looking at whether a gastroenterologist was more likely to send you to UNC,” said Barritt. “We were looking at whether the number of gastroenterologists in a community helps keep you alive and a viable transplant candidate from referral to ultimately getting a transplant.”

“Access to local subspecialty care improved the odds of transplant for our patient population most likely because we are a centrally located tertiary care transplant center and many of our patients continue to receive medical care locally. Access to local experts is a great boon to our center in co-managing these patients and we rely heavily on their expertise to get chronically and often critically ill patients through to liver transplant. As our referral base measures more than 500 miles in diameter, we are unable to follow some of our patients on a weekly basis. Additionally, when our medical center has no available beds for inpatient transfers, our colleagues around the state help facilitate patient care locally,” said Barritt.

The project also tested a clinical transplant database at UNC to see whether it is valid for use as a research database. The investigators hope that in the future they can combine these data with that of certain other transplant centers so they can conduct studies with more generalizable findings than research currently available from large single-center studies or from the United Network of Organ Sharing database, which lacks some patient specific data.

Barritt is an assistant professor in the Department of Medicine, Division of Gastroenterology and Hepatology, UNC School of Medicine. He is also a KL2 Scholar, in the second year of three years of support by NC TraCS. The KL2 program objective is to train and develop junior investigators who will become the next generation of successful translational researchers. It does this by providing classroom and experiential training, mentoring, funding for research and, perhaps most importantly, protected research time.

His colleagues on the project are: Stephen A. Telloni, M.D., Department of Medicine; Clarence W. Potter, M.S., NC TraCS; David A. Gerber, M.D., associate professor, Department of Surgery, Division of Abdominal Transplant; and Paul H. Hayashi, M.D., M.P.H., assistant professor and medical director of liver transplantation.

Source

Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon

January 18, 2012, 6:08 PM EST

By Drew Armstrong and Robert Langreth

Jan. 18 (Bloomberg) -- Two experimental pills from Bristol- Myers Squibb Co. cleared the hepatitis C virus in 36 percent of patients who failed existing drugs, in a small study that may lead to a new oral-therapy approach against the liver disease.

The study released today is the first to suggest that difficult hepatitis C cases may be cured without using the injected drug interferon, said Anna Lok, the lead study author and director of hepatology at the University of Michigan in Ann Arbor. Interferon, a mainstay of existing treatment, causes unpleasant side effects including fatigue and flu-like symptoms.

Drug companies including Bristol-Myers, Merck & Co., Gilead Sciences Inc., and Vertex Pharmaceuticals Inc. are racing to come up with interferon-free treatment. The new results in 21 patients show that such a therapy will be possible, Lok said.

Oral treatments with fewer side effects would vastly increase the number of patients treated, according to an editorial in the New England Journal of Medicine, where the study was published.

“We are on the threshold of a treatment revolution that will greatly improve the effectiveness of HCV therapy,” wrote Raymond Chung, a gastroenternologist at Massachusetts General Hospital in Boston. He called it “a watershed moment in the annals of HCV therapy.”

The study compared Bristol-Myers’s two pills in combination with interferon to the pills alone in 21 hepatitis C patients who weren’t helped by existing therapy. It found that 4 of 11 patients had undetectable virus 24 weeks after treatment with Bristol’s experimental oral drugs daclatasvir and asunaprevir.

Adding injectable drugs, however, boosted the response rate. Results showed that 9 of 10 patients who got the two oral drugs plus interferon and a fourth drug, ribavirin, for 24 weeks had no detectable virus 24 weeks after stopping therapy.

“The combination of drugs we picked may not be the best, and we need to tweak it and find the best combination,” Lok said in a telephone interview from Ann Arbor.

Bristol-Myers, based in New York, sponsored the clinical trial.

--Editors: Angela Zimm, Andrew Pollack

To contact the reporters on this story: Drew Armstrong in New York at darmstrong17@bloomberg.net ; Robert Langreth in New York at rlangreth@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

Source

Also See:

1. Hepatitis C treatment with antivirals is effective: study
2. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

Hepatitis C treatment with antivirals is effective: study

Hepatitis C can be spread through blood and infected needles. (Centers for Disease Control and Prevention)

By Shari Roan, Los Angeles Times / For the Booster Shots blog

January 18, 2012, 2:12 p.m.

A major advance in treating hepatitis C appears to be on the horizon. Researchers reported Wednesday that combining two antiviral medications was effective in stopping the infection in some patients who were not helped by the traditional treatment.

Progress in fighting hepatitis C infection is of high importance because millions of Americans have the virus. However, the standard treatment with the medication interferon, while effective in many people, is linked to severe side effects. "The challenge ... has been to identify regimens that are more effective, shorter, and have a better side-effect profile," said Dr. Raymond T. Chung, director of hepatology at Massachusetts General Hospital.

Hepatitis C is an infectious disease that can cause liver inflammation and damage. It's spread through exposure to infected blood, such as via contaminated needles or through sexual contact.

The new study, published in the New England Journal of Medicine, is a phase-2 trial of 21 people with hepatitis C who had not responded to previous therapy. They were randomly assigned to receive the two antiviral drugs daclatasvir and asunaprevir or those two antivirals with interferon and ribavirin (another drug used to treat hepatitis C infection).

The study showed that virus activity was halted in 36% of the patients receiving only the two antiviral medications over 24 weeks of treatment. Stopping the virus from replicating halts the infection. All but one of the patients in the second group, who were receiving the combination of four medications, showed a positive response to the medication after 24 weeks.

The research, while preliminary, proves that it may be possible to treat hepatitis C infection with antivirals only. Patients with a type of virus called genotype 1b had a particularly strong response to the antivirals. "Overall, these results suggest that further research with combinations of direct-acting antiviral agents, with or without [interferon] and ribavirin, is warranted," wrote the authors, led by Dr. Anna S. Lok, at the University of Michigan Medical Center.

Chung, who wrote a commentary accompanying the study, said: "We are on the threshold of a treatment revolution that will greatly improve the effectiveness of hepatitis C virus therapy by dramatically increasing the number of persons treated."

Studies are underway to further evaluate the effect of combining antiviral medications for hepatitis C treatment.

Source

Also See: First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

January 18, 2012 05:01 PM Eastern Time

Study also Demonstrated 100% Sustained Virologic Response 12-Weeks Post Treatment with Quadruple Therapy

Phase II Investigational Data Published Today in the New England Journal of Medicine

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced the full results, published in the New England Journal of Medicine, from a Phase II clinical trial in patients with hepatitis C virus (HCV) genotype 1 who had not responded to prior therapy with PEG-interferon alfa and ribavirin (‘null responders’¹). The study demonstrated that its primary endpoint of the achievement of sustained virologic response 12-weeks post-treatment (SVR12) is possible with a direct-acting antiviral (DAA)-only combination containing daclatasvir and asunaprevir (4/11 patients, including two of two patients infected with HCV genotype 1b). This study was the first study to demonstrate the possibility that hepatitis C can be cured (defined as sustained virologic response 48 weeks post-treatment or SVR48) without the use of interferon. The study also demonstrated that 100 percent (10/10) of these difficult-to-treat patients dosed with quadruple therapy containing daclatasvir and asunaprevir in combination with PEG-Interferon alfa and ribavirin achieved SVR12.

In this study there were no serious adverse events on treatment or discontinuations due to adverse events. Diarrhea was the most common adverse event in both groups (73% and 70%).

“Even with the recent approval of two protease inhibitors, treatment of hepatitis C patients who have not responded to PEG-interferon alfa and ribavirin has limited success. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in null responders,” said lead investigator Anna Lok, MD, FRCP, director of clinical hepatology and professor in the department of internal medicine at the University of Michigan Medical School in Ann Arbor. “The data seen in this study with Bristol-Myers Squibb’s investigational DAAs daclatasvir and asunaprevir, either as DAA-only therapy or as part of quadruple therapy, are encouraging as we work to advance hepatitis C therapy for this difficult-to-treat patient population. This study also shows for the very first time that sustained viral responses can be achieved without the use of interferon and ribavirin.”

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an investigational, oral, selective NS3 protease inhibitor.

Study Results

Viral Response: Dual DAA Therapy with daclatasvir and asunaprevir (Group A)

Eleven patients were randomized to receive dual DAA therapy for 24 weeks. Seven of the 11 patients (64%) in Group A achieved undetectable viral load by week four, and five patients remained undetectable at the end of treatment. Of these 11 patients, one patient relapsed at four (4) weeks post treatment while four patients (36%) had sustained virological response at 12 weeks post-treatment (SVR12). In follow-up to 48-weeks post treatment, no additional cases of viral relapses were observed.

Six patients, all with HCV genotype 1a, experienced viral breakthrough on dual DAA therapy, and analysis of HCV sequences following breakthrough confirmed resistance to both antivirals. With the addition of PEG-interferon alfa and ribavirin to their regimen (rescue therapy), four of the six patients achieved undetectable viral load. Two of these patients relapsed following the treatment period and two remained undetectable, one with 14 weeks and one with 42 weeks of post treatment follow-up. Two of the six patients did not achieve undetectable HCV RNA and treatment was discontinued.

Viral Response: Quadruple Therapy with daclatasvir, asunaprevir and PEG-Interferon alfa and ribavirin (Group B)

Ten patients were randomized to receive quadruple therapy for 24-weeks. Six of the 10 patients (60%) in Group B achieved undetectable HCV RNA by week four. Ten of the 10 patients (100%) were undetectable by the end of treatment, and all 10 achieved SVR12. No patients experienced viral relapse during 48 weeks of post-treatment observation.

Safety

In the study, there were no serious adverse events on treatment, no deaths, and no treatment discontinuations due to adverse events. Most adverse events were mild to moderate, and the most common AEs were diarrhea (group A: 8/11, 73%; group B: 7/10, 70%), fatigue (group A: 6/11, 55%; group B: 7/10, 70%), headache (group A: 5/11, 45%; group B: 5/10, 50%), and nausea (group A: 2/11, 18%; group B: 5/10, 50%).

Six patients (four from group A, including two receiving rescue therapy, and two from group B) experienced elevated liver enzymes [ALT >3x upper limit of normal (ULN)] which did not require treatment discontinuation or dose interruptions, and all patients stabilized or improved with continued therapy. Six patients, all of whom received PEG-interferon alfa and ribavirin, experienced Grade 3 or 4 neutropenia, a blood disorder characterized by an abnormally low number of white blood cells.

About the Study

This open-label, phase IIa study evaluated the antiviral activity and safety of the combination of daclatasvir and asunaprevir with and without PEG-Interferon alfa and ribavirin in 21 HCV genotype 1 null responders. Patients in the study were randomized to receive one of two treatment regimens for 24 weeks. The 11 patients in Group A received dual-DAA therapy with daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily, both taken orally. The 10 patients in Group B received quadruple therapy with daclatasvir 60 mg once daily, asunaprevir 600 mg twice daily, PEG-interferon alfa 180 µg once weekly, and ribavirin 1000-1200 mg daily (according to body weight) in two divided doses. The primary study objective was to determine the proportion of patients achieving undetectable viral load (HCV RNA <10 IU/mL) 12 weeks post-treatment (SVR12). This dual-DAA combination is now in Phase III development.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is advancing a portfolio of compounds that aims to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials and is currently in Phase III development. Asunaprevir, also known as BMS-650032, is an NS3 protease inhibitor in Phase III development for hepatitis C.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q, and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

¹ Null responders – patients whose virus did not respond to prior treatment with PEG-interferon alfa and ribavirin (HCV RNA decrease <2 log₁₀ at 12 weeks).

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Source

Rituximab Helpful Against HCV Cryoglobulinemic Vasculitis

From Reuters Health Information

By David Douglas

NEW YORK (Reuters Health) Jan 13 - Research funded by the National Institutes of Health shows that rituximab is an effective treatment for refractory mixed cryoglobulinemic vasculitis in patients with hepatitis C.

"Unlike conventional forms of immunosuppressive therapy often used to treat this disease, rituximab was well tolerated and did not worsen the underlying viral hepatitis," said lead investigator Dr. Michael C. Sneller in email to Reuters Health.

Mixed cryoglobulinemic vasculitis is a relatively uncommon complication of hepatitis C virus (HCV) infection, as Dr. Sneller and his colleagues noted online December 6th in Arthritis & Rheumatism.

It's characterized by clonal expansion of B cells that produce IgM rheumatoid factor. The major manifestations are cutaneous vasculitis, arthralgia/arthritis, peripheral neuropathy, and membranoproliferative glomerulonephritis.

Pegylated interferon alpha and ribavirin can result in sustained remission, according to the researchers, but more than 50% of patients with HCV genotype 1, the most common in Europe and the Americas, do not respond.

Rituximab, however, can potentially deplete the expanded population of B cells - although there's been some concerns that it may increase HCV replication.

In an open label study, Dr. Sneller - based at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland - and colleagues randomly assigned 24 patients to four weekly infusions of rituximab, or to continue with best available therapy. Everyone in the trial had either failed attempts to control the lymphoproliferative disease with interferon alpha and ribavirin, or they were intolerant of those drugs.

Patients in the rituximab group could continue on their immunosuppressive medications, but they could not increase the dose or receive new immunosuppressants or plasma exchange.

In the control group, patients were maintained on their current regimen and were allowed to increase or initiate new immunosuppressive treatments as needed.

At six months, 10 of the 12 rituximab patients (83.3%) were in remission, compared to only one control subject (8%).

Of the two rituximab patients not in remission at that point, one had to withdraw after two infusions because of febrile reactions. The other was in remission at four months but subsequently relapsed.

There were no adverse effects in terms of viremia or transaminase levels.

The researchers conclude that rituximab can induce sustained remissions, and "was well tolerated and did not appear to increase HCV replication or worsen the underlying hepatitis."

Dr. Sneller added in his email: "Rituximab may be a safer, more effective alternative to standard immunosuppressive therapy for patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy was not effective."

SOURCE: http://bit.ly/zeAest

Arthritis Rheum 2012.

Source