Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C

J Gastroenterology
DOI 10.1007/s00535-013-0926-7

Shinya Maekawa • Nobuyuki Enomoto
Received: 7 December 2013 / Accepted: 10 December 2013
Springer Japan 2013

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC), and it is estimated that infected individuals total 185 million people worldwide. In Japan, around 2 million are infected with HCV, and more than 20 thousand die from HCV-induced HCC annually. Though viral eradication with antiviral therapies is the most important and effective choice for decreasing HCC-related deaths induced by HCV, complete viral eradication has been quite difficult till recently, especially in patients with genotype-1 HCV infection because of the low response rate to interferon (IFN)-based therapy [1, 2].

In this background, development of novel direct-acting antiviral agents (DAAs) specific for HCV was truly a revolutionary event. In 2011, two first-generation NS3 protease inhibitors (PIs), telaprevir and boceprevir, were firstly approved among all the DAAs for clinical use in USA and Europe for genotype-1 HCV in combination with pegylated-interferon and ribavirin (PR), while telaprevir was approved in Japan in the same 2011 period. As expected, a regimen including telaprevir in combination with pegylated-interferon and ribavirin dramatically improved the sustained viral response (SVR) rate to as high as 80 % in genotype-1 HCV infection. On the other hand, telaprevir has several undesirable problems. Among all, adverse events (AEs) of anemia and skin rash are serious problems of telaprevir, and Grade 3/4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (\8.0 g/dL), might occur [3, 4]. Moreover, cumbersome frequent dosing three times a day (every 7–9 h) could induce poor medication adherence. Under the circumstances, it has been quite stressful for patients as well as clinicians to introduce and monitor this telaprevir-based regimen.

Simeprevir (SMV, TMC435) is classified as a second generation PI with the macrocyclic structure having an advantage in the binding affinity and specificity for NS3 protease compared to the first-generation PI with the linear structure. Due to the difference in the structure, the drugresistance profile is somewhat different from that of telaprevir. Though simeprevir shows cross-resistance with telaprevir at amino acid positions of 155 and 156, most of the resistant mutation occurs at the simeprevir-specific amino acid position of 168 [5]. Though simeprevir is effective in all viral genotypes (genotype 1–6), it has the strongest antiviral activity for genotype-1a and -1b HCV infection. In particular, low AE rate and its patient-friendly once-daily dosing are the important characters of simeprevir aside from its strong antiviral activity. In the international phase II trials of simeprevir in combination with PegIFNa-2a/RBV for treatment-naı¨ve (PILLAR study) [6] and treatment-experienced patients (ASPIRE study) [7] for HCV genotype 1-infected patients, it was demonstrated that simeprevir was generally well tolerated and had a pharmacokinetic profile supporting once-a-day (QD) dosing resulting in high virologic response rates.

In this issue of the Journal of Gastroenterology, Hayashi et al. [8] reported the important results of the phase II Dose and duration Ranging study of Antiviral agent TMC435 in Genotype One HCV treatment-Naı¨ve patients (DRAGON study; TMC435-C215) evaluating once-daily simeprevir with pegylated-interferon and ribavirin therapy for treatment- naı¨ve, high viral-loaded hepatitis C genotype 1-infected patients in Japan. Due to the result of previous phase I study that simeprevir plasma concentration was higher in Japanese healthy volunteers compared with Caucasian volunteers, simeprevir doses of 50/100 mg QD were selected for this study, while simeprevir doses of 150 mg QD were selected in western countries [9]. Through investigating five treatment groups (SMV12/PR24 50 mg, SMV12/PR24 100 mg, SMV24/PR24 50 mg, SMV24/PR24 100 mg, and PR48), it was disclosed that simeprevir-combined groups all achieved high SVR rate (77–92 % compared to 46 % for PR). As to the AEs, simeprevir was well tolerated, and the incidence of anemia and skin rash were similar in their frequency and their grade between all the SMV groups and the PR group. Due to low AEs, therapy discontinuation rate and ribavirin dose reduction was also similar in the SMV groups and the PR group. While an AE of bilirubin elevation was specific to simeprevir, and it reached to grade 3 (2.6–5.0 mg/dL) to 4 ([5.0 mg/dL) in four patients (5 %) leading to the discontinuation of simeprevir in these individuals, the bilirubin level returned to baseline after the end of simeprevir in those patients. Since bilirubin elevation is considered to result from the blockade of bilirubin clearance-associated OATP1B1 and MRP transporters by simeprevir [10], it is considered that the bilirubin elevation by simeprevir does not reflect deterioration of liver function.

Following the results of this phase II DRAGON study, treatment dosage of simeprevir was determined as 100 mg QD in Japan, and successive phase III CONCERTO studies for simeprevir/pegylated-interferon/ribavirin therapy have been conducted (CONCERTO-1 for treatment-naı¨ve, -2 for previous null responder, -3 for previous relapser, and -4 for naı¨ve, null responder and relapser). After the completion of those CONCERTO studies with favorable outcomes for simeprevir-based regimens, once-daily simeprevir with pegylated-interferon and ribavirin therapy for high viralloaded hepatitis C genotype 1-infected patients was just recently approved for clinical use in Japan.

Considering the history of HCV therapy, this new therapy of once-daily simeprevir with pegylated-interferon and ribavirin therapy is ideal in its high efficacy and low AEs. Of course, it is true that DAA combination therapies without IFN (IFN-free therapies) would appear in the near future, and that these IFN-free therapies are advantageous in that they are free from IFN-related AEs. However, in terms of DAA-resistant viral mutants, it is considered that these mutant HCVs generally have low replication fitness, and are sensitive to IFN. Therefore, it is speculated that IFN-based DAA therapies compared to IFN-free DAA therapies are safer in preventing the development of multidrug resistant HCVs.

Taken together, the new regimen of once-daily simeprevir with pegylated-interferon and ribavirin therapy would surely be an important milestone in the therapy for high viral-loaded hepatitis C genotype-1 infected patients in the era of DAA therapy.

References

1. Kim MN, Kim BK, Han KH. Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia- Pacific region. J Gastroenterol. 2013;48(6):681–8.

2. Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med. 2013;19(7):850–8.

3. Chayama K, Hayes CN, Ohishi W, Kawakami Y. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48(1):1–12.

4. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2013;56(1):78–84.

5. Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–87.

6. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918–29.

7. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2013. doi:10.1053/j. gastro.2013.10.058.

8. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatmentnaı ¨ve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2013. doi:10.1007/s00535-013- 0875-1.

9. Verloes R, Shishido A. Phase I safety and PK of TMC435 in healthy volunteers and safety, PK and short-term efficacy in chronic hepatitis C infected individuals. Kobe: Abstract O-32 presented at the Japanese Hepatology Congress; 2009. p. 4–5.

10. Huisman MT, Snoeys J, Monbaliu J, Martens M, Sekar V, Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. Poster 278 presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, USA, October 29– November 2, 2010.

Source

What a Year for Harm Reduction!

Provided by The Huffington Post

Hilary McQuie
Western Regional Director, Harm Reduction Coalition

Posted: 12/22/2013 9:16 am

Harm reduction is a movement for social justice built on a belief in, and respect for, the rights of people who use drugs. Harm reduction is also a set of practical strategies and ideas aimed at reducing negative consequences associated with drug use. Although those working in harm reduction believe that drug criminalization maximizes harm, the focus of most harm reduction policy and practice is in the borderlands between legalization and prohibition. To quote an old social justice slogan, harm reduction is the art of "building a new society in the vacant lots of the old." And those lots are filling up, due to the hard work of people around the world. Here are 10 of the most important harm reduction developments in North America in 2013:

1. "Needle Exchange" in the US Turns 25

A quarter of a century ago, public health activists started doing needle exchange in Tacoma, WA, San Francisco, CA, and New York, NY. These efforts, now referred to as 'syringe access programs', spread and continued and have been widely recognized as the single most successful HIV prevention intervention. To date, however, they are legally excluded from receiving access to the federal funding enjoyed by all other HIV prevention efforts. Perhaps in 2014, we can report that the federal funding ban for syringe access programs was finally lifted for good.

2. States Decriminalize Syringes to Increase Safe Syringe Access

Syringe access policy varies by state, and this year, community organizing led the Nevada legislature to finally pave the way for syringe access programs and over the counter pharmacy sales by fully decriminalizing syringes, making it one of the strongest state enabling laws for syringe access programming. North Carolina partially decriminalized syringes to protect law enforcement from needlestick injury, but without legalizing their existing syringe access programs, yet.

3. Laws Passed in Six States to End Overdose Epidemic by Providing Antidote

Opioid overdose has surpassed auto accidents as the leading cause of accidental death in the US. New laws were passed this year in six states to encourage health care providers and community programs to widely distribute naloxone to treat opioid overdose incidents. Additionally, new programs started providing naloxone access in Colorado, Vermont, North Carolina, Kentucky, Ohio, New Jersey, Minnesota, and Missouri this year. Naloxone is used in opioid overdoses to counteract life-threatening depression of the central nervous system and respiratory system, allowing an overdosing person to breathe normally. Although traditionally administered by emergency response personnel, naloxone can be administered by minimally trained laypeople, which makes it ideal for treating overdose in people who have been prescribed opioid pain medication and in people who use heroin and other illicit opioids.

4. Opioid Overdose Antidote Provided by Rhode Island Walgreens Pharmacists Directly to Patients

2013 saw a statewide scale up of a collaborative pharmacy practice agreement for naloxone, bringing naloxone to all 26 Walgreens stores in Rhode Island and training 80 Walgreens pharmacists in how to counsel patients on, train in, and dispense naloxone (without a prescription) to anyone who asks for it.

5. Federal Agencies Declare Support for Peer-Delivered Naloxone Distribution

Under the Bush Administration, officials in the Office of National Drug Control Policy (ONDCP) opposed peer-delivered naloxone. Then Deputy Director Bertha Madras said drug users "aren't likely to be competent to deal with an overdose emergency", and stated that "rescue programs might take away the drug user's motivation to get into detoxification and drug treatment". Obama's White House Office of National Drug Control Policy takes a position 180 degrees from Madras, supports overdose prevention and naloxone programs, and included them in the 2013 Drug Control Strategy. Also this year, the drug treament agency of the federal government, the Substance Abuse and Mental Health Services Administration (SAMHSA) published their long-awaited "Opioid Overdose Prevention Toolkit" which has five components targeting first responders, community members, patients, prescribers, and overdose survivors and their family members. The toolkit provides information on naloxone distribution and prescription and overdose prevention. Peer-delivered naloxone distribution has definitely gone from an underground movement to a mainstream-supported strategy in 2013. Next year, perhaps we can report some funding for this critical yet unfunded lifesaver.

6. Jail-Based Overdose Prevention and Naloxone Distribution Begins

Opiate overdoses are all too common among people released from jail due to decreased tolerance. In March 2013, the Harm Reduction Coalition's Drug Overdose Prevention and Education (DOPE) Project began providing naloxone to inmates of the San Francisco County Jail as they were discharged. The DOPE Project, in collaboration with SFDPH's Jail Health Services, conducts overdose prevention trainings inside the jail, and is able to put naloxone kits in the property of inmates who choose to participate for pick up when they are released. This is the first non-research study in the country to begin providing naloxone directly to inmates as they re-enter the community.

7. Good Samaritan Laws for People Witnessing Overdoses Gain Traction, Law Enforcement Support

Community activists have been working to get Good Samaritan laws passed to protect people from arrest and prosecution for drug possession when they call 911 to report an overdose. Fourteen states have now enacted these laws, as have ninety college campuses. The Florida effort in 2012 was notably initiated by Palm Beach police, a harbinger of change in law enforcement support for harm reduction measures.

8. Newly-Approved Hepatitis C Treatments Move Closer to Making Interferon-Free Cure a Reality for People Who Inject Drugs.

Hepatitis C remains endemic among people who inject drugs, with chronic infection rates of 70% or more among long-term injectors. While new infections have declined dramatically since peaking in the 1980s, due in part to the expansion of syringe access programs, several states report a new wave of hepatitis C infections among younger injectors. While hepatitis C is curable, treatment has traditionally required use of interferon, a drug with significant psychological and physical side effects that does not work for everyone and is difficult to tolerate for many, particularly current and former substance users. In December, the US Food and Drug Administration (FDA) approved a new hepatitis C medication sofosbuvir (Sovaldi, Gilead Sciences, Inc), which can be used without interferon for some people. Other therapies in development offer hope that all people with hepatitis C will have interferon-free treatment options available by the end of 2014.

9. Community Organizes to Mandate Hepatitis C Testing in New York

An estimated 3-4 million people are infected with the hepatitis C virus, and three quarters of them are unaware of it. Baby boomers - those born between 1945 and 1965 - make up over 70% of people with chronic infection, and are at highest risk of liver complications. Following CDC's 2012 recommendation of a one-time hepatitis C test for all baby boomers, a coalition of harm reduction workers, people who use drugs, and other allies passed a bill in New York mandating that doctors inform their patients and offer a hepatitis C test. As better-tolerated treatments with high cure rates become available, this legislation ensures that thousands of lives that may have been lost to liver cancer and other hepatitis C complications are diagnosed and treated.

10. Montreal Approved to Open Four Supervised Injection Sites

There are approximately 90 supervised injection sites worldwide in Europe and Australia, and only one in North America: InSite in Vancouver, British Columbia. After InSite's long legal fight with their conservative government, Canada's Supreme Court ruled in 2009 that the potential denial of health services and the correlative increase in the risk of death and disease to injection drug users outweigh any benefit that might be derived from maintaining an absolute prohibition on possession of illegal drugs on InSite's premises, allowing the facility to stay open indefinitely. In 2009, the site recorded 276,178 visits (an average of 702 visits per day) by 5,447 unique users; 484 overdoses occurred with no fatalities, due to intervention by medical staff. This month, Montreal was given permission to open four injection sites of their own, ensuring that Vancouver's InSite is the first but not the last legal supervised injection site in North America. Perhaps we finally succeed in opening one in the US in 2014.

Hilary McQuie is Regional Director of the Harm Reduction Coalition, and is based in Oakland, CA http://harmreduction.org/

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Killing Pain: Tramadol the 'Safe' Drug of Abuse

Published: Dec 22, 2013

By John Fauber, Reporter, Milwaukee Journal Sentinel/ MedPage Today

For years following spine surgery, Anthony Fort suffered.

And like many with his condition, the 46-year-old gospel singer and former construction worker used a combination of medications to alleviate his pain.

But as he took more drugs, including narcotic painkillers, Fort was often groggy when awake. When he slept, he gurgled and snored so loudly that his fiancee recorded it so she could convince him he was using too much medication.

On May 18, 2011, he didn't wake up.

According to the Milwaukee County Medical Examiner Office he died of an accidental overdose of opioids.

Tramadol, a "Safe" Pain-Killer

Included in the mix were drugs well-known for their abuse and overdose potential -- hydrocodone and methadone -- and one that the medical world long had thought posed little threat: tramadol.

But doctors -- and the FDA, the agency charged with regulating drug safety -- may have gotten it wrong.

Recent research shows that tramadol has greater potential to be abused and to cause overdoses than was believed when it first appeared on the U.S. market in 1995.

A Journal Sentinel/MedPage Today investigation found that the FDA failed to heed a key piece of research indicating tramadol had the potential to be abused. Instead, the agency recommended not putting tramadol under the Controlled Substance Act. Restrictions on prescribing it are no more stringent than for Lipitor or Viagra.

The Controlled Substance Act places drugs into five progressively restrictive categories based on their abuse potential. At the top of the list are drugs such as heroin. At the other, are some cough medicines with limited amounts of codeine.

In approving tramadol, the FDA decision was based largely on research in which the drug was injected. The FDA also weighed evidence from Europe, where tramadol had been on the market for years.

But the FDA also had research showing that when given to opioid abusers orally in high doses, rather than being injected, it produced opiate-like effects that were similar to oxycodone, the narcotic in OxyContin, one of the most abused drugs in America.

The FDA did ask Ortho-McNeil, the company that marketed the tramadol, to fund a committee of paid consultants who were to watch for abuse problems that might require making it a controlled substance.

That never happened.

Emerging Danger

Now, after 18 years of less restrictive treatment, the U.S. Drug Enforcement Administration has proposed putting tramadol under the Controlled Substances Act. While that has not been done on the federal level, 10 states already have done so on their own.

An analysis by the Journal Sentinel and MedPage Today revealed that tramadol use has increased dramatically since 2008, rising from 25 million prescriptions that year to nearly 40 million in 2012, according to data from IMS Health, a market research firm.

In 2011, the drug was linked to 20,000 emergency department visits around the country.

In Florida alone, there were 379 overdose deaths involving tramadol in 2011, up from 106 in 2003.

In Milwaukee County, 20 people died of a drug overdose involving tramadol from 2010 through October 2013, according to records from the Medical Examiner's Office. In most of those cases, tramadol was one of several opioids that had been taken.

In May of 2011, Fort was found in bed not breathing by his fiancee, Latrice Wells Odom.

She said Fort started taking tramadol about 9 months before he died.

"I said, 'I don't like what it's doing to you,'" she said. "He said, 'Baby, I'm in so much pain.'"

Fort had been taking narcotic painkillers after injuring his back at a construction site several years earlier, Wells Odom said. A beam fell on his back, leading to surgery and the placement of 10 screws and a rod in his spine.

She said he never thought the tramadol might be dangerous.

"Tony's thing was, the doctor gave it to him so it must be safe," she said.

Tramadol was first introduced in Germany in 1977.

Evidence Overlooked

Data from Germany had suggested it was only about one-tenth as potent as morphine when injected. Other data showed that after years of use in Germany and other countries there was very little abuse of the drug.

However, in the early 1990s, researchers at Johns Hopkins University did a study in which high doses of the drug were given orally to opioid abusers. Taken that way, tramadol acted much differently than when injected.

At very high doses it produced opiate-like effects that were similar to high-dose oxycodone.

Taken by mouth, the drug is transformed in the liver to a metabolite known as M1, which is able to attach to and activate opioid receptors in the brain. It is that substance that is believed to produce the desirable, opiate-like effect.

In 1994, Ortho-McNeil, part of the R.W. Johnson Pharmaceutical Research Institute of Johnson & Johnson, sought approval from the FDA to sell Ultram, its brand name version of the drug in the U.S.

The Johns Hopkins study never was published but the company said it was provided to the FDA when it was reviewing the approval for tramadol.

"That paper certainly was accurate," said Thomas Kosten, MD, an addiction specialist and professor of psychiatry at Baylor College of Medicine. "You take enough of it, you can get high from it."

Sharon Walsh, PhD, an opioid researcher at the University of Kentucky College of Medicine, said the research provided important evidence that tramadol had the potential to be abused.

Given the findings of the Hopkins study, it is unlikely the FDA would approve tramadol today as a nonscheduled drug, said Walsh, director of the university's Center for Drug and Alcohol Research.

But in the early 1990s, when the FDA approved the drug, abuse of opioids such as heroin and morphine often was done by addicts who injected the drugs. In the years that followed, dramatic increases in abuse of pill-form opioids such as OxyContin and Vicodin would plague the country.

Following the Money

Journal Sentinel/MedPage Todayinvestigations have showed that opioid companies paid millions of dollars to doctors and nonprofit medical societies that pushed for more liberal use of the drugs in treating chronic, noncancer pain. Yet, rigorous studies never have shown that the drugs are safe and effective when used that way.

Morgan Liscinsky, a spokeswoman for the FDA, said she could not comment on the agency's decision-making process that led to the drug's approval as a noncontrolled substance. As tramadol's public health and abuse risks became more fully recognized, the FDA now has recommended making it a controlled substance, she said.

Liscinsky noted that, at the time, the FDA's advisory committee unanimously said the drug should not be put under the Controlled Substances Act.

Yet there was concern that abuse of the drug might occur in the U.S., which was why the FDA asked an "independent steering committee," to monitor the drug as part of the FDA's marketing approval. Ortho-McNeil paid for the committee's work and also paid consulting fees to its members.

Sidney Schnoll, MD, PhD, a former member of the committee, said he could not remember how much the committee members were paid. In total, the program cost Ortho-McNeil about $15 million a year, said Schnoll, now an executive with Pinney Associates, a Bethesda, Md. company that works with drug and opioid companies.

From early on, Ortho-McNeil's marketing plan for tramadol meant keeping it off the controlled substances list where it would have difficulty competing against other narcotic painkillers such as Tylenol 3 and Tylenol 4, Schnoll said in a 2009 interview. Both Tylenol products contain codeine and are schedule 3 drugs.

The interview was done with two professors, one from the University of Florida and one from Rensselaer Polytechnic Institute in New York, as part of a project at University of Michigan Substance Abuse Center.

"There were equally good products that were cheaper on the market," he said, according to a transcript of the interview. "So they really wouldn't have much of the market. They wanted to see if it would be possible to get the drug onto the market as a noncontrolled substance."

After a decade, the eight-member Ortho-McNeil committee dissolved itself in December 2005, without ever having recommended that tramadol be put under the Controlled Substances Act.

"There was absolutely nothing independent about this group," said Andrew Kolodny, MD, a New York addiction specialist and advocate of tighter controls on opioids.

In an email, Pam Van Houten, a spokeswoman for Johnson & Johnson, said no one from the company was on the committee and only committee members were allowed to attend its deliberations and monthly meetings. Van Houten did, however, add that there were occasional circumstances when company officials were invited to committee meetings.

Moreover, Van Houten said the committee's funding always was disclosed.

Tramadol "Trending"

Walsh, the University of Kentucky researcher, and others have done their own studies on oral tramadol showing that experienced opioid abusers like it as much or more than oxycodone.

In a 2012 study, they gave up to 400 mg of tramadol, about four times the normal single dose, and oxycodone to nine opioid abusers.

On the next day, the test subjects sat at a computer. They were told they would be given the drugs again in increments if they clicked a mouse to earn it. The mouse clicking progressively increased for each additional increment of the drug. To get all the drug, they would have to click the mouse 7,800 times.

Five of the nine test subjects clicked the mouse at least 5,300 times to get the high-dose tramadol, compared with only one who did so to get the high-dose oxycodone.

"That was really surprising to us," said lead author Shanna Babalonis, PhD, an assistant professor of behavioral science at the University of Kentucky.

The likability of oral tramadol can be seen in the large numbers of people who have used it recreationally.

In 2011, 2.6 million people ages 12 and older used tramadol for nonmedical purposes, according to the DEA. The DEA said the drug is most commonly abused by addicts, chronic pain patients, and health professionals.

Over the years, there had been indications that the drug was being abused, but Ortho-McNeil has fought efforts to make tramadol a controlled substance.

In 2006, the company argued that by making it a controlled substance, doctors would be less likely to prescribe it for chronic pain. It cited concerns about the stigma attached to opioids and what it called "opiophobia." The comments were made in a document filed with the FDA in response to an inquiry by the World Health Organization over whether tramadol should become a scheduled narcotic internationally.

Van Houten, the company spokesperson, said the company is reviewing the DEA's proposal to put tramadol under the Controlled Substances Act.

She said the company no longer actively promotes its tramadol product, Ultram, in the U.S.

"Tramadol has been and remains an important medicine used to treat moderate to moderately severe pain in adults," Van Houten said.

DEA Petitions

In 2005, the DEA received four petitions to put tramadol under the Controlled Substances Act in the U.S., three that asked that it be a schedule 3 drug.

Last month, the DEA recommended that it be put under schedule 4 of the act.

Similar concerns about tramadol abuse and overdoses have been raised recently in Great Britain.

In February, the country's Advisory Council on the Misuse of Drugs noted that deaths in which tramadol was mentioned on the death certificate nearly doubled between 2008 and 2011. Prescriptions for tramadol in England also increased from 5.9 million in 2005 in 11.1 million in 2012.

The council recommended that tramadol become a scheduled drug, which would make it a crime to use it or deal it without a prescription. It also said doctors should be given training regarding the drug's possible misuse by patients and the serious complications it can cause.

In the U.S., those who most often prescribe are likely to be on the front line of medicine.

A MedPage Today/Milwaukee Journal Sentinel analysis of IMS Health prescription data shows that over the last 2 years, the top prescribers of tramadol have been family practice doctors, internal medicine physicians, osteopaths, nurse practitioners, and physicians assistants.

More than two-thirds of tramadol prescriptions from 2012 through October, 2013 were written by those health professionals.

Walsh, the University of Kentucky opioid researcher, said she believes that many doctors who prescribe tramadol take their direction from whether a drug is a scheduled narcotic.

"I suspect they don't know about its abuse potential," she said.

Two years after Anthony Fort's death, his former fiancee still has the recording of his loud snoring and gurgling that she made on the day he died.

She was going to play it back to him later in hopes that it would make him realize that the medications he was taking were affecting his sleeping.

After making the recording, she went to the store. She said she only was gone about a half hour.

"I wanted him to listen to it because it scared me," she said. "But it was too late."

Source

"Co-infections and HIV beget each other": Dr Dilip Mathai

Sun, 2013-12-22 08:35 — editor

By Shobha Shukla, Citizen News Service – CNS

HIV in today's context is a chronic condition of the human immune system. HIV is a retrovirus and the infection leads to a progressive reduction in the number of CD4+ T-helper cells (so called because CD4 glycoprotein is found on their surface) which are an essential part of the human immune system. They are the main targets of HIV which destroys infected CD4 cells leading to an overall weakening of the immune system, said Dr Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research, and former Head of Medicine Department, Christian Medical College (CMC), Vellore.Professor (Dr) Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research

Dr Mathai was speaking with Citizen News Service (CNS) at 6th National Conference of AIDS Society of India (ASICON 2013). Dr Mathai added: Normal values for CD4 cells are 500-1200 cells/mm3. When CD4 cells become depleted, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight. Lower numbers of circulating CD4+ T-cells indicate a weakening of the immune system and advancement in the progression of HIV disease.

The goal of anti-retroviral therapy (ART) in HIV is to bring down the viral load and increase the CD4 cell count so that the body reconstitutes its immune system AND increases the CD4 count to a manageable level of 500 and more.

Co-infections and HIV beget each other. As the HIV infection progresses, it interferes more and more with the immune system, making the affect person more prone to contract infections, including opportunistic infections (OIs) that do not usually affect people who have strong immune systems. Co-infections like hepatitis B, hepatitis C, TB and pneumonia, among others, can cause a transient increase (which is called a blip) in the viral load and decrease the CD4 cell count, thus lowering the body’s ability to kill the co-infecting bacteria or virus. This can perpetuate other infections. For example, cure of TB depends both on drugs and the body’s defence mechanism to annihilate the TB bacilli. But if the CD4 count is very low and the viral load increases then the body defence against TB is not so good. The anti TB drugs help in decreasing the total number of TB bacilli, but to annihilate them completely requires the body’s defence mechanism for the drugs to penetrate the cells where the bacilli are. No wonder then that a lot many people living with HIV (PLHIV) die of TB and not of HIV.

In PLHIV there is not only the danger of acquiring co-infections but also the problem of eliminating them. HIV may be controlled through ART but co-infections can damage the body organs. Every co-infection (including HIV) has an effect on inflammation. This inflammation can take its toll of the blood vessels and affect the heart as coronary artery disease is the product of an inflammation. Another problem with co-infections is that some of them may not be systemic like cytomegalia virus of the eye, lung or bone marrow, and can damage the affected organ. In fact, for PLHIV, Hepatitis C and/or TB can be more worrisome for survival than even HIV. Then again diseases that can suddenly flare up, like chicken pox, can disseminate and be fatal in those who are immune compromised, like PLHIV. In a normal competent host chances of dissemination are very low. There can also be co-morbidities like diabetes, stroke, and renal problems as HIV can affect the heart, the kidney, and have secondary effect on the bones.

Thus there is a wide spectrum of diseases and issues to be dealt with for prevention, treatment, and management of HIV—TB and HIV, Hepatitis C/B and HIV, liver disease and HIV, kidney disease and HIV, nutrition and HIV, heart disease and HIV, to name a few. Doctors and other healthcare personnel need to be trained and also kept updated so that they are competent enough to handle their HIV patients well and not let them die of HIV related OIs. So a multi-disciplinary approach is needed—general physicians, specialists, paediatricians, gynaecologists, nurses, psychologists-- all holding hands and working together to ensure that PLHIV have the same quality of life as any other person.

Detecting and diagnosing new cases, enrolling them into care/treatment, retaining them in care and making them adhere to therapy and behavioural change-- all are equally important in controlling the HIV pandemic. There is no point in diagnosing if one cannot treat them; there is no point in holding them in care if they are not willing to be engaged to reach out to the others. We have to reach out to all, especially the young and other vulnerable populations, educating them about the hazards of unsafe sex which increases risk of HIV and other sexually transmitted diseases. In the absence of a cure, the disease will continue to be transmitted if people do not change their risk seeking behaviour like chemical dependence, unsafe sex, injecting drug use, among others.

(This article is based upon a CNS interview with Professor (Dr) Dilip Mathai, Dean, Apollo Institute of Medical Sciences and Research)

- Asian Tribune -

Source

Hep C and Happy Holidays!

December 20, 2013
by Opiferum

Having hepatitis C at this time of the year is not easy. Christmas and New Year’s is typically fuelled by an indulgence of rich foods high in fat, not to mention drenched in alcohol. But the holiday period is also seen as a time during which people get together and celebrate a Hallmark perfect life. No wonder there is yet a card that reads “Merry Christmas” with a picture of someone sitting by the fire-side self-injecting a weekly dose of pegylated interferon. Having to deal with living with the hepatitis C virus is hard enough without the extra burden and stress that Christmas brings. More than any other time of the year, this is when people affected by the hepatitis C are likely to feel the crippling effects of discrimination and isolation. This is because there are some families that simply refuse to have their hepatitis C positive loved one at the Christmas dinner table. So, what can you do to get through the holidays with hep C?

Firstly, be aware of your self-talk. This is a time of year when it is easy to fall into negative-self talk. Factors such as feeling isolated or not measuring up to those picture perfect images on Christmas cards certainly contribute to this. Therefore ask yourself, What is my attitude towards this time of year? It is perfectly ok to acknowledge your feelings about Christmas. There are no “right” or “wrong” feelings to have about Christmas, either. However, if you are drowning in negative self-talk, then maybe it is having a disempowering effect on you that might be causing more stress than is necessary. Instead of using words like “don’t” and “won’t”, for example, try to re-word your phrases to exclude these kinds of negative words. Instead of telling yourself, “I don’t like Christmas at all,” exchange it for a different kind of self-talk, like “Christmas is just another time of the year; I will look for something to like about it no matter how difficult.” It might be as simple as appreciating Christmas lights in the neighbourhood, to feeling a heightened sense of gratitude for the fact you can empathise for those that are in the same position as you.

Be careful of what you eat and drink. At this time of year, there is a universal tendency to overindulge in fatty foods and alcohol. This is because rich food and drinking are all associated with the act of celebrating. Trying to excuse one’s self from not over indulging is difficult, unless you are the sort of person that is lucky enough to be surrounded by people that are aware of the importance diet plays for those living with hepatitis C. If you feel pressure to celebrate Christmas by eating and drinking too much, then prepare for this by bringing your own stash of non-alcoholic beverages for you to have at the dinner table. Another way to help your liver get through the Christmas menu is by requesting smaller portions, or even excusing yourself as a vegetarian. There are plenty of creative ways to get around having to eat too much, or over imbibing in the traditional Christmas drink.

If you are on treatment… It is difficult enough to live with the unpleasant side-effects associated with interferon and ribavirin, but having to deal with the extra stress this time of year brings is another thing altogether. If you are on treatment, then make sure you have enough medication to get you through the holiday period. Know exactly when your next doctor’s appointment is, so that you do not have to stress about when it might be. Having people around you that understand your situation is ideal, even though not necessarily the case for everyone. If you are feeling anxious about getting through the holiday period, then consult your local community centre or hepatitis council for the names of support groups that might be able to make a difference. There is someone out there that will listen to your needs, even if it is just by making a post to an on-line support group.

If you are not on treatment… A lot of people have put off undergoing treatment for hepatitis C because of the well-known harsh side-effects associated with interferon and ribavirin. However, we are entering a new age of therapy for hepatitis C that are not only proving to show incredibly high rates of success, but with side-effects easier to manage. As well, new treatments for hepatitis C are showing to be very effective with previously harder to treat genotypes (namely 1). Where medical treatment is fully subsidised by the Government (i.e. Australia and New Zealand) then be sure to enrol yourself at the local liver clinic (usually a part of the gastroenterology or infectious diseases department of a hospital). Wherever you are, make the most of the clinical services that are available to you. Get in sooner, as this will not only benefit your liver in the long run, but also secure your right to treatment in the future.

Christmas and New Year are both calendar events that are here to stay. The best form of self-care is awareness and prevention. Stay on top of the silly season by laughing it off, or looking for other safe and healthy things to do. Taking care of both your mental and physical health might be more challenging at this time of the year, but with the right attitude, you can do it. May you all manage the testing time ahead without forgetting to look after your liver.

Wishing you all a very hepatitis C friendly Christmas and New Year,

Opi.

Hepatitis C Transmission Confirmed in a Dental Setting

by Mary Govoni, CDA, RDA, RDH, MBA

In September, the Centers for Disease Control and Prevention confirmed that the first patient-to-patient transmission of hepatitis C occurred in a dental setting in the U.S. This transmission occurred in the oral surgery practice in Tulsa that was the subject of intense media publicity earlier this year.

Although the CDC was able to match the viruses of two of the patients through genetic testing, they may never be able to determine how the transmission took place. The suspected routes of transmission are improperly sterilized instruments and the use of unsterile needles in multiple dose medication vials. The good news is that there have not been any previously reported cases in dentistry. The bad news is that this occurred.

Once again this news prompts the need to make sure that everything we do to protect our patients is in line with the CDC Guidelines for Infection Control in Dental Health Care Settings. While the majority of practices that I interact with are clear on what must be heat sterilized, there is less clarity about verifying the sterilization process and the importance of quality control protocols in instrument sterilization.

The first of the quality control measures is the recommendation for packaging of instruments prior to sterilization to ensure sterility of the instruments until the point of use. This includes extra instruments that are stored in drawers or cabinets in the treatment rooms and includes orthodontic instruments. The second is the recommendation for using a process indicator in the instrument packages. This measures the parameters for sterilization – time, temperature, and pressure (steam penetration).

Although most sterilization pouches have indicators incorporated into the pouch, they typically measure only one or two of the parameters – time and temperature. In addition, there are indicator strips that can be placed inside instrument packs or cassettes. It is important to note that autoclave tape, which is used to seal packages and cassettes, is a single parameter indicator – temperature only.

There is one pouch, the Sure-Check Pouch from Crosstex, that is cleared by the FDA as a Class IV indicator. This pouch measures two or more of the criteria for sterilization. An indicator strip that is also cleared by the FDA as a Class V integrator is the Steam Sterilization Integrator Strip from Hu-Friedy. This strip measures all of the criteria – time, temperature, and steam penetration.

These indicators are used to make sure that the instrument packs in each sterilizer load have been exposed to the right parameters for sterilization. If the indicator shows a "failure," the instruments must be repackaged and reprocessed.

Many times it is the instruments in the center of the load that are not sterilized, due to overloading of the sterilizer and the inability of the steam to penetrate into the packages. Without the use of sterilization indicators, there is no way to know which instrument packs are at risk.

These indicators are an additional measure to protect patients, but are not a substitute for weekly monitoring of the sterilizer with a biological indicator or spore test. There are a number of in-office monitoring systems such as Attest from 3M, ConFirm from Crosstex, and SporeCheck from Hu-Friedy.

In addition, there are third-party monitoring services including many that are affiliated with dental schools and dental suppliers, as well as companies such as ConFirm, The Dental Advisor, North Bay Bioscience, and others. The dental practice should keep records of the results of these tests. If a sterilizer fails a spore test, that sterilizer must be taken out of service until the reason for the failure is determined and corrected.

Following appropriate guidelines and protocols for sterilization will not only minimize the risk of a patient-to-patient transmission of a bloodborne infectious disease such as hepatitis C; it will go a long way in reassuring patients that it is safe to go to the dentist.

Mary Govoni, CDA, RDA, RDH, MBA, is the owner of Mary Govoni & Associates, a consulting company based in Michigan. She is a member of the Organization for Safety, Asepsis and Prevention. She can be contacted at mary@marygovoni.com or www.marygovoni.com.

Source

'Serial Infector' Gets 39 Years Linked to Hepatitis C Outbreak

12/20/13

Kwiatkowsi's Victims

In addition to one patient whose death was linked to the hepatitis C infection, other individuals infected with Kwiatkowski’s strain of hepatitis C included:

- A Marine veteran over the age of 50 who, as a result of his infection, has experienced pain, sleeping and weight loss problems, and trouble controlling his diabetes. He has also been unable to travel, something he used to do extensively for his job.

- A male over the age of 70 who has substantial health problems, had to have major surgery, and whose health continues to deteriorate.

- A Navy veteran over the age of 80 with serious health problems, including severe fatigue. He is so fearful of transmitting the hepatitis C virus that he won’t kiss his wife.

- A retiree over the age of 60 who has experienced fatigue and so much stress that she has had to seek counseling.

- An Army veteran over the age of 40 who suffers from fatigue, body aches, loss of appetite, and emotional issues.

- A male over the age of 50 whose health issues are so severe he has been unable to return to work.

The vast majority of health care professionals are dedicated individuals committed to their patients. But in a recent investigation, we came across a hospital worker who was more committed to his own selfish needs than to his patients—he knowingly put patients at risk of exposure to the hepatitis C virus so he could steal and abuse a powerful narcotic prescribed for use during medical procedures.

David Kwiatkowski—who pled guilty to a scheme to divert and obtain the controlled substance fentanyl as well as to product tampering, was sentenced earlier this month to 39 years in prison. Because of Kwiatowski’s actions, at least 45 people became infected with hepatitis C, a virus that attacks the liver and may cause liver damage, liver failure, or cancer. At least one patient died as a result of the infection.

You see, Kwiatkowski himself was infected with hepatitis C. And he admitted that while employed at a New Hampshire hospital and at hospitals in several other states, he stole syringes of fentanyl prepared for patients about to undergo medical procedures, injected himself with the drug, and refilled those same syringes with saline—tainting them with his hepatitis C-positive blood—for use on unsuspecting victims. As a trained health care worker, Kwiatkowski would have known that hepatitis C, a blood-borne viral disease, is primarily transmitted by exposure to infected blood.

How the case began. In May 2012, the New Hampshire Department of Health and Human Services began a public health investigation after it was notified by an area hospital of four patients newly diagnosed with hepatitis C. Three of the individuals had been patients in the hospital’s Cardiac Catheterization Laboratory (CCL), while the fourth was a CCL employee (Kwiatkowski). Although Kwiatkowski led the hospital to believe he had been previously unaware of his hepatitis C status, the investigation showed that he had known of his infection since at least 2010.

Testing confirmed that all four shared a genetically similar virus, indicating a common source of infection. Because Kwiatkowski had previously worked as a traveling technician in multiple hospitals in several states, the information about his activities was shared with those states, which began their own reviews.

The federal Centers for Disease Control and Prevention (CDC) coordinated the overall public health investigation, which ruled out other possible methods of transmission and suspected that a drug diversion scheme was the source of the outbreak. During their investigation, public health authorities recommended that more than 12,000 people who may have crossed paths with Kwiatkowski in various hospitals get tested for possible hepatitis C infection.

In June 2012, the FBI’s Boston Office opened a full criminal investigation into the outbreak…and into Kwiatkowsi. The investigation involved several search warrants and included a search of Kwiatkowski’s vehicle that uncovered needles and syringes. Working with public health agencies along with other federal, state, and local law enforcement partners, we gathered evidence and interviewed dozens of people who either worked with Kwiatkowski or were patients at hospitals that employed him. By July 2012, we were able to arrest him.

According to New Hampshire U.S. Attorney John Kacavas, the 39-year sentence imposed on Kwiatkowski “ensures that this serial infector will no longer be in a position to harm innocent and vulnerable people, extinguishing once and for all the pernicious threat he posed to public health and safety.”

Resource:
- Press release

Source -  Federal Bureau of Investigation

Predicting Survival after Liver Transplantation Based on Pre-Transplant MELD Score: a Systematic Review of the Literature

PLOS One

RESEARCH ARTICLE

Kristin B. Klein, Taenia D. Stafinski, Devidas Menon

Published: December 12, 2013 DOI: 10.1371/journal.pone.0080661

Abstract

The model for end-stage liver disease (MELD) score is used to stratify candidates for liver transplantation based on objective measures of disease severity. MELD has been validated as a predictor of wait-list mortality in transplantation candidates and has been postulated as a predictor of post-transplant survival. The purpose of this study was to examine the predictive value of the pre-transplantation MELD score on post-transplant survival from relevant existing studies. A systematic review and critical appraisal was performed using Cochrane guidelines. PubMed, the Cochrane Library, Embase, and Web of Science were searched for articles published in the English language since 2005 using a structured search strategy. There were 3058 discrete citations identified and screened for possible inclusion. Any study examining the relationship between pre-transplant MELD and post-transplant survival in the general transplant population was included. Thirty-seven studies met these criteria and were included in the review. Studies were all case series that typically involved stratified analyses of survival by MELD. They represented 15 countries and a total of 53,691 patients. There was significant clinical heterogeneity in patient populations across studies, which precluded performance of a meta-analysis. In 15 studies, no statistically significant association between MELD and post-transplant survival was found. In the remaining 22, some association was found. Eleven studies also measured predictive ability with c-statistics. Values were below 0.7 in all but two studies, suggesting poor predictive value. In summary, while the majority of studies reported an association between pre-transplantation MELD score and post-transplant survival, they represented a low level of evidence. Therefore, their findings should be interpreted conservatively.

Citation: Klein KB, Stafinski TD, Menon D (2013) Predicting Survival after Liver Transplantation Based on Pre-Transplant MELD Score: a Systematic Review of the Literature. PLoS ONE 8(12): e80661. doi:10.1371/journal.pone.0080661

Editor: Evren Alici, Karolinska Institutet, Sweden

Received: May 9, 2013; Accepted: October 5, 2013; Published: December 12, 2013

Copyright: © 2013 Klein et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Kristin Klein receives funding from the Clinical Investigators program at the University of Alberta. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist

Introduction

The identification of patients who are most likely to benefit from orthotopic liver transplantation (OLT) is a significant challenge in transplantation medicine. Liver transplantation offers the only curative therapy for patients with end-stage liver disease (ESLD). However, the supply of donor livers remains inadequate to meet the demand, necessitating an effective policy for organ allocation. In order to minimize waitlist mortality, a Model for End-Stage Liver Disease (MELD) - based organ allocation was proposed. First adopted by the United States in February 2002, it has become one of the most widely used approaches to prioritizing liver transplant candidates in countries around the world. The MELD score was initially developed by Malinchoc et al [1] to predict mortality in patients undergoing transjugular intrahepatic portosystemic shunts, but has since been validated as predictor of short-term mortality in patients awaiting transplantation. It uses objective variables (creatinine, bilirubin and the international normalized ratio of prothrombin time (PTINR)) to quantify the severity of ESLD, enabling the prioritization of patients in need of liver transplantation by medical urgency. An ideal system would allocate organs to patients not only at the highest risk of dying without transplantation, but also with the highest likelihood of survival following transplantation.

In recent years, the possibility of using pre-transplant MELD to predict post-transplant survival has been explored in many opinion pieces and expert reviews[2]. However, it has yet to be assessed through a systematic review and critical appraisal of published studies that adheres to internationally accepted systematic review guidelines. The need for such a review is heightened by the lack and infeasibility of RCTs on this topic and the fact that considerable debate over the value of MELD in this context remains. Thus, the aim of this study was to assess the association and predictive value of pre-transplantation MELD score on post-transplantation patient survival through a comprehensive, protocol driven systematic review of studies published to date.

Methods

Identification of potentially relevant studies

To identify relevant studies published as of August 2011, a structured search strategy combining relevant controlled vocabulary terms such as Medical Subject Headings (MeSH) and additional non-indexed terms was first developed. Such terms included Model for End-Stage Liver Disease, MELD, liver transplantation, liver failure, and survival. The search strategy was applied to the following electronic bibliographic databases: PubMed (MEDLINE and non-MEDLINE), the Cochrane Library, EMBASE, and Web of Science; and limited to full text, English language studies of adult patients which were published within the past 10 years. For completeness, reference lists of relevant articles were scanned. Also, an internet search for unpublished studies was performed with the Google® search engine. Full search details are provided in Table A in File S1.

Selection of studies for inclusion in the review

Two researchers independently screened the titles and abstracts of citations identified through the literature search using predetermined inclusion criteria (Table 1). The initial search strategy identified studies published in the last ten years, whereas only studies published since 2005 were included in the review.

Parameter	Inclusion Criteria	Exclusion Criteria
General	Full-text articles published in the English language since 2005	Abstracts
Participants	Adults patients with liver failure	Patient populations not representing the general liver transplant population (ex: patients with HCC or HCV only)
Intervention	Patient’s first orthotopic, whole liver, deceased-donor transplant	Multi-organ transplants, non-standard donor or living donor transplants, split liver transplants, sequential transplants
Comparator	Pre-operative Model for end-stage liver disease score	Delta-Meld, MELD-Na, post-operative MELD score
Outcome	Post-transplantation patient survival	Survival rate not reported by MELD score
Study design	Cohort, cross sectional, RCT, quasi-RCT, or controlled studies	Case study or series, commentaries, and opinion pieces without primary data

Table 1. Inclusion/exclusion criteria for review.

Since the purpose of this study was to assess the predictive ability of MELD in the general transplant patient population, studies focussing on specific subgroups of patients were excluded, along with those involving only unique transplant conditions, such as multi-organ transplants, split livers, and non-standard donors. However, studies that considered these conditions within the context of the broader transplantation population were included in the review. Corresponding papers of citations deemed potentially relevant were then retrieved for full review. The level of consensus among reviewers was assessed using the Kappa Statistic. A score of 0.98 was achieved, indicating excellent agreement. Discrepancies among reviewers were resolved through discussion without the need for third party adjudication.

Extraction of data from included studies

Information from included studies was systematically extracted using a pre-tested data abstraction form. The abstraction form contained elements related to study design, patient population, comparators, outcomes measured, and findings. All studies were reviewed by the primary author, with a second reviewer extracting information on 50% of the studies. Reviewers subsequently met to compare results. No discrepancies were found. Therefore, a second, independent review of the remaining studies was deemed unnecessary.

Critical appraisal of included studies

Studies were appraised using the Oxford Center for Evidence-based Medicine Levels and Grades of Recommendation[3].

Data analysis and synthesis of results

Extracted data were tabulated to facilitate a comparison of findings across studies. A meta-analysis of pre-transplant MELD on post-transplant survival using a random effects model was also planned (see Results section). Prior to presenting pooled or summary estimates, clinical heterogeneity and statistical heterogeneity using the I² statistic were assessed.

Results

Results of the literature search are presented in the PRISMA diagram (Figure 1). The search yielded 3058 discrete citations. Forty-eight full-text articles were retrieved for full consideration, of which 37 met the inclusion/exclusion criteria of the review. Among excluded studies, 6 involved inappropriate comparators or outcomes, 4 did not present primary data, and 1 contained data already captured in an included study. The list of excluded studies, along with reasons for exclusion, is presented in Table B in File S1.

Figure 1. Literature search results and study selection for clinical review.

Description of included studies

The 37 studies comprised both prospective and retrospective case series, and collectively included a total of 53,691 patients. In most, the main objective was not to assess the relationship between MELD and post-transplant survival. Instead, studies examined a broad range of pre-transplant factors that may or may not influence survival through exploratory analyses. Studies originated from several countries, including: Belgium (2), New Zealand (1), the United Kingdom (3), Brazil (6), Spain (5), the United States (7), Singapore (1), Turkey (1), China (1), Korea (1), Switzerland (1), Poland (1), Italy (3), Canada (1), and Germany (3). The majority were single centered. Sample sizes ranged from 46 to 21,673 patients (mean = 1451, median = 222), most of whom were male. None used a power calculation to determine sample size. Sampling methods comprised consecutive patients who met inclusion/exclusion criteria, which differed considerably across studies. Therefore, patients comprising the “general transplant population” may have varied. The point at which MELD was measured in patients was inconsistent across studies, with some using time of placement on the transplant list and others using time of transplant. In most of the studies, the relationship between MELD and survival was examined through stratified analyses of survival across sub-groups defined by MELD score, where MELD cut-off points for sub-groups were determined post-hoc. Further, the majority(25) measured the association between MELD and survival based on univariate analyses alone, and, therefore, did not control for potential confounders. Eleven of the studies assessed the predictive ability of the MELD score on post-transplantation survival using a receiver operating characteristic (ROC) curve and the c-statistic. In 4 of the studies, there was partial overlap of patient populations since they included data from the Transplant Scientific Registry (Cywinski et al [4], Freeman et al [5], Rana et al [6] and Yoo & Thuluvath [7]). All of these studies were kept in the review as each used different MELD categories and follow-up times in their analysis. A detailed summary of each study is presented in Table C in File S1.

As mentioned above, the majority of studies grouped patients by MELD. Specifically, MELD, which represents a continuous variable, was converted to a categorical variable for the analyses. The cut-off points for such categories varied widely across studies and were typically determined post-hoc. (Refer to relevant outcome measures in Table C in File S1). Effect measures also differed, ranging from proportions to hazards ratios, odds ratios, and relative risks, and follow-up time periods were inconsistent. Lastly, characteristics of the “general transplant population” varied. Therefore, given such clinical heterogeneity across studies, a meta-analysis was deemed inappropriate, and a statistical assessment of heterogeneity was not performed.

Quality of included studies

Based on the Oxford Center for Evidence-based Medicine Levels of Evidence, the quality of all of the included studies was level IV. The studies, which involved a comparison of pre-transplant MELD scores with post-transplant survival, were all case series and predominantly retrospective in design. All studies recruited consecutive patients over a specified time period, thereby reducing the risk of selection bias.

Association between Pre-Transplant MELD Score and Post-Transplantation Survival

Of the 37 studies, 15 found no association between pre-transplant MELD score and post-transplant patient survival, while 22 reported poorer survival with higher MELD. A detailed description of the results of each study is presented in Table C in File S1. Based on qualitative analyses, there were no clear differences in studies with statistically significant findings compared to those with no statistically significant findings. In both groups, sample sizes varied, as did follow-up times. However, findings from the two largest studies (N >15,000) both suggested that survival decreased with increasing MELD. One observed this relationship only when patients with MELD scores under 9 were compared to those with scores of 30 or greater, while the other had treated MELD as a continuous variable. At the same time, of the 7 other studies that analysed MELD as a continuous variable, all but one found no statistically significant association between MELD and survival. In most of the studies, information presented on patient characteristics was limited. Therefore, it was not possible to identify any differences in patient populations that could explain inconsistencies in the findings.

Predictive ability of MELD score for post-transplantation survival

Eleven studies presented a receiver operating characteristic (ROC) curve to determine the predictive ability of pre-transplant MELD score to determine post-transplantation survival. The area under the curve is used to produce a concordance value called the c-statistic. A c-statistic of 0.50 indicates no predictive ability, and is expected if the results are due to chance alone. In contrast, a c-statistic of 1 represents perfect discrimination. Values under 0.7 suggest poor predictive power, while those greater than 0.70 indicate a useful test, and those higher than 0.80 imply excellent predictive accuracy[2]. Among the 11 studies, 10 reported c-statistics less than <0.7, indicating that MELD poorly predicted post-transplant survival. This included the largest study contributing to the review[6]. In 1 study, the c-statistic decreased over time, from 0.711 for 3-month post-transplant survival to 0.679 for 12-month survival[8]. In the single study with a high c-statistic[9], there was no clear difference in sample size, follow-up time, or patient population when compared to the studies with lower values.

Discussion

This review assessed the association and predictive ability of pre-transplantation MELD score on post-transplantation survival in adults with end-stage liver disease. It highlighted discrepancies in findings across studies. Such discrepancies may be related to the nature of the studies, The vast majority were retrospective case series that relied upon exploratory stratified analyses of data to detect a relationship between MELD and post-transplant survival. As such, analytical techniques, rather than study design, were used to control for confounding. In addition, most of the studies were single centered, with each site having its own process for prioritizing patients for transplant. Therefore, patients constituting the general transplant population may have varied across studies. Thus, while using pre-transplant MELD to predict post-transplant survival in transplant candidates may be attractive, there is little evidence to support it. Prospective studies designed specifically to examine this relationship are needed. MELD score does appear to have a greater impact on mortality when observed in combination with other known risk factors for post-transplant mortality, including sub-optimal livers, low graft-to-body ratio and presence of Hepatitis C. Further research in the area of particular patient subgroups (such as those with hepatitis C) may show a stronger association between MELD and post-transplant outcome.

Based on the studies conducted to date, which collectively represent a low level of evidence, MELD could be correlated with survival, but appears to have limited predictive ability. The vast majority of studies presenting concordance statistics found that pre-transplant MELD score offered minimal discriminating power for post-transplantation survival. However, the c-statistic may be of limited value in determining the predictive ability[10]. This is because the c-statistic is intended for diagnostic models, rather than prognostic models. The two types differ in that prognostic models add the element of time. Specifically, diagnostic models are designed to determine the current state of the patient and accurately identify an existing disease state. In contrast, prognostic models are designed to estimate the probability of a future state where the outcome is not yet known and subject to chance.

This review is limited by heterogeneity in key parameters of studies used to date, which precluded performance of a meta-analysis. Studies reported different comparators (in terms of MELD categories) and applied time-points for outcomes. Studies comparing standardized MELD categories would be beneficial in determining whether or not there is, in fact, a threshold level at which liver transplantation does not offer sufficient survival to warrant the use of scarce donor livers. A more accurate assessment of post-transplant survival would also need to look at other factors, such as quality of life. Research examining the combinations of patient factors using more appropriate statistical techniques may also be valuable in improving the predictive ability of pre-transplant elements on post-transplant outcome.

Conclusions

This study provides a comprehensive review of recent articles examining the relationship between pre-operative MELDS score and post-transplantation survival. Based on the results of studies conducted to date, it appears that the use of MELD does not serve as a reliable predictor of post-transplantation survival. This may be a reflection of a reliance on less than ideal analytical measures. However, the use of pre-transplant characteristics may always fall short of ensuring optimal organ allocation due to variability in immeasurable patient factors and the complexity of perioperative and postoperative conditions.

Supporting Information

Table A in File S1. Literature Search. Table B in File S1. Excluded Studies. Table C in File S1. Description of Included Studies [Download File S1, Checklist S1]

Acknowledgments

The authors would like to thank Leigh-Ann Topfer for assistance with the literature search, Mohamed El Shayeb for assistance with manuscript selection, and Andrea Dunn for assistance with data extraction.

Author Contributions

Conceived and designed the experiments: KK TS DM. Performed the experiments: KK TS. Analyzed the data: KK TS. Contributed reagents/materials/analysis tools: N/A. Wrote the manuscript: KK TS.

References

Source

Transplant vs resection for the management of HCC meeting Milan Criteria in the MELD exception era at a single institution in a UNOS region with short wait times

J Surg Oncol. 2013 Dec 17. doi: 10.1002/jso.23531. [Epub ahead of print]

Squires MH 3rd, Hanish SI, Fisher SB, Garrett C, Kooby DA, Sarmiento JM, Cardona K, Adams AB, Russell MC, Magliocca JF, Knechtle SJ, Staley CA 3rd,Maithel SK.

Abstract

BACKGROUND: Management of hepatocellular carcinoma (HCC) in the Model for End-Stage Liver Disease (MELD) exception era remains regionally variable. Outcomes were compared for patients undergoing transplant versus resection at a single institution in a UNOS region with short wait times for organ availability.

METHODS: All patients who underwent resection of HCC from January 2000 to August 2012 and patients who underwent transplant post-January 2006, during the Milan Criteria (MC)-based MELD exception policy for HCC, were identified. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS).

RESULTS: Two hundred fifty-seven patients were analyzed, of whom 131 underwent transplant and 126 underwent resection. All transplant patients met MC; 45 (36%) resection patients met MC. Median follow-up time was 30 months. Median wait time to transplant was 55 days; no patients dropped off the waitlist while awaiting an organ. Among patients meeting MC, transplant demonstrated significantly greater 5-year OS (65.7% vs. 43.8%; P = 0.005) and RFS (85.3% vs. 22.7%; P < 0.001) versus resection. For patients with hepatitis C, transplant (n = 87) demonstrated significantly improved 5-year outcomes compared to patients meeting MC who underwent resection (n = 21; OS: 63.5% vs. 23.3%; P = 0.001; RFS: 83.5% vs. 23.7%; P < 0.001).

CONCLUSION: In a region with short waitlist times for organ availability, liver transplant is associated with improved survival compared to resection for HCC within MC and should be considered for all patients meeting MC, particularly those with hepatitis C. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.

© 2013 Wiley Periodicals, Inc.

KEYWORDS: Milan Criteria, hepatic resection, hepatocellular carcinoma, liver transplant, waitlist time

PMID: 24347475 [PubMed - as supplied by publisher]

Source

Canadian guidelines for management and treatment of HIV/hepatitis C coinfection in adults

Canadian Journal of Infectious Diseases and  Medical Microbiology

Special Article
Winter 2013, Volume 24 Issue 4: 217-238

CIHR Canadian HIV Trials Network Co-Infection and Concurrent Diseases Core: Canadian guidelines for management and treatment of HIV/hepatitis C coinfection in adults - http://bit.ly/1gKrkwp

M Hull | M Klein | S Shafran | A Tseng | P Giguère | P Côté | M Poliquin | C Cooper | on behalf of The CIHR Canadian HIV Trials Network HIV/Hepatitis C Management and Treatment Guidelines Working Group

BACKGROUND: Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV, and is responsible for a heavy burden of morbidity and mortality. HIV-HCV management is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens.

OBJECTIVE: To develop national standards for the management of HCV-HIV coinfected adults in the Canadian context.

METHODS: A panel with specific clinical expertise in HIV-HCV co-infection was convened by The CIHR HIV Trials Network to review current literature, existing guidelines and protocols. Following broad solicitation for input, consensus recommendations were approved by the working group, and were characterized using a Class (benefit verses harm) and Level (strength of certainty) quality-of-evidence scale.

RESULTS: All HIV-HCV coinfected individuals should be assessed for HCV therapy. Individuals unable to initiate HCV therapy should initiate antiretroviral therapy to slow liver disease progression. Standard of care for genotype 1 is pegylated interferon and weight-based ribavirin dosing plus an HCV protease inhibitor; traditional dual therapy for 24 weeks (for genotype 2/3 with virological clearance at week 4); or 48 weeks (for genotypes 2-6). Therapy deferral for individuals with mild liver disease may be considered. HIV should not be considered a barrier to liver transplantation in coinfected patients.

DISCUSSION: Recommendations may not supersede individual clinical judgement.

Antivirals | Direct-acting antivirals | HCV | HIV | Pharmacokinetics

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