Can Chronic Disease Management Programs Improve Outcomes in Patients With Cirrhosis?

Gastroenterology
Volume 145, Issue 5 , Pages 1153-1155, November 2013

Christian A. Mayorga, Amit G. Singal

published online 23 September 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor

Wigg AJ, McCormick R, Wundke R, et al. Efficacy of a chronic disease management model for patients with chronic liver failure. Clin Gastroenterol Hepatol 2013;11:850–858.

Cirrhosis affects >5.5 million patients and costs nearly $4 billion annually. Furthermore, there are nearly 30,000 new diagnoses of cirrhosis per year (Hepatology 2002;36:227–242). The prevalence of cirrhosis is increasing owing to an aging population of patients with chronic hepatitis C virus infection and an increasing prevalence of nonalcoholic fatty liver disease. Unfortunately, our current episodic system of health care delivery is suboptimal for patients with chronic diseases, such as cirrhosis (Gastroenterology 2010;139:14–16 e1). Patients with cirrhosis are at high risk of hospitalization, including nearly one third of patients requiring readmission within 1 month (Clin Gastroenterol Hepatol 2013;11:1335–1141). In other chronic diseases, such as congestive heart failure, chronic disease management (CDM) models have significantly improved clinical outcomes, including disease-specific admission rates, all-cause admission rates, and overall survival (Eur J Heart Fail 2005;7:1133–1144). CDM improves outcomes through several components including delivery system design, decision support systems, coordination of care between providers, and self-management support systems (Milbank Q 1996;74:511–544). The authors of this study sought to determine the impact of a CDM intervention on patients with decompensated cirrhosis (Clin Gastroenterol Hepatol 2013;11:850–858).

In this single-center, randomized, controlled, pilot study, the authors enrolled 60 adult patients who had been admitted with any cirrhosis-related decompensation (ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma (HCC), hepatorenal syndrome, alcoholic hepatitis, or sepsis). Patients were randomized 2:1 to CDM (n = 40) or usual care (n = 20), respectively, and then followed for 12 months. The multifaceted CDM intervention was administered by hepatology nursing staff after hospital discharge and continued for the duration of the 12-month trial. The intervention included nurse case management, decision support tools, patient and caretaker education, and nurse-generated patient data sheets for providers. Specifically, delivery system design measures included multidisciplinary care in clinic, home visits by a nurse within 1 week of discharge, and rapid access to care pathways as needed. Nurses provided self-management support, including patient and caregiver education, to optimize care between visits. Finally, decision support tools, such as evidence-based protocols for cirrhosis complications, and clinical information systems, such as patient data sheets, were implemented.

Patients enrolled in the CDM group had a 30% higher attendance rate at planned outpatient appointments compared to the usual care group (incidence rate ratio [IRR], 1.3; 95% confidence interval [CI], 1.1–1.6). Several quality-of-care indicators were higher in the intervention group than the usual care group, including significant differences in rates of HCC screening, vaccination, and liver transplant assessments. However, there was no difference in the primary study endpoint of cirrhosis-related hospital days between the CDM and usual care groups (17.8 vs 11.0 days per person-year, respectively; IRR, 1.6; 95% CI, 0.5–4.8). Similarly, the authors found no difference in cirrhosis-related admission rates (IRR, 2.2; 95% CI, 1.0–4.5), all-cause admission rates (IRR, 1.7; 95% CI, 1.0–3.7), median length of hospitalization (hazard ratio 1.3; 95% CI, 0.9–1.9), or overall survival (hazard ratio, 0.6; 95% CI, 0.3–.5).

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Comment

CDM programs have been shown to improve clinical outcomes in several chronic diseases. In chronic obstructive pulmonary disease, for instance, CDM models resulted in a significant reduction in hospitalization rate (Arch Intern Med 2007;167:551–561). Similarly, for congestive heart failure, the use of CDM programs has been associated with significant reductions in both hospitalization and mortality rates (Eur J Heart Fail 2005;7:1133–1144). Although the upfront cost of these programs is not trivial, this cost may be offset by a substantial increase in quality-adjusted life-years and perhaps cost-savings with reduced downstream hospitalizations (Heart 2008;94:1601–1606). Cirrhosis is currently responsible for significant morbidity and health care costs and parallels other target populations of prior CDM efforts.

This pilot study is the first prospective, randomized trial assessing the impact of a CDM model in the management of chronic liver disease. In contrast with other chronic diseases in which CDM intervention significantly improves clinical outcomes, this study showed no difference in cirrhosis-related hospital days, all-cause admission rates, or median length of hospitalization. In fact, there was a nonsignificant trend toward worse outcomes in the intervention group, with more liver-related hospital days and higher all-cause admission rates.

The negative findings of this study may be related to intrinsic differences between patients with cirrhosis and those with other chronic diseases. The authors hypothesize that patients with cirrhosis may be more marginalized from health care services than other chronic diseases. It is also possible that acute exacerbations of cirrhosis are unpredictable and unavoidable, even in the setting of high-quality care. For example, hepatic encephalopathy can be a unique and challenging barrier to providing consistent outpatient care to patients with cirrhosis, including sudden exacerbations owing to a host of etiologies, including infection, medication noncompliance, and renal failure.

Alternatively, CDM interventions may be effective in patients with cirrhosis but simply not detected by this study owing to its limitations. First, this was a pilot study and was not powered a priori for all planned analyses (although the authors performed a post hoc power analysis). Furthermore, the small sample size led to imbalances in several measured (and likely unmeasured) confounders between the intervention group and usual care group. There were higher rates of reversible insults, such as spontaneous bacterial peritonitis and alcoholic hepatitis, in the usual care group. Similarly, there was a trend toward higher Model for End-stage Liver Disease scores and comorbidity index in the intervention group.

Furthermore, this study was conducted in a tertiary care center, with easy access to subspecialty care. This is a setting where CDM may be unnecessary, because rates of quality care were high among patients in the usual care group, with >80% of patients receiving HCC surveillance, variceal screening, and spontaneous bacterial peritonitis prophylaxis as needed. Prior studies have demonstrated that subspecialty consultation from a gastroenterologist results in shorter lengths of hospitalization and lower 30-day readmission rates among patients with cirrhosis (Hepatology 2001;34:1089–1095). Therefore, it is possible that CDM interventions may be more beneficial in a community hospital setting where expert consultation is scarcer or in a subgroup of high-risk patients.

Although the authors chose the components of their CDM intervention based on available evidence from other chronic diseases, it is possible that different components are necessary to improve outcomes in patients with cirrhosis. For example, a high proportion of admissions in the intervention group were for elective procedures, such as paracentesis, liver biopsy, or endoscopic procedures. Availability of an outpatient procedure facility could have prevented 48% of hospitalizations in the intervention group and should be included in future CDM intervention trials. Furthermore, several of the components of the CDM intervention in this study, such home visits and patient education, were directed to outpatient care, although the primary study outcomes were all inpatient based. Future studies are needed to characterize reasons for readmission and prolonged hospitalization among patients with cirrhosis to help develop an effective intervention strategy.

Interestingly, there was no difference in the primary and secondary outcomes of the study despite an improvement in several quality measures, such as HCC surveillance, vaccination, and liver transplant evaluation. Although process measures are more sensitive to differences in quality of care, outcomes are often of greater interest. It is possible that improvements in process measures would translate to improved outcomes with longer follow-up; however, it is also possible that there is a disconnect between these quality metrics and the outcomes of interest. Although a recent study from HALT-C helped to establish a link between HCC surveillance process measures and downstream outcomes (Am J Gastroenterol 2013;108:425–432), similar studies are needed for other cirrhosis quality metrics.

Despite not finding a difference in outcomes with CDM, this is an important proof-of-principle pilot study with several strengths. The study raises several interesting questions regarding the benefits of CDM among patients with decompensated cirrhosis. Future studies are needed to determine the optimal components of a CDM program as well as the most appropriate quality measures. Larger studies with longer follow-up are then needed to determine the effectiveness and cost-effectiveness of CDM interventions in improving outcomes among this patient population.

PII: S0016-5085(13)01313-9

doi:10.1053/j.gastro.2013.09.014

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection—A Randomized Trial

Gastroenterology
Volume 145, Issue 5 , Pages 1035-1044.e5, November 2013

Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown Jr., Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, Mark S. Sulkowski, Protocol 6086 Investigators

Received 22 February 2013; accepted 30 July 2013. published online 06 August 2013.

Abstract

Background & Aims

Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.

Methods

Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).

Results

Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.

Conclusions

Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Keywords: EPO, Erythropoiesis, DAA, Side Effect

Abbreviations used in this paper: CI, confidence interval, EPO, erythropoietin, HCV, hepatitis C virus, RBV, ribavirin, SVR, sustained virologic response

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F.D.A. Urging a Tighter Rein on Painkillers

By BARRY MEIER
Published: October 24, 2013

Hydrocone-containing drugs, like these at a Vermont pharmacy, were prescribed for an estimated 47 million patients in 2011.

The Food and Drug Administration on Thursday recommended tighter controls on how doctors prescribe the most commonly used narcotic painkillers, changes that are expected to take place as early as next year.

The move, which represents a major policy shift, follows a decade-long debate over whether the widely abused drugs, which contain the narcotic hydrocodone, should be controlled as tightly as more powerful painkillers like OxyContin.

The drugs at issue contain a combination of hydrocodone and an over-the-counter painkiller like acetaminophen or aspirin and are sold either as generics or under brand names like Vicodin or Lortab. Doctors use the medications to treat pain from injuries, arthritis, dental extractions and other problems.

The change would reduce the number of refills patients could get before going back to see their doctor. Patients would also be required to take a prescription to a pharmacy, rather than have a doctor call it in.

Prescription drugs account for about three-quarters of all drug overdose deaths in the United States, with the number of deaths from narcotic painkillers, or opioids, quadrupling since 1999, according to federal data. Drugs containing hydrocodone represent a huge share — about 70 percent — of all opioid prescriptions, and the looser rules governing them, some experts say, have contributed to their abuse.

Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said she expected the new regulations to go into effect in 2014. The recommendation requires the approval of the Department of Health and Human Services and adoption by the Drug Enforcement Administration, which has long pushed for the measure.

For years, F.D.A. officials had rejected recommendations from the D.E.A. and others for stronger prescribing controls on the drugs, saying the action would create undue hardships for patients. A number of doctors’ groups, including the American Medical Association and pharmacy organizations, have continued to fight the measure, citing the impact on patients.

In a telephone interview, Dr. Woodcock said that F.D.A. officials were aware that changing the prescribing rules would affect patients. She said, however, that the impact on public health caused by the abuse of the drugs as well as their medical use had reached a tipping point.

“These are very difficult trade-offs that our society has to make,” she said. “The reason we approve these drugs is for people in pain. But we can’t ignore the epidemic on the other side.”

The new regulations would reduce by half, to 90 days, the supply of the drug a patient could obtain without a new prescription.

Currently, a patient can refill a prescription for such drugs five times over a six-month period before needing a new prescription. Federal data suggest that most patients take such medications for only 14 days, creating the potential for excess pills to be sold or to be taken out of medicine chests by curious teenagers and others.

The F.D.A. recommendation is likely to have a significant impact on the availability of the drugs, as well as on how pharmacies operate and even the types of medical professionals who can prescribe the medications.

In 2011, about 131 million prescriptions for hydrocodone-containing medications were written for about 47 million patients, according to government estimates. That amounts to about five billion pills.

Technically, the change involves the reclassification of hydrocodone-containing painkillers as Schedule II medications from their current classification as Schedule III drugs. The scheduling system, which is overseen by the Drug Enforcement Administration, classifies drugs based on their medical use and their potential for abuse and addiction.

Schedule II drugs are those drugs with the highest potential for abuse that can be legally prescribed. They include painkillers like oxycodone — the active ingredient in OxyContin — methadone and fentanyl, as well as Adderall and Ritalin, which are prescribed for attention deficit hyperactivity disorder.

In recent years, the question of whether to tighten prescribing controls over hydrocodone-containing drugs has been the subject of intense lobbying.

Last year, for example, lobbyists for druggists and chain pharmacies mobilized to derail a measure passed in the Senate that would mandate the types of restrictions that the F.D.A. is now recommending.

At the time, the lobbying arm of the American Cancer Society said that making patients see doctors more often to get prescriptions would impose added burdens and costs on them.

Senator Joe Manchin III, Democrat of West Virginia, expressed dismay when the proposal died in the House of Representatives.

“They got their victory — but not at my expense,” said Mr. Manchin, whose state has been hard hit by prescription drug abuse. “The people who will pay the price are the young boys and girls in communities across this nation.”

Dr. Woodcock, of the F.D.A., said that requiring patients with long-lasting pain to see a doctor after three months, rather than six, for a new prescription could benefit them. “If you are needing chronic therapy of this magnitude,” she said, “you should be seeing your prescriber.”

A D.E.A. spokeswoman, Barbara Carreno, said that agency officials would not comment on the agency’s recommendation.

One of the trade groups that opposed the change, the National Community Pharmacists Association, said in a statement on Thursday that the move would “likely pose significant hardships for many patients and delay relief for vulnerable patients with legitimate chronic pain.”

Penney Cowan, the executive director of the American Chronic Pain Association, an advocacy group, said she believed that drugs like Vicodin should be only one part of a treatment program for patients with long-term pain. But she added that the new rules could make it harder for some patients to find doctors to prescribe the drugs or pharmacies to fill the prescriptions.

“We are hearing from more and more people having difficulty finding access to care,” Ms. Cowan said.

Earlier this year, an expert advisory panel to the F.D.A. voted 19 to 10 in favor of reclassifying hydrocodone-containing painkillers as Schedule II drugs. While such recommendations are not binding, the agency often follows them.

Along with changing how doctors prescribe these drugs, the classification change would also impose added storage and record-keeping requirements on druggists. In some states, nurse practitioners and other health care professionals who can currently prescribe hydrocodone-

containing drugs may no longer be able to do so.
Source

Liver transplants: Frequently Asked Questions answered by a renowned liver transplant surgeon

Dr Vinay Kumaran October 24, 2013 at 4:35 pm

The liver is one of the most vital organs in our body which processes nutrients and gets rid of toxins. It plays a vital role in maintain the body’s metabolic balance. Sadly, liver-related diseases are on the rise and more and more people need liver transplants. Dr Vinay Kumaran, Head of the Liver Transplantation and Hepatobiliary and Pancreatic Surgery at the Kokilaben Dhirubhai Ambani Hospital, Mumbai tells us all about liver transplants.

Who needs a liver transplant? Why?

A liver transplant is most commonly required by patients whose liver is failing due to cirrhosis or due to acute liver failure. Some patients with liver cancer are also candidates for liver transplant. Cancer often develops in those who have cirrhosis already and extensive surgery to remove the tumour is not possible in such cases. There are rarer indications like some genetic diseases as well. (Read: Top 6 natural remedies to keep your liver healthy)

Are there many cases where a transplant cannot be done even if a patient needs one?

A transplant cannot be done unless there is a donor. In most cases there is a living donor from the family who volunteers to undergo and operation to remove part of the liver which is transplanted into the patient. Occasionally, the family of a brain dead patient agrees to donate the organs but this is quite rare. (Read: Hundreds die in India for lack of organs)

Who can donate? How does one ‘find’ a suitable donor?

For living donor liver transplant, the donor is a family member whose blood group is compatible with the patient. The donor must be 18 to 60 years of age. Other tests are required to determine that the liver is not fatty and that the anatomy and size of the liver are suitable for donation and that the donor is fit to undergo the operation.

Can liver be taken from cadavers too like the eyes? How can one pledge their liver?

Yes, in a very specific situation. The cadaver should be a person who has died of brain damage (head injury, stroke, etc) and is on a ventilator at the time of death. The heart continues to beat for some time after brain death and we can continue to ventilate the lungs and give medicines to maintain blood pressure and nutrition. As long as adequate blood flow and oxygen delivery can be maintained to the other organs of the cadaver, they can be removed and transplanted with the permission of the next of kin. We can apply online for a donor card which states that we want our organs and tissues to be used after death. However, the donor card is little more than a gesture. What we really need to do is make sure our family knows that we want our organs donated in case we are left in a situation in which we are brain dead. The eyes and some tissues can even be used in the usual form of death when the heart stops first.

How is the liver ‘transplanted’?

The donor and recipient operations go on together. The patient’s own liver is removed. Meanwhile the donor liver (part of it in case of living donor transplants) is removed. The donor liver is flushed with a preservative solution and the blood vessels and bile duct are prepared for joining to the patient’s blood vessels and bile duct. This often involves extending the blood vessel with a vein graft. The donor liver is then implanted in place of the recipient’s liver by joining the corresponding blood vessels and bile ducts.

What about the donor after he/she has donated? Can he/she lead a normal life?

The risk to the donor from the operation is 0.1 to 0.5% depending on how much of the liver needs to be removed. The hospitalization is typically 1 week. It takes about a month before the donor feels recovered enough to return to work. For 3 months the donor has to avoid lifting heavy weights as with any abdominal surgery. Long term problems are rare but hernias can occur and some donors have had intestinal obstruction due to the intestine getting stuck to the scar of surgery. These can occur after any abdominal surgery. Life is otherwise normal. There are no medicines in the long term and no dietary restrictions. Beyond 3 months there are no restrictions on activity either. (Read: Organ donation – all your queries answered)

Pre-op care: The patient is often very sick before a liver transplant and his condition needs to be medically improved to the point where a transplant can safely be done. This comprises chiefly of identifying and treating any infection and making sure that the other organs (particularly the kidneys which tend to be affected by the liver disease or the medicines used to treat it) are working well.

Post-op care: After transplant the patient needs immune-suppressants (medicines to prevent the body from rejecting the new liver). These medicines make the patient susceptible to infection and the patient is also given prophylactic antibiotics and anti-fungals and sometimes anti-virals as well. Over a period of time the requirement of these medicines comes down and they are gradually withdrawn. At least one immunosuppressant medicine continues lifelong. The ICU stay of the recipient is typically 4-5 days and the hospital stay 2-3 weeks.

We have only one liver, so if one donates his/her liver will they not die, without a liver?

The liver has two qualities which make it possible for a donor to donate part of the liver. The first is ‘reserve’. The liver has enough functional reserve that up to 75% of the liver can be removed if required (in liver donors we restrict it to 70% in order to have a margin of safety). The remaining 25% is enough to perform the functions required of the liver. The other quality is the ability to ‘regenerate’. After removal of part of the liver, the remaining liver rapidly grows back to its full size in a few weeks. (Read: Organ donation: Rules you should know)

When is a liver transplant ‘successful’? What is the rate of success of a liver transplant?

A liver transplant can be said to be successful when the patient returns to a normal productive life. The success rate is about 85-90% at one year after transplant and about 75% 5 years after transplant. Some patients will have a recurrence of their disease, side effects of the medicines, complications of the transplant etc. hence the difference.

What are the side/after effects of getting a liver transplant? What is the rate of rejection?

The patient has to be on medicines to prevent rejection for the rest of their life. This increases somewhat their risk of getting infections and such infections have to be recognized and treated. There is also a higher than usual risk of cancer over their lifetimes, predominantly skin cancers (this seems to be much less of a problem in Indian patients because of our darker skin). The medicines have side effects including a risk of kidney problems, diabetes and blood pressure over the years at a higher rate than the normal populations. In general, the life of a liver transplant patient is similar to that of a patient with a chronic but controllable medical condition like high blood pressure in that periodic (once in 3 months long term) checkups and adjustment of medication is required. Episodes of rejection occur in 10 to 30% of patients who have undergone a liver transplant. These are usually easy to recognize (from periodic blood tests) and easy to treat (by increasing the dose or adding immunosuppressive medicines). Rejection that does not respond to treatment and leads to loss of the liver is very rare.

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FDA Panel Recommends Approval of Simeprevir for Hepatitis C – Excellent Summary from Medscape

Medscape Medical News

Troy Brown, RN
October 24, 2013

An advisory committee to the US Food and Drug Administration (FDA) unanimously recommended simeprevir (Janssen) for the treatment of chronic hepatitis C virus (HCV) genotype 1 (GT1) infection, combined with peginterferon alfa and ribavirin in adults with compensated liver disease (including cirrhosis) who are treatment naïve or who have failed previous interferon therapy with or without ribavirin.

Simeprevir is an HCV protease inhibitor, and if approved it will be the third HCV protease inhibitor approved in the US. Boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals, Inc) were approved in 2011, according to background information provided by the FDA. The proposed dose is 150 mg once daily, in combination with peginterferon alfa and ribavirin.

"We clearly need better drugs, and the evidence is strong that this is a better drug than we have," voting member Curt H. Hagedorn, MD, Chief, Medicine Service, at Central Arkansas Veterans Healthcare Service, in Little Rock, Arkansas, noted.

The vote follows a discussion of data from 3 phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1. Patients in the treatment groups (N = 781) were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virologic response to therapy. Patients in the control groups (N = 397) were given placebo for 12 weeks combined with PR for 48 weeks.

Those in trials C208 and C216 were treatment-naïve, and those in HPC3007 had received 24 weeks or more of a pegylated interferon-based treatment and had relapsed within 1 year after the last medication dose. Efficacy data from C208 and C216 were pooled because the studies were nearly identical in design.

Efficacy

The trials' primary endpoint was sustained virologic response 12 weeks after the anticipated end of treatment (SVR12), which was defined as an undetectable HCV RNA at treatment end and HCV RNA < 25 IU/mL 12 weeks after the anticipated end of treatment.

The pooled results from C208 and C216 showed an SVR12 rate of 80% in the treatment group and 50% in the control group. For the relapsed patients in HPC3007, the SVR12 rate was 79% in the treatment group and 36% in the control group.

Secondary endpoints for all 3 trials included SVR24 and SVR 72. Both endpoints correlated well with the primary endpoint of SVR12, but data were incomplete at the week 60 data cut-off.

SVR rates were lower in patients with a high baseline viral load, advanced disease on liver histology (bridging fibrosis and cirrhosis), older age, African American ethnicity, and absence of the IL28B CC genetic polymorphism.

The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the US) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.

In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment groups vs 43% in the control group for the 2 pooled trials, and 78% in the treatment group vs 24% in the control group for the relapser trial. The committee recommends screening all patients with GT1a infection for the Q80K viral polymorphisms before initiating simeprevir (combined with pegylated interferon and ribavirin) and considering alternative treatment options for those with this polymorphism.

SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses.

Mean simeprevir area under the concentration-time curve 24-h postdose (AUC_24h) values were 2.4 and 5.2-fold higher, respectively, in HCV-uninfected subjects with moderate or severe hepatic dysfunction, compared to healthy controls. Mean simeprevir AUC_24h values were also approximately 3.4-fold higher in HCV infected patients of East Asian ancestry, compared with the pooled Phase 3 population which was about 91% Caucasian. For this reason, the committee would like to see additional studies in patients of East Asian origin.

Safety

A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment.

In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions.

Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).

"I think this is a great opportunity at treating more HCV infected patients," said voting member Amanda H. Corbett, PharmD, BCPS, FCCP, a clinical associate professor at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy.

"Efficacy was clearly demonstrated and the safety profile is clearly favorable," explained voting member Thomas P. Giordano, MD, MPH, an associate professor of medicine at Baylor College of Medicine, medical director of HIV services at Harris Health System, and a research scientist at HSR&D Center of Excellence, Michael E. DeBakey VA Medical Center, in Houston, Texas.

Several committee members remarked on the need for postmarketing studies in racial and ethnic minorities, patients coinfected with HIV, and other underrepresented populations. A number of members suggested that the FDA should be more proactive with the pharmaceutical industry at the beginning of the clinical trial process to ensure a more diverse study population that more accurately represents the clinical population being studied.

The committee members have disclosed no relevant financial relationships.

US Food and Drug Administration (FDA)-Antiviral Drugs Advisory Committee Meeting. FDA Briefing, Janssen Briefing

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Biotron's drug enhances antiviral activity in HIV/HCV infected patients

Friday, October 25, 2013 by Proactive Investors

Biotron's preliminary data from a Phase 2 pilot study of patients co-infected with Hepatitis C and HIV demonstrates that 100% of Genotype 3 patients completing 28 days of treatment with BIT225 in, combination with interferon and ribavirin, had undetectable Hepatitis C levels.

Biotron (ASX:BIT) will trade higher after preliminary data from a study of patients co-infected with Hepatitis C and HIV demonstrates that 100% of Genotype 3 patients completing 28 days of treatment with BIT225 in, combination with interferon and ribavirin, had undetectable Hepatitis C levels.

Patients received interferon (IFN) and ribavirin (RBV) for 7 days prior to receiving 300 mg of BIT225 twice daily plus IFN/RBV for 28 days. After that time, patients continued to take IFN/RBV for a total of 48 weeks.

All patients had undetectable levels of HIV at time of enrolment and continued to take anti-retroviral drugs throughout the study, conducted at Siriraj Hospital in Bangkok.

Interim analysis of virus levels in the treated patients indicates that all six Hepatitic C virus (HCV) Genotype 3 subjects who completed 28 days of BIT225 therapy had undetectable levels of HCV 12 weeks into the study.

Notably, response to treatment at this time point is generally a good indication of final outcome at 48 weeks.

Other new classes of direct-acting antiviral drugs in development have response rates as low as 37% after 12 weeks of treatment. In contrast, the company saw a 100% response at 12 weeks, with only 4 weeks of treatment with BIT225.

The current approved treatment for HIV/HCV co-infected patients is IFN/RBV, however up to 50% of patients are unresponsive.

Biotron’s BIT225 targets the HCV viral protein p7, which has crucial roles in virus replication and reproduction. It is a new target, and BIT225 is a first-in-class direct acting antiviral for the treatment of HCV.

A growing data set is underscoring the significance of Biotron’s new generation anti-viral drug portfolio, and BIT225 is also in development for treatment of HIV, with demonstrated clinical efficacy against HIV in reservoir cells.

New HIV Guidelines Address Broad Range of Medical Conditions

Medscape Medical News > Conference News

Daniel M. Keller, PhD
October 24, 2013

BRUSSELS — Updated guidelines from the European AIDS Clinical Society (EACS) are a roadmap for the assessment and treatment of people infected with HIV. They go beyond HIV, and address the prevention and management of comorbidities, the management of chronic infection with hepatitis viruses, and the treatment of opportunistic infections.

Three experts presented the updated guidelines here at the 14th European AIDS Conference to a nearly packed auditorium.

One hot area is when to start antiretroviral therapy, said Nathan Clumeck, MD, from the Saint-Pierre University Hospital in Brussels, who is head of the antiretroviral section of the guidelines and cochair of the conference. It is "surprising to still be asking the question after so many years."

He referred to recent American and French guidelines that recommend beginning antiretrovirals for all HIV-infected people, and noted that the strength of the American recommendation is that it varies with CD4+ lymphocyte count and takes into account clinical condition, such as pregnancy, past AIDS-defining illness, hepatitis virus coinfection, risk for HIV transmission, and older age.

The EACS update differs from some other major guidelines because it takes a nuanced position on antiretrovirals.

The guidelines state that antiretrovirals should be considered and actively discussed with any person infected with HIV, even if that person is asymptomatic and has a CD4 count above 500/mm³. This clinical equipoise is intended to balance the benefits of viral suppression against the risks for adverse drug reactions.

In addition, they state that symptomatic infections or certain clinical conditions warrant a recommendation for therapy, not just a consideration.

The update addresses the public health issue of treatment as prevention to reduce the possibility of transmitting HIV to sexual partners. However, panelists at a news conference said they agreed that clinicians must serve the patient over the community at large, and that the patient's condition and desires must be primary.

The antiretroviral section of the guidelines includes information on adverse effects, interactions with other drugs (such as antidepressants, antihypertensives, and analgesics), dose adjustments for impaired hepatic or renal function, and administration of drugs for people with swallowing difficulties.

There is also information on switch strategies, which takes into account dosing simplification, better adherence, and prevention of or improvement in metabolic abnormalities. In addition, the guidelines lay out a strategy for antiretroviral initiation in patients coinfected with HIV and tuberculosis, based on CD4 count and drug–drug interactions, and provides a table of such interactions.

Managing Comorbidities

The aim of the section on the prevention and management of comorbidities was to provide recommendations based on levels of evidence and guidelines from outside HIV medicine, but "to not write a medical textbook," said George Behrens, MD, from the Hannover Medical School in Germany, who presented that section.

"We really welcome any comment you may want to make, whether positive or negative," he said, noting that the guidelines are a work in progress. The guidelines take into account differences in healthcare systems across Europe, but it was impossible to consider all aspects of the operation of all the systems, he explained.

Two new topics are addressed in the updated guidelines: the approach to fracture reduction and the sexual and reproductive health of men and women infected with HIV.

Dr. Behrens noted that bone disease and bone health are "very complex" issues. Tenofovir can exacerbate the decreased bone mass related to HIV, although how this affects fracture risk has not been established. Besides the intake of sufficient calcium and vitamin D and the appropriate use of bisphosphonates, the guidelines put reducing fall risks at the top of the list of measures to avoid fractures.

Reproductive health issues addressed include the sexual transmission of HIV, approaches to reproduction for serodiscordant couples who want to have children, screening and treatment of sexually transmitted infections, and sexual dysfunction.

The guidelines also deal with the general medical management of comorbidities.

It is recommended that treatment for hypertension begin with an ACE inhibitor, angiotensin-receptor blocker, or calcium-channel blocker, depending on patient age and ethnicity. Most patients will require more than 1 drug for adequate blood pressure control.

The diagnosis and management of diabetes are also addressed, especially in light of comorbidities and antiretroviral therapy. The guidelines note that glycated hemoglobin levels can be unreliable in the presence of hemoglobinopathies, high erythrocyte turnover, severe liver or kidney dysfunction, or older age, and when abacavir is used.

Finally, Dr. Behrens showed a rather extensive algorithm for the diagnosis and management of HIV-associated neurocognitive impairment in people without obvious confounding conditions. The algorithm begins with a 3-question screening test, and proceeds to more extensive neuropsychologic testing, brain imaging, and cerebrospinal fluid examination.

He said that future guidelines will likely address cancers and lung diseases.

Managing Hepatitis

Jürgen Rockstroh, MD, head of the HIV outpatient clinic at the University of Bonn in Germany, addressed the management of patients with hepatitis B virus and HIV coinfection. He presented an algorithm for treatment indications based on the usual tests for hepatitis B. However, when actual treatments are prescribed, other factors are taken into consideration, he noted, such as CD4 count, the specific antiretroviral administered, and whether the patient has symptomatic HIV disease.

He then discussed diagnostic procedures for people with hepatitis C virus and HIV coinfection, including serology, liver fibrosis assessment, and hepatitis C and IL28b genotypes. He noted that the new standard of treatment for newly diagnosed genotype 1 is a regimen of the direct-acting antiviral drugs boceprevir and telaprevir in combination with pegylated-interferon and ribavirin. These drugs are associated with toxic effects, so treatment can be delayed if fibrosis is absent or minimal because newer direct-acting antiviral drugs are expected soon. In addition, the guidelines contain a management strategy based on a 3 × 3 matrix of responder status (naïve, relapser, or nonresponder) and degree of fibrosis.

Dr. Rockstroh also discussed the treatment of other hepatitis C genotypes. Genotypes 2 and 3 respond well to pegylated interferon and ribavirin. Genotype 4 is similar to genotype 1, in that it is not sensitive to the current direct-acting antiviral drugs, but it appears to be susceptible to the next-generation drugs. With these agents, expected as soon as next year, "hepatitis C treatment will be easier to administer with better response rates," he noted, and a shorter treatment duration will probably become standard.

Dr. Clumeck reports financial relationships with Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, MSD, Pfizer, Roche, and Janssen. Dr. Behrens reports financial relationships with Abbott, Boehringer Ingelheim, BMS, MSD, Gilead, and Janssen. Dr. Rockstroh reports financial relationships with Bionor, BMS, Boehringer Ingelheim, GlaxoSmithKline, ViiV, Abbott, Gilead, Pfizer, Merck, Tibotec, Roche, Novartis, and Janssen.

14th European AIDS Conference. Presented October 18, 2013.

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FDA panel unanimously approves simeprevir for HCV genotype 1

Provided by Healio

October 24, 2013

The FDA’s Antiviral Drugs Advisory Committee today voted that available data overwhelmingly supports approval of simeprevir in combination with pegylated interferon and ribavirin for treatment of hepatitis C genotype 1 infections.

The panel voted 19-0 with no abstentions after researchers presented study results demonstrating the once-daily protease inhibitor pill manufactured by Janssen Pharmaceuticals, a Johnson & Johnson company, was superior to placebo in achieving a sustained virologic response (SVR) in treatment-naive patients with HCV and those who relapsed after prior pegylated interferon and ribavirin (PR) therapy.

“I thought the evidence was pretty overwhelming,” committee member Dean Follmann, PhD, chief, biostatistics research branch, National Institute of Allergy and Infectious Diseases, said. “It was probably the easiest vote I ever had.”

Presenters provided safety and efficacy details from four double-blind, placebo-controlled studies — two phase 3 studies on treatment-naive patients, one phase 3 study on prior relapsers and one phase 2b study on prior relapsers and nonresponders.

The studies demonstrated positive SVR results in most cases, but a subpopulation of HCV patients — those with genotype 1a and a Q80K polymorphism — responded similarly to controls in naive or relapse trials.

Due to the reduction in efficacy apparent in these subjects, the FDA’s Division of Antiviral Products stated it intends to recommend screening all genotype 1a subjects for the Q80K viral polymorphism before beginning simeprevir with PR therapy in order to potentially consider alternative treatment options.

During discussion of the proposal, the panel voiced questions over whether it was enough to suggest physicians “consider” alternative treatment as opposed to “recommending” another treatment.

The panel also discussed aspects of simeprevir’s safety profile and agreed without a vote that a recommendation for sun-protection measures should be included with the warnings and precautions section of simeprevir’s prescribing information because of photosensitivity reactions during clinical trials.

Additional skin reactions during clinical trials also prompted discussions of whether skin rash should be included in the warnings and precautions section. The question arose because of apparent differences between presentation and management strategy for rash and photosensitivity.

“There are varying opinions about what should be on the label in what sections,” Committee Chairman Yoshihiko Murata, MD, PhD, division of infectious diseases, University of Rochester School of Medicine and Dentistry, said in summarizing the discussion. No final vote was conducted on the discussion point.

The panel also advised that further postmarketing studies should be conducted to better define potential risks to several portions of the population and means to optimize use of simeprevir.

A final decision by the FDA is expected next month.

On Friday, the panel will hear details regarding sofosbuvir (Gilead Sciences).

An FDA background report on sofosbuvir concluded that adding the medication to standard drug therapy cured 90% of those with HCV genotypes 1, 4, 5 and 6 during a 12-week period.

Healio.com/Hepatology will cover the meeting.

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J&J-Medivir Hepatitis C Pills Wins U.S. Panel Backing

Provided by Bloomberg

By Anna Edney - Oct 24, 2013 4:00 PM ET

Johnson & Johnson (JNJ) and Medivir’s experimental hepatitis C treatment should be approved, advisers to the U.S. government said, propelling the companies into a position to enter a competitive market for new drugs.

The Food and Drug Administration’s 19-member advisory panel unanimously recommended the therapy, known as simeprevir, be used in combination with other medicines for the most common form of hepatitis C. The FDA, which doesn’t have to follow the panel’s advice, is expected to decide on the drug by Nov. 27.

J&J, Medivir, Gilead Sciences Inc. (GILD) and AbbVie Inc. (ABBV) are among companies developing new pills for hepatitis C to alleviate the burden of current treatments, including interferon injections, which can cause flu-like symptoms. The market for hepatitis C drugs may reach more than $100 billion over a decade, according to Bloomberg Industries. Advisers tomorrow will consider a hepatitis C therapy from Gilead.

“As someone who treats patients with chronic hepatitis C every day, I think this regimen represents a much safer one and a much simpler one than what’s currently existing,” Marc Ghany, a panel member and physician in the liver diseases branch of the National Institute of Diabetes, Digestive and Kidney Diseases, said after the vote.

The panel discussed a recommendation made by FDA staff and supported by J&J, based in New Brunswick, New Jersey, to screen potential simeprevir patients for a genetic mutation called Q80K polymorphism that renders the drug ineffective.

Genetic Defect

The Q80K polymorphism was found in 48 percent of U.S. patients with a genotype 1a hepatitis C infection in clinical trials compared with 19 percent of patients in Europe, J&J said. The mutation is almost nonexistent in those with a genotype 1b infection.

A study of an all-oral combination of simeprevir with Gilead’s sofosbuvir has shown that the regimen mitigates the effect Q80K has on simeprevir, Gaston Picchio, hepatitis disease area leader at J&J’s Janssen unit, said during the meeting.

Data from the study is expected to be released in November at the American Association for the Study of Liver Diseases’ annual conference in Washington.

J&J, the world’s biggest seller of health-care products, and Medivir, based in Huddinge, Sweden, are seeking approval for their once-daily pill to treat chronic hepatitis C patients with the genotype 1 infection. About 70 percent of U.S. patients have the genotype 1 form of the disease. Hepatitis C is divided into 6 genotypes.

Patient Population

About 4 million Americans have the disease, which can cause liver cirrhosis, according to the National Institutes of Health. Hepatitis C can be passed through infected blood or body fluids, most commonly through needle-sharing by drug users.

Treatment for patients now includes interferon and a pill called ribavirin. Most patients take the combination with Merck& Co.’s Victrelis or Vertex Pharmaceuticals Inc. (VRTX)’s Incivek for as long as 48 weeks. Simeprevir is in a class of drugs called protease inhibitors that also include Victrelis and Incivek.

Clinical trials found simeprevir can reduce treatment time in half to 24 weeks. The medicine cured about 80 percent of patients who hadn’t been treated before compared with 50 percent of those who took pegylated interferon and ribavirin. Seventy-nine percent of simeprevir users who failed other treatments were cured compared with 37 percent who took only the older drugs, according to J&J.

The most common major side effects of simeprevir were rash and photosensitivity. Panel members agreed with the FDA that the prescribing information for the drug should include a recommendation for patients to use sun protection and avoid tanning beds.

The drug from Foster City, California-based Gilead that advisers will weigh tomorrow, sofosbuvir, may be the first to market in a new class of drugs called nucleotide polymerase inhibitors. Sofosbuvir is effective across all genotypes and can shrink treatment time to 12 weeks.

To contact the reporter on this story: Anna Edney in Washington at aedney@bloomberg.net

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

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FDA Advisory Committee Recommends Approval of Simeprevir for Combination Treatment of Genotype 1 Chronic Hepatitis C in Adult Patients

RARITAN, N.J., Oct. 24, 2013 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) announced today that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) voted unanimously (19 to 0) to recommend approval of the investigational protease inhibitor simeprevir (TMC435) administered once daily as a 150 mg capsule with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis. The Advisory Committee recommended the approval of simeprevir based on analyses of data from clinical trials in patients who are treatment-naive or who have failed previous interferon-based therapy.

"We are pleased with the positive recommendation from the Advisory Committee for simeprevir and appreciate the rigorous review of our data," said Katia Boven, M.D., Medical Department Head, Infectious Diseases and Vaccines, Janssen. "It is our hope that the FDA will consider this recommendation and, upon completion of its review process, make simeprevir available to patients with genotype 1 chronic hepatitis C."

The FDA granted a Priority Review designation in May to the New Drug Application (NDA) filed by Janssen for simeprevir. Recommendations and findings from the Advisory Committee are based in part on efficacy and safety data from an extensive clinical development program for simeprevir and will be considered by the FDA in its review of the NDA for simeprevir, but the FDA is not required to follow them.  

The regulatory submission for simeprevir is supported in part by data from three pivotal Phase 3 studies – QUEST-1 and QUEST-2 in treatment-naive patients and PROMISE in patients who have relapsed after prior interferon-based treatment – as well as data from the Phase 2b ASPIRE study in prior non-responder patients. Janssen R&D Ireland presented data from the QUEST-1 and QUEST-2 studies earlier this year at the 48^th Annual Meeting of the European Association for the Study of the Liver (EASL) in Amsterdam, The Netherlands, and presented data from PROMISE at Digestive Disease Week 2013 (DDW) in Orlando, Florida. Data from ASPIRE were presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in 2012.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Simeprevir
Simeprevir (TMC435) is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and its affiliated companies and Medivir AB for the treatment of genotype 1 and genotype 4 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for simeprevir in Nordic countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved on September 27, 2013 in Japan for the treatment of genotype 1 hepatitis C and a Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

For additional information about simeprevir clinical trials, please visit www.clinicaltrials.gov.

About Janssen Research & Development, LLC

Janssen Research & Development, LLC is headquartered in Raritan, N.J. and has affiliated facilities in Europe, the United States and Asia. Janssen Research & Development is leveraging a combination of internal and external innovation to discover and develop novel medicines and solutions in five distinct therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and Vaccines, and Cardiovascular and Metabolism. For more information about Janssen Research & Development, LLC visit www.janssenrnd.com.

Janssen Research & Development, LLC is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Media Contact: Craig Stoltz
Mobile: +1 (215) 325-3612

Media Contact: Daniel De Schryver
Mobile: +49 173 76 89 149

Investor Contact: Stan Panasewicz
Office: +1 (732) 524-2524

Investor Contact: Louise Mehrotra
Office: +1 (732) 524-6491

SOURCE Janssen Research & Development, LLC

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FDA advisers unanimously back J&J hepatitis C drug

SILVER SPRING, Md. (AP) — An experimental hepatitis C drug from Johnson & Johnson has won unanimous support from government experts who say the medication should be approved to treat patients infected with the liver-destroying virus.

All 19 members of a panel of Food and Drug Administration advisers voted unanimously in favor of approving J&J's simeprevir, a daily pill designed to eliminate the most common form of hepatitis C.

The FDA is not required to follow the group's recommendation, though it often does. A decision on the drug is expected next month.

More than 3 million people in the U.S. have hepatitis C, a blood-borne disease that causes liver damage and is blamed for 15,000 deaths a year. J&J is one of a half-dozen companies working to develop more effective treatments for the virus.

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Clinical Trial: Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

Study Start Date: May 2010

Estimated Completion Date: March 2016

Interventions

• Drug: RBV
• Drug: Ribavirin
• Drug: BI 207127
• Drug: BI 201335
• Drug: BI 207217

Inclusion criteria

• Chronic hepatitis C virus (HCV) infection of genotype (GT) 1
• Parts 1-3:Treatment naive to Interferon -alfa (IFN), Pegylated interferon -alfa (PegIFN), ribavirin (RBV), and any direct acting antiviral agent for chronic hepatitis C
• Part 4: Treatment experienced with confirmed prior virological failure to an approved dose of PegIFN/RBV (null-response)
• HCV RNA >=10,000 IU/mL at screening
• Liver biopsy within two years or fibroscan within six months prior to baseline
• Liver biopsy within two years or fibroscan within 6 months prior to screening
• Age 18-75 years

Exclusion criteria

• Hepatitis C virus (HCV) infection of mixed genotype
• Evidence of liver disease due to causes other than chronic HCV infection
• Positive ELISA for human immunodeficiency virus (HIV)
• Hepatitis B virus (HBV) infection
• Decompensated liver disease or history of decompensated liver disease
• Active or suspected malignancy within the last 5 years
• Ongoing or historical photosensitivity or recurrent rash
• History of alcohol or drug abuse (except cannabis) within the past 12 months
• Body mass index (BMI)I <18 or > 35 kg/m2
• Usage of any investigational drugs within 30 days prior to enrolment, or 5 half-lives, whichever is longer; o the planned usage of an investigational drug during the course of the current study
• Known hypersensitivity to any ingredient of the study drugs
• A condition that is defined as one which in the opinion of the investigator may interfere with the patient's capability for participation in the trial or may influence the results of the trial
• Alpha fetoprotein >100ng/mL at screening; if >20ng/mL and <=100ng/mL, patients can be included if there is no evidence of liver cancer in an appropriate imaging study within 6 months prior to randomisation
• Total bilirubin > 2 mg/dL with ratio of direct/indirect > 1
• AST or ALT >5xULN
• INR prolonged to >1.7xULN
• Requirement for chronic systemic corticosteroids
• Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to enrolment or 5 half-lives, whichever is longer
• Received silymarin or glycyrrhizin or Sho-saiko-to within 30 days prior to enrolment
• Contraindications pertaining to PegIFN or RBV

Study Locations And Contact Information

• 1241.21.40002 Boehringer Ingelheim Investigational Site, Bucharest
• 1241.21.49001 Boehringer Ingelheim Investigational Site, Frankfurt am Main
• 1241.21.49008 Boehringer Ingelheim Investigational Site, Mainz
• 1241.21.34005 Boehringer Ingelheim Investigational Site, Barcelona
• 1241.21.43001 Boehringer Ingelheim Investigational Site, Wien
• 1241.21.0008 Boehringer Ingelheim Investigational Site, Springfield Massachusetts
• 1241.21.0012 Boehringer Ingelheim Investigational Site, Arlington Texas
• 1241.21.35104 Boehringer Ingelheim Investigational Site, Coimbra
• 1241.21.0004 Boehringer Ingelheim Investigational Site, San Francisco California
• 1241.21.0010 Boehringer Ingelheim Investigational Site, Houston Texas
• 1241.21.0011 Boehringer Ingelheim Investigational Site, Palm Harbor Florida
• 1241.21.49005 Boehringer Ingelheim Investigational Site, Esslingen
• 1241.21.33007 Boehringer Ingelheim Investigational Site, Grenoble cédex 9
• 1241.21.40003 Boehringer Ingelheim Investigational Site, Bucharest
• 1241.21.35105 Boehringer Ingelheim Investigational Site, Lisboa
• 1241.21.61002 Boehringer Ingelheim Investigational Site, Heidelberg Victoria
• 1241.21.33005 Boehringer Ingelheim Investigational Site, Clichy
• 1241.21.0014 Boehringer Ingelheim Investigational Site, Oceanside California
• 1241.21.64001 Boehringer Ingelheim Investigational Site, Auckland NZ
• 1241.21.0017 Boehringer Ingelheim Investigational Site, Seattle Washington
• 1241.21.49002 Boehringer Ingelheim Investigational Site, Berlin
• 1241.21.43002 Boehringer Ingelheim Investigational Site, Wien
• 1241.21.33002 Boehringer Ingelheim Investigational Site, Montpellier
• 1241.21.33001 Boehringer Ingelheim Investigational Site, Marseille
• 1241.21.35101 Boehringer Ingelheim Investigational Site, Lisboa
• 1241.21.33008 Boehringer Ingelheim Investigational Site, Paris
• 1241.21.43003 Boehringer Ingelheim Investigational Site, Linz
• 1241.21.0005 Boehringer Ingelheim Investigational Site, Austin Texas
• 1241.21.49006 Boehringer Ingelheim Investigational Site, Hamburg
• 1241.21.33006 Boehringer Ingelheim Investigational Site, Vandoeuvre Cedex
• 1241.21.34001 Boehringer Ingelheim Investigational Site, Majadahonda-Madrid
• 1241.21.0006 Boehringer Ingelheim Investigational Site, San Diego California
• 1241.21.0015 Boehringer Ingelheim Investigational Site, Portland Oregon
• 1241.21.34003 Boehringer Ingelheim Investigational Site, Madrid
• 1241.21.0016 Boehringer Ingelheim Investigational Site, Richmond Virginia
• 1241.21.35102 Boehringer Ingelheim Investigational Site, Porto
• 1241.21.0003 Boehringer Ingelheim Investigational Site, La Jolla California
• 1241.21.34004 Boehringer Ingelheim Investigational Site, Madrid
• 1241.21.0018 Boehringer Ingelheim Investigational Site, San Diego California
• 1241.21.49004 Boehringer Ingelheim Investigational Site, Leipzig
• 1241.21.0013 Boehringer Ingelheim Investigational Site, Valparaiso Indiana
• 1241.21.41006 Boehringer Ingelheim Investigational Site, Bern
• 1241.21.41003 Boehringer Ingelheim Investigational Site, Basel
• 1241.21.0019 Boehringer Ingelheim Investigational Site, Fayetteville North Carolina
• 1241.21.34006 Boehringer Ingelheim Investigational Site, Valencia
• 1241.21.41001 Boehringer Ingelheim Investigational Site, St. Gallen
• 1241.21.34002 Boehringer Ingelheim Investigational Site, Barcelona
• 1241.21.0007 Boehringer Ingelheim Investigational Site, Dallas Texas
• 1241.21.35103 Boehringer Ingelheim Investigational Site, Aveiro
• 1241.21.40001 Boehringer Ingelheim Investigational Site, Bucharest
• 1241.21.49007 Boehringer Ingelheim Investigational Site, Düsseldorf
• 1241.21.33003 Boehringer Ingelheim Investigational Site, Lyon
• 1241.21.49009 Boehringer Ingelheim Investigational Site, Hannover
• 1241.21.33004 Boehringer Ingelheim Investigational Site, Paris
• 1241.21.41002 Boehringer Ingelheim Investigational Site, Zürich
• 1241.21.49003 Boehringer Ingelheim Investigational Site, Berlin
• 1241.21.61001 Boehringer Ingelheim Investigational Site, Melbourne Victoria

Description:

The substances BI 201335 and BI 207127 are being developed for the treatment of chronic hepatitis C virus infection. BI 201335 and BI 207127 work by preventing the virus from replicating. The currently available medications pegylated interferon alfa and ribavirin for hepatitis C ca have considerable adverse events in patients and in many cases are not sufficiently effective. This is particularly the case in treatment of patients infected with genotype 1 of HCV. A combination therapy of these new substances without pegylated interferon alfa may be associated with fewer adverse events that currently available (pegylated interferon-alfa-based) medication and may also provide a treatment option to the large number of patients with contraindications or intolerance to pegylated interferon alfa.

See this on ClinicalTrials.gov

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Chronic Hepatitis B Management Based on Standard Guidelines in Community Primary Care and Specialty Clinics

Dig Dis Sci. 2013 Oct 13. [Epub ahead of print]

Ku KC, Li J, Ha NB, Martin M, Nguyen VG, Nguyen MH.

College of Osteopathic Medicine, Touro University Nevada, Henderson, NV, USA.

Abstract

BACKGROUND AND AIMS: Prior studies have underlined the need for increased screening and awareness of chronic hepatitis B (CHB), especially in certain high-risk populations. However, few studies have examined the patterns of evaluation and management of CHB between primary care physicians (PCP) and specialists according to commonly-used professional guidelines. Our goal was to examine whether necessary laboratory parameters used to determine disease status and eligibility for antiviral therapy were performed by PCPs and specialists.

METHODS: We conducted a retrospective study of 253 treatment-naïve CHB patients who were evaluated by PCP only (n = 63) or by specialists (n = 190) for CHB at a community multispecialty medical center between March 2007 and June 2009. Criteria for CHB management and treatment eligibility were based on the American Association for the Study of Liver Diseases 2007 guideline and the US Panel 2006 algorithm. Required parameters for optimal evaluation for CHB included hepatitis B e antigen (HBeAg), HBV DNA, and alanine aminotransferase (ALT). Preferred antiviral agents for CHB included pegylated interferon, adefovir, and entecavir.

RESULTS: The majority of patients were Asians (90 %) and male (54 %) with a mean age of 43 ± 11.6 years. Compared to PCPs, specialists were more likely to order laboratory testing for ALT (94 vs. 86 %, P = 0.05), HBeAg (67 vs. 41 %, P < 0.0001) and HBV DNA (83 vs. 52 %, P < 0.0001). The proportion of patients having all three laboratory parameters was significantly higher among those evaluated by specialists compared to PCP (62 vs. 33 %, P < 0.0001). A total of 55 patients were initiated on antiviral treatment (n = 47 by specialists and n = 6 by PCPs). Lamivudine was prescribed more often by PCPs than specialists (33 vs. 2 %, P = 0.05). Preferred agents were used 96 % of the time by specialists compared to 67 % of those treated by PCPs (P = 0.05).

CONCLUSION: Patients evaluated by specialists for CHB are more likely to undergo more complete laboratory evaluation and, if eligible, are also more likely to be treated with preferred longer-term agents for CHB compared to those evaluated by PCPs only. A collaborative model of care involving both PCP and specialists may further optimize management of patients with CHB.

PMID: 24122622 [PubMed - as supplied by publisher]

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Is the genotype 3 of the hepatitis C virus the new villain?

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Viral Hepatitis

Nicolas Goossens¹, Francesco Negro^1,2,*

DOI: 10.1002/hep.26905

Copyright © 2013 American Association for the Study of Liver Diseases

Keywords:protease inhibitor; polymerase inhibitor; steatosis; cirrhosis; hepatocellular carcinoma

Abstract

The genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to-treat infection, with higher cure rates (~70%) than other viral genotypes with the standard combination of pegylated interferon-α and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir, have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. Conclusion: Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments. (Hepatology 2013;)

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AIDS-Free World? Doable, but Not Easy

Published: Oct 23, 2013

By Michael Smith, North American Correspondent, MedPage Today

The prospect of a world without AIDS is real, but getting there won't be easy.

That's the bottom line in a series of papers on the topic published in three journals in advance of a translational medicine conference on the topic slated for early November in San Francisco.

"Achieving an AIDS-free world is no longer an idealistic aspiration -- it is an achievable goal," argued Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and Hilary Marston, MD, also of the institute.

But getting there will require "effective implementation" of current ways of preventing AIDS, combined with finding new interventions, Fauci and Marston argued online in Cell and The Lancet.

And the path forward, while now at least partly visible, remains littered with roadblocks.

For instance, evidence is mounting that highly active antiretroviral therapy (HAART) can dramatically inhibit the transmission of HIV between sexual partners.

In principle, if every person infected with HIV were immediately to start taking appropriate medications, the progress of the HIV/AIDS pandemic could slow and begin to reverse, argued Myron Cohen, MD of the University of North Carolina in Chapel Hill, and colleagues.

But, they wrote in The Lancet, "challenges to this approach are substantial."

For so-called treatment-as-prevention to work, they argued, will require universal access to medications that begins soon after a person is infected with HIV.

But "not all HIV-infected individuals can be located, especially people with acute and early infection who are most contagious," the investigators noted.

Current guidelines in the developed world call for HIV treatment to be started as soon as possible after diagnosis, but not all countries have embraced the idea, they added.

"Some experts do not believe that immediate or early (therapy) is justified by present evidence, or that healthcare infrastructure for this approach is sufficient," Cohen and colleagues wrote.

An important issue is how widely the idea of treatment-as-prevention applies. The major study -- one led by Cohen -- showed a 96% reduction in the risk of transmission among heterosexual couples in which one partner was HIV-positive and the other was not.

But the ability of antiretroviral therapy to cut transmission among men who have sex with men (MSM) and injection drugs users remains to be seen, the investigators noted.

Indeed, stable HIV incidence in some communities of MSM where antiretroviral therapy is established and widely used "emphasizes the concern that not enough is known about treatment as prevention for this crucial population," they argued.

While treatment-as-prevention has scooped recent headlines, HAART also has its original use -- preventing the progression of HIV infection to full-blown AIDS, argued researchers led by Steven Deeks, MD, of the University of California San Francisco.

Properly followed, they pointed out (also in The Lancet), HAART prevents a host of AIDS-related illnesses. However, "a new set of HIV-associated complications has emerged, resulting in a novel chronic disease that for many will span several decades of life."

The therapy doesn't completely restore the immune system, they noted, so that complications such as cardiovascular disease and cancer are becoming more important among HIV patients.

Moreover, anti-HIV drugs themselves have cumulative toxicities that -- over years of treatment -- "can cause clinically-relevant metabolic disturbances and end-organ damage."

Especially in developing countries, the "multimorbidity" associated even with properly treated HIV could overwhelm some healthcare systems, Deeks and colleagues argued.

The holy grails of HIV research -- a vaccine and a cure -- remain elusive, Fauci and Marston commented, but intense research is underway on both fronts.

There has been some halting progress toward a vaccine, they noted, and a cure for HIV "is no longer beyond the imagination."

Primary source: The Lancet
Source reference: Cohen MS, et al "Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: Where do we go from here?" Lancet 2013; DOI: 10.1016/S0140-6736(13)61998-4.

Additional source: The Lancet
Source reference:Deeks SG, et al "The end of AIDS: HIV infection as a chronic disease" Lancet 2013; DOI: 10.1016/S0140-6736(13)61809-7.

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