May 21, 2013

Interferon-free, treat-all approach cost effective, beneficial for chronic HCV

Provided by Healio

May 21, 2013

ORLANDO, Fla. — An orally administered, interferon-free regimen with a treat-all approach for patients with chronic hepatitis C may be more beneficial and more cost effective than interferon-based triple therapy, according to data presented at Digestive Disease Week.

Researchers used a decision analytic Markov model to compare four methods of treatment for chronic HCV genotype 1: Triple therapy with pegylated interferon, ribavirin and a direct-acting antiviral (DAA) with (method 1) or without biopsy guidance (method 2); and an orally administered, interferon-free regimen with (method 3) or without biopsy guidance (method 4). The methods that incorporated biopsy began treatment at fibrosis stage F2 – F4, with repeated biopsies every 5 years until patients were aged 70 years.

A treatment-naive, 50 year-old patient served as a reference case. Investigators based treatment outcomes for methods 3 and 4 on study results presented at scientific meetings, and baseline cost and utility for methods 3 and 4 were calibrated to match triple therapy.

“As all-oral regimens are in the process of being developed by various pharmaceutical and biotechnology companies, interest has been focused on efficacy and side-effect profiles of these therapies,” researcher Heshaam M. Mir, MD, director of research in the Liver & Obesity program at Inova Fairfax Hospital in Falls Church, Va., told “We did not see a great deal published in the literature nor presented at the major liver conferences discussing the economic impact of these all-oral regimens. We thought it would be an area of interest for the medical community.”

Method 4 was the most cost-effective approach, with an incremental cost-effectiveness ratio (ICER) of $16,289 per quality-adjusted life-year (QALY). Departure from baseline cost and utility of oral therapy did not raise the ICER above $50,000/QALY for this approach. This treatment also presented the lowest risk for developing cirrhosis (6.8%), decompensation or hepatocellular carcinoma (11%) and transplantation (2.7%) and was linked to the largest number of QALYs (18.351) compared with the other methods.

“A validated Markov model showed that an all-oral, interferon-free, treat-all regimen was the most cost-effective approach for treating chronic hepatitis C genotype 1 patients,” Mir said. “In addition to the economic advantage, it reduced the number of chronic hepatitis C patients reaching advanced liver disease, and increased life expectancy.”

Disclosure: Researcher Zobair M. Younossi reported serving on advisory committees/review panels for Salix Pharmaceuticals, Vertex Pharmaceuticals, Tibotec and GlaxoSmithKline, along with consulting services for Gilead Sciences and Conatus Pharmaceuticals.

For more information:

Younossi ZM. Sa1067: Interferon-Based and Interferon-Free Regimens for Patients with Chronic Hepatitis C, Genotype 1: Potential Cost-Effectiveness of Biopsy-Guided Treatment Versus Treat All Strategies. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla.


Low Potassium Linked with Liver Disease

By Kristina Fiore, Staff Writer, MedPage Today

Published: May 21, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that this cross-sectional study demonstrated an association between non-alcoholic fatty liver disease and lower potassium levels in a Chinese population.
  • Be aware that the mean potassium difference between those with and without NAFLD was extremely small, made significant due to the large sample size.

Patients with non-alcoholic fatty liver disease (NAFLD) also had low potassium levels, researchers in China found.

In a population-based, cross-sectional study, patients with NAFLD had significantly lower serum potassium levels than those who did not have the liver condition (4.09 mM versus 4.14 mM, P<0.0001), Guang Ning, MD, of Shanghai Jiao-Tong University School of Medicine, and colleagues reported online in Clinical Endocrinology.

NAFLD has become an increasing burden on the healthcare system in recent years, so researchers have been interested in identifying risk factors for the condition, particularly with regard to environmental exposures, they noted in their introduction.

Some studies have shown that lack of potassium -- needed for normal cellular function and metabolic balance -- may contribute to various metabolic disorders, including insulin resistance, which may ultimately increase the risk of NAFLD.

To more closely assess the relationship between serum potassium and NAFLD, the researchers enrolled 8,592 Chinese patients -- 2,663 men and 5,929 women -- in their study. Three out of 10 patients in the overall cohort (30.3%) had NAFLD, with the prevalence gradually decreasing across increasing serum potassium quartiles.

Not only did those with NAFLD have significantly lower serum potassium levels than those without, but the prevalence of NAFLD in patients with hypokalemia was significantly higher than that seen in patients with normal serum potassium (40.5% versus 29.6%, P<0.0001).

Patients with lower serum potassium levels also had a larger waist circumference and more severe insulin resistance, and these associations held in multivariate linear regression analyses, they reported.

Compared with patients in the highest quartile of serum potassium, those in the lowest quartile had a higher risk of:

  • NAFLD (OR 1.33, 95% CI 1.11-1.60)
  • Insulin resistance (OR 1.81, 95% CI 1.49-2.19)
  • Central obesity (OR 1.58, 95% CI 1.30-1.93)

In adjusted subgroup analyses, the researchers also found a significant relationship between serum potassium levels and the following factors:

  • Female sex (OR 1.11, 95% CI 1.03-1.19, P=0.006)
  • Younger age (OR 1.13, 95% CI 1.04-1.23, P=0.005)
  • Central obesity (OR 1.16, 95% CI 1.07-1.25, P=0.0001)
  • Insulin resistance (OR 1.17, 95% CI 1.06-1.30, P=0.003)

One potential mechanism linking low potassium levels with NAFLD is insulin resistance, the researchers said. Potassium depletion could cause low nitric oxide levels and endothelial dysfunction, they noted, which could ultimately lead to insulin resistance, as well as hypertriglyceridemia and glucose intolerance.

The study was limited, however, because NAFLD was diagnosed via ultrasound, instead of the gold standard of liver biopsy, and by the fact that the researchers did not assess dietary potassium intake.

Still, the researchers concluded that decreased serum potassium is associated with the prevalence of NAFLD and that insulin resistance and central obesity may play an important role in this association.

They called for further observational studies and clinical trials to determine whether correcting potassium deficiency can effectively reduce the incidence of NAFLD.

The study was supported by the Ministry of Health of China, the National Natural Science Foundation of China, and the Shanghai New Excellent Youth Program.

The researchers reported no conflicts of interest.

Primary source: Clinical Endocrinology
Source reference:
Sun K, et al "Low serum potassium level is associated with non-alcoholic fatty liver disease and its related metabolic disorders" Clinical Endocrinol 2013; DOI: 10.1111/cen.12168.


Baby Boomers Urged to Get Tested for Hepatitis C Virus

Tue May 21, 2013 11:45am EDT

Saint Luke's Liver Disease Management Center says testing is key to saving lives, 'silent infection' rampant among baby boomers

PR Newswire

KANSAS CITY, Mo., May 21, 2013

KANSAS CITY, Mo., May 21, 2013 /PRNewswire-USNewswire/ -- If you're a baby boomer, you may not know that odds are high that you're carrying the hepatitis C virus, putting yourself at risk for illness that can range from minor to life threatening.

Hepatitis C is a contagious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The disease can range in severity from a mild illness lasting a few weeks, to a serious, lifelong condition that can lead to cirrhosis of the liver or liver cancer. The virus is transmitted through contact with the blood of an infected person.

Liver specialists at Saint Luke's Liver Disease Management Center join experts at the National Viral Hepatitis Roundtable in urging people born from 1945 to 1965 to get screened. "Most people with chronic HCV have no symptoms and are completely unaware they carry this 'silent' virus," said Frederic Regenstein, M.D., medical director, Saint Luke's Liver Disease Management Center. "It is vital that boomers and other populations at increased risk for hepatitis C get tested, and that they receive appropriate testing, including a follow up test when needed.

"Without appropriate testing, those with hepatitis C are less likely to learn about their infection and get the critical care and treatment that they need in order to prevent cancer, and other serious health consequences. May is National Hepatitis Awareness Month, and a perfect time to look into screening," Dr. Regenstein added.

A new report from the Centers for Disease Control (CDC) underscores the severe impact of hepatitis C among baby boomers (individuals born from 1945 through 1965). Baby boomers accounted for 67 percent of all reported hepatitis C cases and 72 percent of all reported deaths among persons with hepatitis C. The CDC recommends that all baby boomers get tested for hepatitis C.

The recent CDC data comes from enhanced hepatitis C surveillance in eight areas across the country. The findings indicate that half of those identified as having a positive hepatitis C antibody blood test reported to the health department also had the appropriate follow-up testing to determine if they are still infected. The other half did not have a follow-up test reported. Without the hepatitis C follow-up test, individuals do not know if they still have hepatitis C and cannot get the care and treatment they need. In this study, deaths were higher among those who did not have a follow-up test reported to the health department.

Left untreated, hepatitis C can cause serious liver damage, including liver cancer – the fastest-rising cause of cancer-related death in the U.S. In fact, deaths from hepatitis C-related illness, such as liver failure and liver cancer, have nearly doubled over the past decade, now accounting for more than 15,000 deaths in the U.S. each year. The CDC estimates that testing baby boomers for hepatitis C could identify more than 800,000 additional people with hepatitis C and save more than 120,000 lives.

According to the updated guidance, individuals tested for hepatitis C should receive a screening blood test, called an antibody test, in order to determine if the person has ever been infected with the hepatitis C virus. For those with a positive hepatitis C antibody test, a follow-up test is needed to determine if a person is still infected. In order to help ensure that patients are properly diagnosed, it is critical that providers conduct follow-up testing to ensure they receive life-saving care and treatment.

About Saint Luke's Liver Disease Management Center
At Saint Luke's Liver Disease Management Center, patients throughout the Midwest and across the United States have access to liver disease treatment options provided by a multidisciplinary physician group. From preventive care to liver transplantation, Saint Luke's provides a full range of services for patients with disorders of the liver, bile ducts, and pancreas.

Screenings are available; check local health departments for information.

SOURCE Saint Luke's Health System


Is the HCV Pipeline Heading in the Right Direction?

Volume 144, Issue 3 , Pages 482-485, March 2013

Andrew Aronsohn

Andrew J. Muir

Tracy Swan

Donald Jensen

University of Chicago Medical Center, Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, Center for Liver Diseases, Chicago, Illinois

Division of Gastroenterology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina

Treatment Action Group, New York, New York

University of Chicago Medical Center, Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, Center for Liver Diseases, Chicago, Illinois

published online 24 January 2013.

Hepatitis C (HCV) is a global health concern, with >180 million people infected worldwide. Advances in HCV therapy do not necessarily result in improvement of patient outcomes unless specific patient needs and therapeutic options are incorporated into development plans. In this commentary, we explore the lessons learned from the first generation of direct-acting antivirals (DAAs) and apply this insight to optimize delivery, safety, and efficacy to patients who will receive future generation of DAAs.

Lessons Learned From the First-Generation DAAs

The release of boceprevir and telaprevir in May 2011 marked a new era in HCV therapy. For many patients with genotype 1 HCV, DAA-based therapy has offered a significant improvement from previous standard of care.1, 2 However, first-generation DAA-based therapy is not a panacea, and to date, many patients remain untreated. Identification of the therapeutic need of at-risk patients will be of increasing importance as new HCV medications are under development.

Access to Care

In an era where a significant proportion of patients can now be cured of HCV, lack of adequate awareness, screening, access to care, and affordability of therapy persist; therefore, many infected patients remain both undiagnosed and untreated. Patients with limited resources, including those from developing countries with limited access to medical care, are among those with the highest prevalence of HCV and are unlikely to benefit from advances in HCV therapy.3 Reduction of HCV-related burden of disease will be realized only if a global infrastructure is in place to allow for cost-effective screening and delivery of HCV care. First, in resource-limited regions, consideration should be given to allocate therapy to patients based on need such as those with more advanced disease. Targeting effective therapy on a global scale is not a “one size fits all” approach. Patients who reside in resource-limited regions may not have access to the newest generations of DAA therapy and creative approaches for therapy that control cost should be sought. For example, in East Asian countries with a high prevalence of interleukin (IL)-28b CC genotype, focus on improvements in screening, and treatment with peginterferon alfa/ribavirin (PEG/RBV) may yield more overall benefit than attempting to pay for increasingly expensive DAA regimens that offer relatively small improvements in efficacy. Next, policy promoting effective linkage to care will be needed to ensure access to HCV care for all patients. This type of policy would include increases in mid-level providers specializing in HCV treatment, expansion of HCV treatment into the realm of primary care, and improvement in physician education along with incentivizing HCV care. Finally, ongoing research should prioritize simplified therapeutic algorithms that reduce the cost of initial evaluation and monitoring during therapy.

Currently Underserved Populations

Cirrhosis is becoming increasingly common among patients with HCV.4 Recently reported data from the CUPIC (Compassionate Use of Protease Inhibitors in Viral C Cirrhosis) cohort, a French early access program consisting of cirrhotic nonresponders, revealed poor tolerability of telaprevir and boceprevir-based treatment.5 A 16-week interim analysis reporting data from 292 patients receiving telaprevir and 205 patients receiving boceprevir showed significantly more patients with serious adverse events, including 6 deaths, when compared with published clinical trials (32.7%–45.2% SAE in CUPIC versus 9%–14% in clinical trials).5 Ongoing development programs should prioritize identification of features predictive of good treatment outcomes as well as development of better tolerated treatment regimens for cirrhotic patients.

HIV coinfection

HIV/HCV coinfection carries increased risk of progression to fibrosis and decompensation compared with the monoinfection.6 Although small phase II studies have shown improved efficacy and acceptable safety profiles in telaprevir- or boceprevir-based therapy in this population, treatment remains off label in coinfected patients and treatment decisions are currently being based on limited data.7, 8 Despite these limitations, off-label use will continue to occur to provide therapy to those most in need. Drug development programs should prioritize early and robust study of drug–drug interactions (DDI), ideally in parallel with phase II studies. Efforts should also be made to obtain labeling that extends to the HIV/HCV coinfected population because this will likely be necessary for widespread reimbursement. Rapid development and dissemination of treatment guidelines by specialty societies will also be important in guiding treatment decisions and reimbursement.

Post liver transplantation

HCV treatment with PEG/RBV in the post liver transplant population has yielded suboptimal results owing to low sustained virologic response rates, poor tolerability, and adverse events such as acute rejection.9 Unfortunately, extensive DDI with commonly used immunosuppressants have hindered the use of first-generation DAAs in this population (70-fold increase in tacrolimus concentration and 4.6-fold increase in cyclosporine concentration when administered with telaprevir).10 Many transplant centers have devised internal protocols using DAA-based treatment by extrapolating data from pharmacokinetic studies in an effort to make treatment as safe as possible. Although investigation to optimize the current treatment regimen is ongoing and of importance, first-generation DAAs may not be durable agents in this population, and prospective studies using newer generation DAAs, ideally without need for interferon, should be aggressively pursued.

Patients with medical comorbidities

Patients with multiple medical comorbidities are unlikely to be candidates for telaprevir- or boceprevir-based therapy owing to concerns over tolerability and a relative paucity of robust DDI data available for patients on multiple medications. Polypharmacy in the setting of multiple comorbidities is especially prevalent in older patients. These patients are at increased risk of HCV-related morbidity and mortality and have unique therapeutic needs that are not fully addressed by currently available HCV therapy. In addition, HCV has a high prevalence among patients with chronic kidney disease and is an independent risk factor for mortality in patients who are undergoing hemodialysis.11 Currently, there are no published efficacy, pharmacokinetic, or safety data for the use of telaprevir or boceprevir given in combination with PEG/RBV in patients with severe chronic kidney disease.12 Ribavirin is renally cleared and therefore carries increased risk in this patient population. Consideration should be given to devising dosing schedules based on renal clearance with DAA regimens.

The Next Generation of HCV Therapy

Ongoing clinical trials hold considerable promise for improvements in HCV therapy. Newer NS3/4A protease inhibitors, NS4B inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, lambda interferon, and cyclophilin inhibitors are currently under development with hopes to deliver effective, safe and, shorter duration of therapy when compared with current standard of care (Table 1).13, 14, 15, 16, 17, 18, 19, 20, 21 Agents featuring increased potency that allow for simultaneous targeting of various aspects of HCV replication using multiple agents will likely result in interferon-free therapy.

Table 1. Direct-Acting Antiviral Agents Currently in Phase 3 Trials

Drug Type of agent Interferon-containing regimen Genotype Response in phase II trials Anticipated completion of phase III trials
Simeprevir (TMC 435)13 Protease inhibitor Yes 1 75%–86% SVR 24 in treatment naive January 2013
Faldaprevir (BI 201335)14 Protease inhibitor Yes 1 71%–83% SVR 24 in treatment naive February 2014
BI 20712715 NS5B inhibitor (given in combination with faldaprevir) No 1 52%–69% SVR 12 in treatment naive August 2015
Daclatasvir (BMS 790052)16 NS5a inhibitor Yes 1 64%–65% SVR12 in treatment naive January 2014
Asunaprevir (BMS 650032)17 Protease inhibitor (given in combination with daclatasvir) No 1 63%–87% SVR4 in null responders July 2014
Sofosbuvir (GS 7977)18, 19 Nucleotide polymerase inhibitor Yes 1 90% SVR 12 in treatment naive July 2013
    No 2,3 100% SVR in treatment naive July 2013
GS 588520 NS5a inhibitor (given in combination with sofosbuvir) No 1 No SVR data available Dec 2014
ABT-450/r, ABT 267, ABT-33321 Protease inhibitor, NS5A inhibitor, non-nucleoside polymerase inhibitor No 1 SVR 85%–99% in treatment naive/null responders October 2014

SVR, sustained virologic response.

Anticipated Challenges

Will All Patients Be Able to Be Treated Without Interferon?

Interferon-free HCV therapy will represent a breakthrough in HCV treatment. Trials to date are encouraging, but have begun to reveal important interactions between drug, host, and virus that need to be better understood before interferon-free therapy becomes a mainstay of treatment. Previously unidentified host and viral characteristics may create a requirement for interferon-based therapy for some, raising the possibility that all oral regimens may not be appropriate for all patients. In addition, the cost of newly developed interferon-free regimens may be prohibitive, especially in many resource-limited regions of the world. Enthusiasm over the possibility of an “all-oral” cure for HCV must be balanced with realization that cost of therapy will create a disparity among those who can receive interferon-free therapy and those who do not have access. HCV will carry an extensive global burden of disease, even in an interferon-free era, if efforts are not made to diminish this disparity.

Off-Label Prescribing

First-generation DAAs are already being used off label to treat HIV coinfected patients and post liver transplant patients with significant HCV recurrence. Future availability of multiple DAAs with unique antiviral mechanisms may lead to “mixing and matching” therapeutic combinations that have yet to be thoroughly investigated. Off-label interferon-free combinations with limited supporting data may lead to unintended adverse events, emergence of viral resistance, and missed opportunities to treat with available therapy that is known to be highly effective and safe. Patients with decompensated cirrhosis and/or renal insufficiency are examples of patients with significant need for therapy; however, physiologic response to exposure of new DAAs with or without interferon is unpredictable. Treatment with future DAA regimens off label, without appropriate pharmacokinetic and dosing studies, may pose a significant risk to patients. Despite these risks, off-label prescribing will likely occur; therefore, it should be acknowledged and efforts should be made to reduce risk to patients. First, education of patients and providers is essential to gain an understanding of the risks of off-label prescribing. Next, for patients with no other options except off-label treatment, efforts should be made to collaborate and report experience of safety and outcomes. Finally, marketing concerns may dictate access to optimal combination therapy. Even if off-label regimens are promising, payers may not be willing to offer reimbursement. Public–private research partnerships to facilitate development of best-in-class regimens from different sponsors should be considered to encourage clinical collaboration between pharmaceutical companies.

Focusing Drug Development on Patients in Need

Clinical trials focusing on patients with few comorbidities are important to show efficacy and safety; however, because sustained virologic response rates using newer agents approach and exceed 90% in younger, healthy patients with no cirrhosis, we risk creating an oversaturated market for these patients while struggling to treat patients with limited resources and with more extensive liver disease and comorbidities. This disparity has already emerged since approval of the first-generation of DAAs and is at risk of further propagation unless specific attention is given to these underserved populations. Small, open-label studies should be conducted in parallel with phase III, for sicker patients who are ineligible for clinical trials. These trials would offer potentially life-saving treatment and would begin to characterize risks and benefits of different treatment regimens in currently underserved populations. In addition, the robust HCV pipeline comes at a cost. Money spent on research and development will ultimately be passed on to patients and our health care system overall. Payers may not cover costs of incremental improvements of medical therapy once standard of care treatment reaches an acceptable safety and efficacy profile. We should be conscious of reaching a point of diminishing returns in patients with high potential of cure and redirect research effort and funding to benefit those in need including those without access to any DAAs.

Hopes and Expectations: Overcoming Disparities in HCV Therapy

What can be done to ensure the HCV pipeline is heading in the right direction? Focus on appropriate allocation of therapy and accessibility to these resources is key. Large, multicenter, prospective, observational studies such as PEGBase, HCV-TARGET, CUPIC, and ANRS CO13 HEPAVIH, all of which aim to gather data from thousands of patients treated with triple therapy since the approval of telaprevir and boceprevir, are already underway and will be crucial in capturing data that is missing from published clinical trials. Because these observational registries obtain data from many providers from multiple sites, the quality of data should be carefully assessed. Standardization of data entry and judicious quality assurance monitoring, preferably though a centralized site, should be employed to ensure reliable and useful data are available. Continued involvement of key stakeholders such as advocacy and patient groups is essential to ensure that vulnerable and underserved populations have appropriate representation. In addition, both the need and potential danger of off-label prescribing of HCV therapy should be acknowledged with steps taken to allow for the safest possible outcomes. Finally, we should not assume that in upcoming years all patients will have access to HCV treatment. HCV is a global epidemic and many patients in resource-limited countries will not have access to DAA-based therapy. Efforts to develop a cost-effective treatment strategy for these populations is essential.

Advances in HCV therapy will bring new challenges. Success of the upcoming generations of DAAs will not be measured in incremental improvements of sustained virologic response, but rather by the availability of treatment options and accessibility to care for all patients infected with HCV.




30 Years of HIV: Looking Back, Looking Ahead


By Michael Smith, North American Correspondent, MedPage Today

Published: May 20, 2013

There was no fanfare on May 20, 1983 when Science published what is undoubtedly among the most important medical papers of the 20th century.

In the usual dry prose, researchers from the Institut Pasteur in Paris described a new retrovirus, which they dubbed lymphoadenopathy associated virus, or LAV.

It was, they reported, a "typical type-C RNA tumor virus" with a tropism for T-lymphocytes and was similar to -- but clearly distinct from -- human T-cell leukemia viruses, which had recently been discovered.

Today, we know it simply as HIV.

That paper made very little immediate impression, according to Françoise Barré-Sinoussi, PhD, of the Pasteur institute, who was the lead author and who later shared the 2008 Nobel prize in medicine for the discovery with the senior author Luc Montagnier, PhD.

Partly that was because HIV/AIDS -- although mysterious and deadly -- was not yet seen as a global threat.

Finding the virus "was not just an academic problem," Barré-Sinoussi told MedPage Today. "But there were only a few cases and we did not yet have the idea of the magnitude of the infection, the magnitude of the epidemic."

And the scientific community wanted more before breaking out the champagne. "We had to accumulate more data about the links between the virus itself and the disease," she said.

For those studying the issue, "it was a very important paper," commented Anthony Fauci, MD, director of the National Institute for Allergy and Infectious Diseases.

But it wasn't a "slam-dunk," he told MedPage Today. "Although it was clear they had isolated the virus ... there was no way to definitively diagnose people who were presenting at hospitals" so there was a missing link.

It was still necessary to demonstrate epidemiological links between the virus and people with AIDS, a demonstration that came the next year with papers by Robert Gallo, MD, then at the National Cancer Institute, and colleagues, Fauci said.

That research provided "epidemiological and serological proof that the virus was unequivocally associated with the disease that we were just then starting to call AIDS," he said.

But as that data accumulated, it became evident that French discovery was indeed significant -- the cause of the disease was finally known. Researchers optimistically talked about vaccines and cures as if they would be -- not easy, perhaps -- but not out of reach.

This week in Paris, the Pasteur institute will play host to an international symposium to mark the 30th anniversary of that discovery and there is a renewed sense of optimism about the pandemic.

But there is also an understanding that HIV remains a tough challenge, Fauci said. He is to deliver a keynote talk and part of its title sums up the past three decades of HIV/AIDS research: "much accomplished, much to do."

Among the "much to do," Fauci said, is to crack the tough problems of a vaccine and a cure -- the same tough problems that have dogged the field since 1983.

At that time, he said, "we didn't realize that HIV was such a difficult virus" and it wasn't yet clear that it would not easily surrender to medical science.

On the vaccine front, for instance, the usual approach is to try to mimic nature -- cause an immune response that first halts, then clears, and then protects against the disease.

But in HIV, that's not nature's way, Fauci noted. With vanishingly few exceptions, no one mounts an immune response that stops, clears, and protects against HIV.

"If you're going to develop a vaccine you're going to have to do better than nature," he said.

So far, of course, researchers have not managed to do that.

Along with the 20,000-foot view that Fauci brings to the table, the Paris symposium will hear more about the basic science of HIV and its interaction with the immune system, which 30 years later, is still not completely understood, according to Barré-Sinoussi.

"We need to have some new discoveries in the field of immunology," she said. "There are still some missing pieces of the puzzle."

Barré-Sinoussi said she's also expecting to hear more about the so-called "functional cures" that made headlines earlier this year. In a functional cure, patients still remain infected, but they can control the virus without the aid of antiretroviral medications.

Exactly how that can be made to happen reliably remains an open question that -- if it could be answered -- would change the face of the HIV/AIDS pandemic.

She's looking forward to reports on the mechanisms by which HIV establishes itself in the body and then persists despite antiretroviral medications that prevent it from replicating.

And there will be more details at the symposium about vaccine research, including a debate on the best way to move forward after the partial success of a major trial 4 years ago and the recent failure of another.

What Barré-Sinoussi is not expecting is anything dramatic. An announcement of a breakthrough "would be wonderful, but I don't think we will have that."

On the other hand, no one immediately recognized the breakthrough by her and her colleagues 30 years ago, so time may tell.


Co-infection with hepatitis B does not alter treatment response in chronic hepatitis C

Clin Res Hepatol Gastroenterol. 2013 May 9. pii: S2210-7401(13)00052-1. doi: 10.1016/j.clinre.2013.03.002. [Epub ahead of print]

Uyanikoglu A, Akyuz F, Baran B, Simsek BP, Ermis F, Demir K, Gulluoglu M, Badur S, Kaymakoglu S.

Harran University, Faculty of Medicine, Department of Gastroenterology, Sanliurfa, Turkey. Electronic address:


BACKGROUND/AIM: To investigate the clinical features and treatment response in patients with hepatitis B (HBV) and hepatitis C virus (HCV) co-infection receiving anti-HCV therapy.

PATIENTS AND METHOD: Patients with HBV/HCV co-infection, who were eligible for anti-HCV therapy, were included in the study. Patients had detectable HBsAg for at least 6months and detectable HCV-RNA before the initiation of therapy. Primary end-point was the proportion of patients achieving sustained virological response (SVR). HBV serology and HBV-DNA results obtained during the follow-up were assessed to determine HBV clearance or reactivation after anti-HCV therapy.

RESULTS: There were 612 patients in the HCV cohort and 52 (8.5%) of them were HBV/HCV co-infected. Twenty-eight patients (20 male, mean age: 47±12) received anti-HCV treatment and followed-up for a mean duration of 53months (12-156). Fifteen patients received peginterferon/ribavirin combination while the remaining patients received standard interferon/ribavirin combination (n=6) or standard interferon monotherapy (n=7). Patients receiving interferon monotherapy were under chronic hemodialysis therapy. SVR was achieved in 14 (50%) patients at the end of follow-up. The proportion of patients with SVR in three treatment arms were not significantly different (P=0.78). Eight of 11 patients with detectable HBV-DNA cleared HBV-DNA during treatment. Seven (25%) patients experienced a rebound in HBV-DNA, and one patient experienced an acute hepatitis flare which was controlled by tenofovir therapy. Two (7%) patients cleared HBsAg and one of them was seroconverted to anti-HBs.

CONCLUSION: Co-infection with HBV does not have a negative impact on the efficacy of anti-HCV treatment, but HBV-DNA should be monitored to overcome the risk of HBV exacerbation.

Copyright © 2013. Published by Elsevier Masson SAS.


New Direct-Acting Antivirals Promising for Hepatitis C Treatment

Provided by HCPLive


By Debra Wood, RN | May 20, 2013

Antiviral hepatitis C drugs on the horizon could spur more people to accept treatment and improve patient outcomes, Andrew J. Muir, MD, MHS, associate professor of medicine and clinical director of hepatology at Duke University in Durham, NC, reported at Digestive Disease Week 2013, held May 18-21, 2013, in Orlando, Fla.

“It’s a great time in hepatitis C and for telling patients the great things that are going to come to help them,” Muir said.

According to Muir, approximately 3.2 million people have hepatitis C, and about half of the cases have been detected while one third have been referred to care. Only 5 percent to 6 percent of patients have been successfully treated, Muir said.

“I hope the new drugs and response rates will bring people out,” Muir said. “We need to be proactive to make that happen.”

The Centers for Disease Control and Prevention has recommended screening baby boomers for hepatitis C, but the U.S. Preventive Services Task Force has been less enthusiastic, issuing a Grade B recommendation for people at risk and a Grade C recommendation for people at average risk who were born between 1945 and 1965.

Muir indicated the field has been held back by the inability to prove treatment has saved lives. However, more recent studies have shown reductions in liver-related mortality and transplants.

“There is proof that effective treatment leads to improved clinical outcomes,” Muir said, later adding that “sustained virologic response rates show we can cure most people.”

But Muir noted there are still issues with side effects and treatment duration, which is currently 24 to 48 weeks. Muir called the infection rate found in the CUPIC (Compassionate Use of Protease Inhibitors in Cirrhotics) trial concerning, as more than half of the patients who had compensated cirrhosis and were taking the three drug regimen of pegylated interferon/ribavrin and telaprevir or boceprevir experienced a serious adverse event.

“The infection often began a cascade that led to their demise,” Muir said. He continues to use the therapies but indicated he has changed how he counsels patients to avoid scaring them off. Also, the U.S. Food and Drug Administration (FDA) has added a black box warning to telaprevir related to patients dying after a progressive rash and systemic symptoms.

The OPTIMIZE trial assessed whether a twice-daily regimen of telaprevir was as effective as a thrice-daily regimen when both are administered with pegylated interferon/ribavrin, and it found a similar outcome. Muir called twice-daily dosing a “reasonable option” for patients challenged by the thrice-daily regimen, though he cautioned that the FDA has not yet approved it.

Reporting on three new drugs — simeprevir, faldoprevir, and sofusbuvir — Muir noted, “We are starting to get more drugs demonstrating nice potency.” Clinical trials are also under way on interferon-free regimens. Since many patients continue to hold off on starting treatment because they are waiting for new options, Muir recommended educating them about liver wellness. For patients with significant liver disease, he suggested clinicians discuss benefits and risks and document the session.

With more treatment options in the pipeline, Muir called it an “amazingly wonderful time to be a physician in a liver clinic,” because patients have options and most who receive treatment can live well for years.

“Bottom line: Interferon-free treatments are at hand and just around the corner,” moderator Adrian M. Di Bisceglie, MD, FACP, FACP, Bander chair of internal medicine and chief of hepatology at the Saint Louis University School of Medicine, in Missouri, said after the session. He expects approvals for some uses as soon as the end of the year.

“When we have that, it will transform how we think about the treatment of hepatitis C,” Di Gisceglie added. “An easy, one- to two-drug treatment regimen — that’s what we are looking forward to.”


Primary efficacy and safety findings from phase III study of Simeprevir in treatment-experienced patients demonstrate sustained virologic response


21-May-13 Stockholm, Sweden — Medivir AB (OMX: MVIR) reports that its partner Janssen R&D Ireland (Janssen) today announced primary efficacy and safety results from the global phase III PROMISE study. Results demonstrated that use of the investigational protease inhibitor simeprevir (TMC435) led to sustained virologic response 12 weeks after the end of treatment (SVR12) in 79 percent of treatment-experienced genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir was administered once daily with pegylated interferon and ribavirin.

In the study, 37 percent of patients receiving pegylated interferon and ribavirin (placebo) alone achieved SVR12. In the simeprevir arm, on-treatment failure rates were 3 percent and relapse rates were 19 percent, compared to 27 percent and 48 percent in the placebo arm. All patients had previously relapsed following pegylated interferon-based therapy.

The data were presented today as a late breaker oral presentation at Digestive Disease Week 2013 in Orlando, Florida based on abstract number 869b, “Simeprevir (TMC435) With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon-Based Therapy: Results From PROMISE, a Phase III Trial.”

“We are very pleased with these data from this phase III study in relapsers. The data demonstrate high cure rates in these treatment-experienced patients. Together with the very good safety profile and the fact that a large proportion of the patients were eligible to end all treatments in a shorter time frame as compared to current standard of care, should provide new hope for large patient groups with this disease”, said Charlotte Edenius, EVP Research and Development, Medivir AB.

Study design
In PROMISE, patients were randomized to receive simeprevir or placebo for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks. In findings related to a secondary endpoint, 93 percent of patients receiving simeprevir were able to shorten therapy with pegylated interferon and ribavirin to 24 weeks as a result of meeting response-guided therapy (RGT) criteria. 83 percent of those patients meeting response-guided therapy criteria to stop treatment at 24 weeks achieved SVR12.

Patients enrolled in PROMISE were stratified by hepatitis C virus (HCV) genotype 1 subtype and IL28B genotype. SVR12 rates among patients treated with simeprevir according to IL28B genotype were 89 percent for the CC allele, 78 percent for the CT allele, and 65 percent for the TT allele, compared to 53 percent for the CC allele, 34 percent for the CT allele and 19 percent for the TT allele in the placebo arm.

Among patients with METAVIR scores F0 to F2, 82 percent of patients treated with simeprevir and 41 percent with placebo achieved SVR12. Among patients with METAVIR scores F3 and F4, 73 percent and 74 percent of patients treated with simeprevir and 20 percent and 26 percent treated with placebo achieved SVR12, respectively. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver and patients are scored on a five-point scale.

The most common adverse events seen in patients receiving simeprevir in PROMISE were fatigue (32 percent versus 42 percent for placebo), headache (32 percent versus 36 percent for placebo) and influenza-like illness (30 percent versus 20 percent for placebo). In the simeprevir arm, rash (19 percent versus 14 percent for placebo), itching (24 percent versus 17 percent for placebo), neutropenia (15 percent versus 17 percent for placebo), anemia (11 percent versus 6 percent for placebo), increased bilirubin (6 percent versus 2 percent for placebo), and photosensitivity conditions (4 percent versus none for placebo) were also observed. One patient in the simeprevir arm and no patients in the placebo arm discontinued treatment due to an adverse event.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR
Mobile: +46 708 537 292

PROMISE is a global, phase III, randomized, double-blind, placebo-controlled clinical trial assessing the efficacy, safety and tolerability of simeprevir plus pegylated interferon and ribavirin versus pegylated interferon and ribavirin alone in adult patients with genotype 1 chronic hepatitis C with compensated liver disease, including all stages of liver fibrosis, who relapsed after previous interferon-based therapy.

In the PROMISE trial, 393 patients were randomized to receive one 150 mg capsule of simeprevir or placebo once daily plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin alone for either 12 or 36 weeks based on response-guided therapy criteria. Patients in the simeprevir arm were considered to have met response-guided therapy criteria if their HCV RNA levels were

About Simeprevir
Simeprevir is an investigational NS3/4A protease inhibitor jointly developed by Medivir AB and Janssen R&D Ireland for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells. New drug applications were recently submitted for simeprevir in Japan and the United States for the treatment of genotype 1 hepatitis C, and a Marketing Authorisation Application was submitted to the European Medicines Agency seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C. The U.S. FDA has granted Priority Review to the New Drug Application. Janssen Pharmaceutical K.K. also recently announced the submission of a new drug application for simeprevir in Japan for the treatment of genotype 1 hepatitis C.

Global phase III studies of simeprevir include PROMISE in adult patients who have relapsed after prior interferon-based treatment, QUEST-1 and QUEST-2 in treatment-naïve adult patients, and ATTAIN in prior null-responder adult patients. In parallel to these trials, phase III studies for simeprevir are ongoing in treatment-naïve and treatment-experienced HIV-HCV co-infected patients and HCV genotype 4 patients.

Simeprevir is also being studied in phase II interferon-free trials with and without ribavirin in combination with:

· Janssen’s non-nucleoside inhibitor TMC647055 and ritonavir in treatment-naïve genotype 1a and 1b HCV patients;
· Gilead Sciences, Inc.’s nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naïve and previous null-responder genotype 1 HCV patients; and
· Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naive and previous null-responder genotype 1 HCV patients.

In addition, Janssen Pharmaceuticals, Inc. has entered into a non-exclusive collaboration with Vertex Pharmaceuticals to evaluate in a phase II study the safety and efficacy of an all-oral regimen of simeprevir and Vertex’s investigational nucleotide analogue polymerase inhibitor VX-135 for the treatment of HCV. As a first step, Janssen Pharmaceuticals, Inc. is conducting a drug-drug interaction (DDI) study with simeprevir and VX-135.

Janssen Pharmaceuticals, Inc. also has plans to initiate a phase II trial of an investigational interferon-free regimen with simeprevir, TMC647055 and Idenix’s IDX719, a once-daily, pan-genotypic NS5A inhibitor, with and without ribavirin.

For additional information about simeprevir clinical trials, please visit

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease and liver transplants, is a rapidly evolving treatment area with a clear need for innovative treatments. Approximately 150 million people are infected with hepatitis C worldwide, and about 350,000 people per year die from the disease. 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 Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website:
Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s lives.

SVR associated with lower risk for diabetes in HCV

Provided by Healio

May 20, 2013

ORLANDO, Fla. — Patients with hepatitis C who achieve a sustained virologic response after treatment have a lower risk of developing type 2 diabetes, according to research presented here at Digestive Disease Week.

“There are intrahepatic factors and extrahepatic factors that link diabetes and HCV,” Sarah Hyder, MD, a gastroenterology fellow at Brown University, told Infectious Disease News. “Considering this link, we postulated that successful treatment of HCV could decrease the risk for new-onset diabetes in these patients.”

Hyder and colleagues used data from the Veterans Affairs Clinical Case Registry to identify patients with HCV, without pre-existing diabetes, who initiated antiviral treatment between 1998 and 2007. They evaluated the incidence of diabetes among patients who achieved sustained virologic response (SVR) and those who did not clear the infection.

Among the 27,636 patients, 7,617 (27.5%) achieved SVR and 15,243 (55.8%) did not. After a median follow-up of 5 years, 831 of the responders (11%) developed diabetes, and 2,428 of the non-responders (16%) developed diabetes. After controlling for known diabetes risk factors, SVR was independently associated with decreased incidence of new-onset diabetes (HR=0.77; 95% CI, 0.71-0.84). In addition, increasing age, non-white race, hypertension and cirrhosis were associated with an increased risk for new-onset diabetes.

“There are a lot of patients who don’t achieve SVR, either because they can’t tolerate treatment and discontinue, or because they have a resistant genotype of HCV,” Hyder said. “Hopefully, in the era of non-interferon based regimens, patients will be able to tolerate therapy better, and we’ll hopefully see an increased clearance rate and a decreased risk for HCV-associated diabetes. Successful treatment of HCV will provide significant benefits to health outcomes beyond liver-related morbidity and mortality.”

For more information:

Hyder S. #608. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando, Fla.

Disclosure: Hyder reports no relevant financial disclosures.


Nosocomial infections common in patients with cirrhosis

Provided by Healio

May 20, 2013

ORLANDO, Fla. — Most infections among patients with cirrhosis were nosocomial or health care-associated infections, according to study findings presented here at Digestive Disease Week. In addition, use of proton pump inhibitors was an independent predictor of these infections.

“Hospital-acquired and health care-associated infections are considered common in cirrhosis, but population-based data on the occurrence of these infections and their potential impact on outcome are limited,” Konstantina Sargenti, MD, of the department of gastroenterology at Skåne University Hospital in Sweden, said during a presentation. “Acute kidney injury and systemic inflammatory response syndrome indicate poor prognosis in cirrhosis, but it is unclear if they are more common in the presence of these infections.”

Sargenti and colleagues conducted a retrospective study that included all patients diagnosed with liver cirrhosis from 2000 to 2010, in an area with a population of approximately 250,000. They reviewed the patients’ medical records for information on infections, proton pump inhibitor use, acute kidney injury and systemic inflammatory response syndrome, and followed the patients until death, transplantation or the end of 2011.

Among the 344 patients with liver cirrhosis, 122 patients developed 230 bacterial infections: 66 were community-acquired (29%), 119 were health care-associated (51%) and 45 were nosocomial (20%). The most common infections were urinary tract infections (26%), spontaneous bacterial peritonitis (19%), pneumonia (16%) and spontaneous bacteremia (16%).

The researchers found that proton pump inhibitor use (OR=2.07; 95% CI, 1.05-4.06) and decompensated patient status (OR=1.78; 95% CI, 0.57-5.56) were related to nosocomial and health care-associated infections. These infections were not associated with inpatient mortality or systemic inflammatory response syndrome.

“Nosocomial infections appeared to have an impact on outcome as they were related to the occurrence of acute kidney injury and a prolonged length of hospital stay compared to health care-associated or community-acquired infections,” Sargenti said.

For more information:

Sargenti K. #515. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando, Fla.

Disclosure: Sargenti reports no relevant financial disclosures.