November 26, 2013

Man contracts HIV via donor blood

Provided by Japan Times

November 26, 2013

KYODO

A man in his 60s contracted HIV after receiving blood donated by an infected man that slipped through safety checks by the Japan Red Cross Society, the health ministry and the Red Cross said Tuesday.

It is the first time since 2003 that someone has been found to have been infected with the virus apparently via a blood transfusion.

Health minister Norihisa Taumra confirmed earlier in the day that blood donated by an HIV-positive man in his 40s that slipped through safety checks was used in two transfusions at separate medical institutions. Officials are trying to determine if the other recipient got the virus.

In 2003, there was a similar case of a patient being infected with HIV-tainted blood used in a transfusion, prompting the Red Cross to strengthen its safety checks the following year.

The Red Cross said during a Tuesday meeting of the ministry’s blood program panel that it will change its current safety screening method of examining blood samples jointly in batches of 20 donations to examining every blood sample by next summer.

The ministry said the blood recipient received a transfusion in October as part of treatment for a chronic digestive disease.

The man was found to be HIV-positive during blood screening in November but had also donated blood in February that slipped through the checks and was provided to medical institutions.

It is possible the infected blood slipped through the virus-detection system because HIV levels are low during the early stage of infection.

After the virus was detected in November, the man admitted he had had risky sexual contact shortly before he donated in February, but had lied about this earlier.

The ministry now suspects the man donated blood to discover whether he was infected with HIV.

Taking this into account, the Red Cross will train doctors to better discern who could be at risk of infections when interviewing blood donors.

The man had also given blood in January 2012, but the ministry believes this donation was not tainted because because he was most likely infected either at the end of last year or beginning of this year.

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Wednesday, November 27, 2013 by Proactive Investors

drug_research_350_529534dde3ef5

An independent study has found that Biotron's BIT225 drug candidate is effective against more genotypes of the Hepatitis C virus than previously demonstrated.

Biotron Limited's (ASX: BIT) shares are set to trade higher after receiving independent evidence that its BIT225 drug candidate for the treatment of the Hepatitis C virus is effective against more genotypes than previously demonstrated.

A new scientific paper published in the peer-reviewed journal Antiviral Research demonstrated that BIT225 is active against HCV genotypes 1, 2, 4, 5 and 6 using an in vitro cell culture assay.

This adds to the company’s studies, which demonstrated that it is active against genotypes 1 and 3, and indicates that its compound has pan-genotype activity.

Biotron’s BIT225 compound is the first in a new class of direct acting antiviral drugs for Hepatitis C. It specifically targets the p7 protein, which is involved in virus assembly.

It has recently received ethics approval to conduct a three month Phase 2 dosing study of its BIT225 drug candidate for the treatment of the Hepatitis C virus in Thailand.

The Hepatitis C global market is currently estimated at US$3.3 billion, but is expected to expand to over US$15 billion as safe, effective therapies enter the market.

Proactive Investors Australia is the market leader in producing news, articles and research reports on ASX “Small and Mid-cap” stocks with distribution in Australia, UK, North America and Hong Kong / China.

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Supplement Combo Lessens HIV Progression

Published: Nov 26, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • In a randomized study of HIV-infected adults who had not received antiretroviral therapy-naive, 24-month supplementation with a single supplement containing multivitamins and selenium was safe, significantly reducing the risk of immune decline and morbidity.
  • Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any endpoint.

Early in HIV infection, a combination of multivitamin and selenium supplements slowed the progress of the disease, researchers reported.

In a randomized placebo-controlled clinical trial in Botswana, the combination cut -- by about half -- the risk of reaching the point of needing antiretroviral therapy, according to Marianna Baum, PhD, of Florida International University in Miami, and colleagues.

But multivitamins or selenium alone had no significant effect, Baum and colleagues reported in the Nov. 27 issue of the Journal of the American Medical Association.

The approach has previously been shown to improve mortality among people with HIV, the authors noted, but studies have focused on people with more advanced disease, with important comorbidities such as tuberculosis, or already on antiretroviral therapy.

The Botswana study is the first to study the effect of micronutrient supplementation on patients whose plasma CD4-positive T-cell count was greater than 350 per microliter and who were not on antiretroviral therapy during the study, Baum and colleagues reported.

One implication of the findings is that "you may not need always to use an HIV medication to achieve at least part of what we try to accomplish with therapy," commented David Wohl, MD, of the University of North Carolina in Chapel Hill, N.C., who was not part of the study.

"What's nice about this study," he told MedPage Today, is that a simple and inexpensive intervention could have "effects that were fairly profound" and that slowed the decline of immune function.

On the other hand, HIV therapy, when it's eventually used, would probably "trump any effect of micronutrients," he said.

In Botswana, Baum and colleagues enrolled 878 people with a median CD4 cell count of 420 cells per microliter and randomly assigned them to one of four study arms: placebo, micronutrients, selenium, or micronutrients plus selenium.

The study medications were taken daily. The micronutrient pills contained thiamine, riboflavin, niacin, B6, B12, folic acid, and vitamins C and E. Those in the selenium arms got 200 mg of the element daily.

The primary endpoint was HIV progression, defined originally as reaching a CD4 cell count of less than 200 per microliter. Because of a change in national guidelines in March 2008, the researchers redefined HIV progression as reaching a CD4 count of less than 250 cells per microliter.

In a Cox regression model, adjusted for a range of factors and taking interactions between the supplements into consideration, only micronutrients plus selenium had a significant effect, Baum and colleagues reported.

After a median follow-up of 24 months, the combination, compared with placebo, had an adjusted hazard ratio for reaching the endpoint of 0.46 (95% CI 0.25-0.85, which was significant (P=0.01).

The absolute event rate, the researchers reported, was 4.79 per 100 person-years among those getting the combination, and 9.22 per 100 person-years among those getting placebo, they reported.

Multivitamins plus selenium also reduced the risk of an important secondary endpoint -- the combination of disease progression, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier. The adjusted HR was 0.56 and was significant (P=0.03).

The authors reported that there was was no effect of supplementation on HIV viral load. Also, reported adverse events were deemed as unlikely to be related to the intervention.

The study had support from the National Institute on Drug Abuse. The authors did not report any potential conflicts.

Primary source: Journal of the American Medical Association
Source reference: Baum MK, et al "Effect of micronutrient supplementation on disease progression in asymptomatic, antiretroviral-naive, HIV-infected adults in Botswana: A randomized clinical trial" JAMA 2013; 310(20): 2154-2163.

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Provided by blog.AODS.gov

Jonathan-Mermin-100

November 25, 2013 • 1 comment • By Jonathan Mermin, MD, MPH, Director, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention

Health care providers at all levels of the health care system can help reduce health disparities and prevent viral hepatitis by learning more about the prevention, care, and treatment of this disease. This is one of the goals of the Action Plan for the Prevention, Care and Treatment of Viral Hepatitis [PDF 673KB], to “Build a U.S. health-care workforce prepared to prevent and diagnose viral hepatitis and provide care and treatment to infected persons.”

Medical providers who share information regarding risk for certain diseases are one of the most powerful motivators for a patient to accept an intervention or change behaviors. But providers must first have the information needed to share with patients. Increasing the number of providers who are knowledgeable about viral hepatitis testing, care, and treatment is critical to maximizing the benefits afforded by viral hepatitis testing and treatment options.

The Centers for Disease Control and Prevention (CDC) and the U.S. Department of Health and Human Services (HHS) have collaborated with other federal agencies and universities to create educational opportunities for health care providers to receive training in this area of disease prevention and control.

Hepatitis C Online Course

The University of Washington in collaboration with the International Antiviral Society-USA (IAS-USA) was funded by CDC to create a self-study, interactive course for medical providers on Hepatitis C. Features include a master bibliography, embedded video, and clinical calculators. Free CME/CNE credit available.

Hepatitis Web Study

The University of Washington – Seattle Prevention Training Center was funded by CDC to develop a website that offers interactive case studies covering topics related to prevention, management, and treatment of viral hepatitis. Free CME/CNE credit available.
http://depts.washington.edu/hepstudy/

KnowHepatitis.org

The University of Alabama at Birmingham – National Training Center for Integrated Hepatitis, HIV/STD Prevention Services was funded by CDC to develop a website dedicated to the provision of practice-focused distance learning programs and training for frontline workers.
http://www.knowhepatitis.org/

Medscape

Medscape and CDC have worked together to provide the following educational opportunities:

ACT on HCV – A Practical Introduction to Treating HCV from AASLD

The American Association for the Study of Liver Diseases (AASLD) has launched an educational program providing practical strategies for managing patients with hepatitis C. Five interactive modules, webinars, and an experiential component address an overview of HCV, genotyping and predictors of response, selecting patients, initiating treatment and the first eight weeks, and managing side effects of therapy. Registration is free, but required.
http://liverlearning.aasld.org/aasld/2012/Curriculum/22640

Broader use of these training resources by medical providers will have a positive impact on our efforts to support viral hepatitis testing, care, and treatment. To receive viral hepatitis updates from CDC, including training opportunities, please sign up to receive email communications through GovDelivery and follow CDC’s Division of Viral Hepatitis on Twitter @cdchep .

Related posts:

  1. Updates on National HIV/AIDS Strategy and Viral Hepatitis Action Plan Shared with Primary Care and HIV Providers
  2. New Resource on How Health Reform Supports Viral Hepatitis Prevention, Care, and Treatment
  3. Viral Hepatitis Policy Meets Practice at the Liver Meeting
  4. FDA and Partners Recommend Action to Reduce Viral Hepatitis Risk Among Health Care Personnel
  5. HHS Announces New Action Plan to Prevent, Care, and Treat Viral Hepatitis

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World J Gastroenterol 2013 November 14; 19(42): 7316-7326

Published online 2013 November 14. doi: 10.3748/wjg.v19.i42.7316.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Marco Vivarelli, Roberto Montalti, Hepatobiliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, 60129 Ancona, Italy

Andrea Risaliti, Department of Surgery and Transplantation, University of Udine, 33100 Udine, Italy

Author contributions: Vivarelli M conceived and designed the study; Montalti R drafted the article and acquired, analyzed and interpreted the data; Risaliti A revised the manuscript.

Correspondence to: Marco Vivarelli, MD, Hepatobiliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. “Ospedali Riuniti”, Via Conca 71, 60129 Ancona, Italy. vivarelli63@libero.it

Telephone: +39-71-5965099 Fax: +39-71-5965100

Received July 3, 2013; Revised August 8, 2013; Accepted September 16, 2013;

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor, and overall, it is one of the most frequent cancers. The association of HCC with chronic liver disease, and cirrhosis in particular, is well known, making treatment complex and challenging. The treatment of HCC must take into account the presence and stage of chronic liver disease, with the aim of preserving hepatic function that is often already impaired, the stage of HCC and the clinical condition of the patient. The different treatment options include surgical resection, transplantation, local ablation, chemoembolization, radioembolization and molecular targeted therapies; these treatments can be combined in various ways to achieve different goals. Ideally, liver transplantation is best treatment for early stage HCC on cirrhosis because it removes both the tumor and the chronic disease that produced it; however, the application of this powerful tool is limited by the scarcity of donors. Downstaging and bridging are different strategies for the management of HCC patients who will undergo liver transplantation. Several professionals, including gastroenterologists, radiologists and surgeons, are involved in the choice of the most appropriate treatment for a single case, and a multidisciplinary approach is necessary to optimize the outcome. The purpose of this review is to provide a comprehensive description of the current treatment options for patients with HCC by analyzing the advantages, disadvantages and rationale for their use.

Keywords: Hepatocellular carcinoma, Multimodal treatment, Locoregional treatments, Molecular targeted therapies, Liver resection, Liver transplantation

Core tip: Hepatocellular carcinoma (HCC) occurs frequently, and its association with cirrhosis makes treatment complex and challenging. The treatment of HCC must take into account the presence and stage of chronic liver disease with the aim of preserving hepatic function that is often already impaired. The different treatment options include surgical resection, transplantation, local ablation, chemoembolization, radioembolization and molecular targeted therapies. Downstaging and bridging are different strategies for the management of HCC patients who will undergo liver transplantation. The purpose of this review is to provide a comprehensive description of the current treatment options for patients with HCC.

INTRODUCTION

Hepatocellular carcinoma (HCC) accounts for nearly 90% of the primary liver tumors and is currently the third leading cause of cancer death worldwide. Approximately 500000 new cases of HCC are diagnosed worldwide each year, with a peak incidence observed in countries in which the hepatitis B virus (HBV) is endemic, such as Southeast Asia and sub-Saharan Africa[1]. As the number of carriers of chronic liver disease increases, HCC has become a major public health issue.

The main risk factor for HCC is the presence of chronic liver disease, particularly when the disease has already resulted in liver cirrhosis. The constant process of destruction and repair within the parenchyma that is associated with cirrhosis increases hepatocyte metabolism and amplifies the risk of mutations in a multistep progression from hyperplastic nodule to early HCC and finally to moderately/poorly differentiated HCC.

Hepatitis B and C viruses (HBV and HCV) are known to have oncogenic potential, and the risk of HCC in HBV and HCV carriers is increased independently of the presence of cirrhosis[2,3]. Malignant transformation of hepatocytes in the infected liver could be caused by chronic inflammation and the oxidative DNA damage that leads to genetic and epigenetic changes. There is also evidence that proteins encoded by HBV and HCV may have a direct role in hepatocarcinogenesis; in fact, proteins encoded in the genome of each of these viruses have been linked to alterations in hepatocyte physiology and hepatocellular signal transduction[4]. Other causes of chronic liver diseases, such as alcohol abuse, non-alcoholic steatohepatitis (NASH), hemochromatosis, α1-antitrypsin deficiency, autoimmune disease and Wilson disease are associated with a higher risk of developing HCC and require close patient monitoring. In Western countries, obesity and metabolic syndromes associated with type II diabetes, which are strictly related with NASH, are now emerging as new potential predisposing factors for HCC[1].

Among patients with cirrhosis, the cumulative 5-year risk of developing HCC ranges from 5% to 30%, depending on the presence and stage of underlying liver disease, ethnicity, age, sex and duration of the exposure to primary hepatotropic viruses[1,5].

The main peculiarity of HCC is that the treatment of the tumor must take into account the presence and stage of chronic liver disease, with the aim of preserving hepatic function that is often already impaired. A key step in the choice of therapy is therefore the correct assessment of the functional reserve of the liver, which is often more important than the staging of the tumor itself.

Several options are available for the treatment of HCC, and these can often be combined; the choice of treatment and the timing of its administration therefore must be balanced accurately.

The aim of the present review is to provide an update than can be useful in clinical practice for determining the most appropriate treatment for HCC patients.

HCC SCREENING

The achievement of a curative treatment for HCC depends on the detection of the tumor at an early stage. Once the population at risk is identified, screening of HCC is based on ultrasonography and measurement of serum alpha-fetoprotein (s-AFP) levels.

It is recommended that patients with advanced liver fibrosis (F3) or established cirrhosis undergo a liver ultrasound (US) and serum measurements every 6 mo[6]. In these patients, ultrasound has a sensitivity between 58% and 89% and a specificity of 90%[7]. The sensitivity of s-AFP measurements is lower and ranges between 25% and 65% when values above 20 ng/mL are considered positive[1]. The sensitivity and specificity of s-AFP measurement for the detection of HCC increase proportionally with higher blood s-AFP levels, particularly when the level is above 400 ng/mL.

Once the presence of HCC is confirmed, the s-AFP level can be correlated with tumor stage, particularly with the size and multifocality of the tumor and the presence of microvascular invasion. Overall, a screening strategy that combines abdominal ultrasonography and measurement of s-AFP every 6 mo in patients with cirrhosis can reduce HCC mortality by approximately 40%[8,9].

WJG-19-7316-g001

Figure 1 Diagnostic algorithm for hepatocellular carcinoma. Modified by Forner et al[11]. MDCT: Multidetector computed tomography; MR: Magnetic resonance; CT: Computed tomography; MRI: Magnetic resonance imaging.

The nature of nodules with a diameter of less than 1 cm cannot be precisely defined during ultrasound, and a follow-up control after 3-4 mo is required. Nodules detected at US with a diameter greater than 10 mm must be further investigated with contrast-enhanced triphasic or quadriphasic computed tomography (CT) imaging or magnetic resonance (MR) imaging. The diagnosis of HCC is based on an arterial hypervascular phase (wash-in) followed by disappearance of the contrast in the venous phase (wash-out)[12].

Recent reports have demonstrated that MR has a higher sensitivity compared with CT[13]; however, if the data from the first imaging procedure are not conclusive, confirmation using a different technique is recommended. In cases in which the diagnosis is uncertain, a s-AFP level > 400 ng/mL has a high positive predictive value[1]. Histological confirmation through percutaneous liver biopsy should be restricted to those nodules with features on MR or CT that are not typical enough to allow a diagnosis[14]. In fact, the histological diagnosis of HCC is complex, requires a great degree of expertise and relies on the assumption that the core of the nodule has been effectively sampled by the small needle that is used for the percutaneous biopsy. The sensitivity and specificity reported for nodules less than 20 mm in diameter is 60%[15]. A risk of tumor seeding in the path of the puncture has been reported in approximately 2.5% of the cases with a median time of development of 17 mo[16].

HCC staging

The severity of chronic liver disease is usually classified according to the Child-Pugh and model for end-stage liver disease (MELD) scores, and the tumor is staged with the TNM system; in the setting of liver transplantation, the indication for liver replacement is based mainly on the Milan criteria[17]. Another staging system that has gained acceptance is the Barcelona Clinic Liver Cancer (BCLC) score, the advantage of which is that it takes into account the characteristics of the tumor as well as the liver function and the general conditions of the patient[8] (Figure 2). The BCLC system was developed after a retrospective analysis of several cohort studies on patients with HCC at different stages. This system identifies patients with early HCC who may benefit from curative therapies (stage 0 and A), those at intermediate (stage B) or advanced (stage C) stages who may benefit from palliative treatments and those with a very poor life expectancy (stage D). BCLC is the most commonly used staging system in Europe, and it has been approved by the European Association for the Study of the Liver (EASL) and the AASLD.

WJG-19-7316-g002

Figure 2 The Barcelona Clinic Liver Cancer staging system and treatment allocation. Copyright © 2010, American Association for the Study of Liver Diseases. CLT: Cadaveric liver transplantation; HCC: Hepatocellular carcinoma; LDLT: Living donor liver transplantation; PEI: Percutaneous ethanol injection; RF: Radiofrequency; PST: Performance status.

Multidisciplinary management of HCC

Given the complexity of the clinical scenario, the decision on the most appropriate treatment for a patient with HCC should be made by a multidisciplinary team that includes a hepatologist, hepatobiliary surgeon, transplant surgeon, radiologist and pathologist[18]. No single treatment strategy can be applied to all patients, and treatment should be individualized.

In the management of HCC, attention must be focused on the presence and degree of the underlying chronic liver disease at first observation, which will influence the choice of the treatment[19].

Liver resection can be offered to patients with well-preserved liver function; however, the amount of parenchyma that can be removed in carriers of chronic liver disease is inferior to that which is considered as the safety limit in a normal liver (a “future remnant liver” that is ≥ 30% of the hepatic volume is generally considered acceptable)[19]. Despite a normal liver function, the regenerative potential of a liver that harbors a chronic disease can be surprisingly low.

In cases of impaired liver function, non-surgical procedures or liver transplantation (LT) can be offered; in this setting, the number, size and location of the nodules determine the choice of treatment.

Surgical resection, transplantation and ablation are the treatments that offer the highest rates of complete response and are therefore considered as curative[10]. There are no randomized trials comparing the efficacy of these three approaches, and all evidence is based on the rate of cure reported in different series.

Transarterial chemoembolization (TACE) is the least invasive approach; however, it cannot be considered curative.

Ideally, LT is best treatment for early stage HCC on cirrhosis because it removes both the tumor and the chronic disease that has produced it. However, the application of this powerful tool is limited by the scarcity of donors, which results in strict patient selection criteria to optimize the results.

Candidates for LT for whom a long waiting time (> 6 mo) is predicted may be offered resection, local ablation or transarterial chemoembolization as a ‘bridge’ to transplantation to minimize the risk of tumor progression while they are on the waiting list[20]. The same procedures can also be utilized in attempts downstage tumors that are beyond the eligibility criteria for LT at the time of diagnosis.

Yu et al[21] performed a study on HCC patients who exceeded the University of California San Francisco (UCSF) criteria for LT; these patients were downstaged to fit the UCSF criteria using locoregional therapy and finally underwent LT. Patients who were successfully downstaged prior to transplantation had tumor-free and overall survival rates similar to those observed in patients who met the criteria from the beginning.

A 5-year survival comparable to that of “within criteria” HCC patients can be achieved using LT after successful downstaging. Successful downstaging should include tumor size, number of viable tumors and s-αFP concentrations before and after downstaging. Then, a minimum observation period of 3 mo is recommended before considering LT[22].

If a patient’s hepatic function allows it, liver resection can be offered prior to future transplantation by pursuing two different strategies: first, resection can be used as the primary therapy with LT offered as a rescue therapy should the patient develop tumor recurrence or postoperative liver failure (salvage transplantation); second, resection can be performed on patients with a high risk of tumor progression while awaiting transplantation (bridge to transplantation)[23,24].

SURGICAL RESECTION

When performed in specialized centers, hepatic resection (HR) can be highly effective, with 5-year overall survival rates well above 50% in the major series[25]. Resection is the recommended treatment for patients without advanced fibrosis as long as an R0 resection can be performed with a low risk of postoperative liver failure[14].

The elements that must be taken into account when considering resection of the cirrhotic liver are the Child-Pugh and MELD scores of the underlying liver disease, the degree of portal hypertension and the extension of the parenchymal excision required to obtain a free resection margin.

The aim of HR is to obtain radical resection with limited surgical morbidity; to achieve this goal, patient selection is crucial. For the last several decades, the selection of candidates for resection has been based on Child-Pugh classification. However, Child-Pugh classification is far from accurate for predicting postoperative liver failure; in fact, some Child-Pugh A patients already have liver functional impairment with an increased bilirubin concentration, clinically significant portal hypertension or even minor fluid retention necessitating diuretic treatment[26]. The further investigation of hepatic functional reserve tests, such as the aminopyrine breath test or clearance of indocyanine green (ICG), has been proposed; however, their predictive value remains poorly validated. In Japan, the ICG retention rate is utilized to identify the best candidates for resection[27], whereas portal pressure and bilirubin are the variables used in Europe and the United States[10]. Recently, a preoperative MELD score ≥ 10 was associated with a higher incidence (40%) of postoperative liver failure[28].

Markers of portal hypertension including a porto-caval gradient > 10 mmHg, the presence of esophageal varices, splenomegaly and a platelet count lower than 1× 1011/L are predictors of postoperative morbidity and mortality[29]. In patients without relevant portal hypertension and normal concentrations of bilirubin, the 5-year survival is 70%, whereas this value is 50% for individuals with portal hypertension and is even lower when both these risk factors are present[30,31].

By integrating all of these factors, HR can be safely performed on patients with Child-Pugh class A chronic liver disease, a MELD score ≤ 10, a platelet count > 100.000/mm3 and a porto-caval gradient <10 mmHg. These factors dramatically limit the potential number of candidates, and overall, less than 30% of patients are candidates for HR[29].

After HR, the 5-year survival for cirrhotic patients with HCC ranges from 30% to 50%, whereas the operative mortality ranges from 3% to 8%[29]. The severity of cirrhosis, size of the tumor, number of tumors, presence of vascular tumor invasion and presence of satellite nodules are well-established prognostic factors for recurrence and survival[27,32,33]. Late recurrence is mainly due to the carcinogenic effect of underlying chronic liver disease[34].

Absolute contraindications to HR are the presence of extrahepatic metastases or neoplastic invasion of the main portal trunk. Neoplastic portal vein thrombosis is a poor prognostic factor; however, in highly selected cases, hemi-hepatectomy can be feasible, particularly when thrombosis of a main branch of the portal vein has led to hypertrophy of the contralateral hemiliver.

When compared with open surgery, laparoscopy in cirrhotic patients could have the advantage of avoiding the interruption of collateral abdominal veins that are present as a result of portal hypertension. Several studies have indeed demonstrated the benefits of the laparoscopic approach in terms reduced bleeding and lower postoperative morbidity and mortality[35,36].

LIVER TRANSPLANTATION

HCC is the only solid cancer that can be treated with transplantation. Transplantation is the best curative option for patients with decompensated (Child-Pugh B or C) cirrhosis; however, due to the shortage of donors, it can only be offered to a limited number of patients. Candidates for LT are patients with tumors that have favorable pathological features and therefore a low likelihood of recurrence.

The most widely adopted criteria for selecting HCC carriers for transplantation are the Milan criteria. According to these criteria, LT can be considered only for patients with a single tumor < 5 cm in diameter or for patients with up to 3 tumors < 3 cm without macrovascular invasion[17]. A recent systematic review of 90 studies that followed 17780 patients over a 15-year period identified the Milan criteria as an independent prognostic factor of outcome after LT[37].

Despite recent discussions concerning the restrictive nature of the Milan criteria, these criteria have been adopted by the vast majority of transplant centers. The results of LT in HCC within the Milan criteria are outstanding, with 5-year survival approaching 80%, which is similar to that observed in patients transplanted for benign diseases[30,38,39]. Outside the Milan criteria, survival is significantly reduced, which is likely due to an increased prevalence of variables associated with risk of recurrence, such as microvascular invasion, in tumors at more advanced stages[40].

Neoadjuvant therapy through TACE can occasionally downstage tumors that were outside the Milan criteria at the time of diagnosis; in these cases, the results of LT are similar to those achieved when the criteria were met at first observation[41].

The time spent on the waiting list is a key factor that must be considered when assessing the results of LT in HCC patients; it depends on the availability of donors in a given area and on the system used to prioritize organ allocation. It was demonstrated that 15%-20% of patients with HCC initially within the Milan criteria experience tumor progression until they dropped out from the waiting list; this highlights the need to analyze the results of LT using an intention to treat approach[42]. Although treatments aimed at delaying tumor progression, such as ablation and transarterial chemoembolization, are widely used, their efficacy is unproven[43]. Live donation is a valid strategy for extending the donor pool; however, its applicability is reduced because of societal constraints, scarcity of appropriate donors and the possible morbidity and mortality of donors[44].

Currently, organs are allocated worldwide based on MELD score; however, HCC patients with low MELD scores are given extra points to shorten their waiting time and avoid tumor progression. This policy is questioned by some authors because it might be disadvantageous for patients without HCC[45].

LOCOREGIONAL TREATMENTS

Local ablation techniques have been developed for patients with surgical contraindications and can be performed either through a percutaneous approach or, less commonly, through laparoscopy. These maneuvers include percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation, cryoablation, laser-induced thermotherapy, high-intensity focused ultrasound and irreversible electroporation[46].

The first percutaneous treatment was PEI, which induces coagulative necrosis of the lesion as a result of cellular dehydration, protein denaturation and chemical occlusion of small tumor vessels due to the effects of the injected absolute alcohol. Ablation techniques such as RFA, microwave ablation, and laser ablation utilize high temperatures; conversely, cryoablation causes direct tumor freezing[47].

The evaluation of responses to locoregional treatments and molecular-targeted therapies of HCC is currently based on modified RECIST (mRECIST) criteria, which measure the diameter of the viable tumor component of target lesions[48].

Radiofrequency ablation

RFA is the technique of choice for local destruction of liver tumors. RFA induces coagulative necrosis of the tumor with safety margins around the lesion and is the most commonly used local ablative technique. RFA has largely replaced PEI because it produces better results in terms of recurrence-free survival and requires fewer treatment sessions[49]. RFA can be performed percutaneously under imaging guidance (ultrasound, CT or MRI) or during surgery guided by intraoperative US. The advantage of RF in the treatment of HCC in cirrhotic patients is that it allows selective destruction of the tumor, sparing the surrounding parenchyma, and can be easily repeated in case of recurrence. Complete ablation of lesions smaller than 2 cm is possible in more than 90% of cases[50].

There are several major limits to the use of RF: (1) complete necrosis is rarely observed when the tumor diameter is > 3 cm or when the tumor is adjacent to a major blood vessel due to the cooling effect of the blood flow; (2) it is difficult to reach some areas of the liver parenchyma percutaneously (e.g., segment 1); (3) subcapsular lesions can undergo rupture in the peritoneum; (4) bladder injury can occur when lesions in segments IVb-5 are treated; and (5) targeting the lesion can be difficult under ultrasound guidance in livers with multinodular cirrhosis.

Taking these limitations into account, the benefit of RF in the treatment of HCC has been well demonstrated, with overall 5-year survival rates between 33% and 55% in selected series[51]. The effectiveness of RFA has led to the proposal of this technique as an alternative to HR.

In the only randomized prospective trial with balanced groups of patients comparing HR to RFA for HCC < 3 cm in patients with cirrhosis, no difference was observed in terms of overall and disease-free survival, whereas RF was associated with lower perioperative morbidity (4.2% vs 55.5%, P < 0.05) and mortality (0% vs 1.1%)[52]. However, in a retrospective comparative study of Child-Pugh class A patients, surgery was significantly more effective for patients with single tumors > 3 cm in diameter, with an overall 3-year survival of 66% after surgery (vs 37% after RFA, P = 0.004) and a 3-year disease-free survival of 44% (vs19%, P = 0.001)[53]. This observation was confirmed by subsequent studies performed by different groups[54-56]. A recent systematic review and meta-analysis of 12 controlled trials showed a not notable difference in the short-term effectiveness of RFA and HR in the treatment of early-stage hepatocellular carcinoma meeting Milan criteria, but the long-term efficacy of HR was better than that of RFA[57]. However, HR was associated with more complications and a longer hospital stay.

Rather than competing techniques, RFA and HR are effective therapeutic options that can be chosen based on the severity of chronic liver disease as well as the size and location of the tumor.

Transarterial chemoembolization

Transarterial chemoembolization (TACE) is the most commonly used initial treatment for unresectable HCC[58] and is also the first-line therapy for downstaging tumors that exceed the criteria for transplantation or to avoid tumor progression in patients awaiting LT. TACE may also be considered as a neoadjuvant treatment that can be utilized before HR or RF ablation to reduce tumor volume and possibly target satellite micrometastases[59].

The rationale behind TACE use is the well-characterized angiogenic activity of HCC that results in hypervascular arterial feeding. This technique depends on the intra-arterial infusion of a cytotoxic chemotherapeutic agent emulsioned with Lipiodol followed by embolization of the feeding vessels through a trans-arterial catheter[60]. TACE is a well-established treatment for HCC in cirrhotic patients, and its efficacy for improving survival compared with the other supporting treatments has been demonstrated[61].

The maximum and sustained retention of the chemotherapeutic agent is used as a measure of the success of TACE; thus, embolic microspheres are employed that have the ability to sequester chemotherapeutic agents. The concentration of these microspheres is increased within the tumor, and their contents are subsequently released in a controlled manner over a 1-wk period, which reduces the systemic toxicity to a minimum[62].

Doxorubicin-eluting beads (DEB) are another transarterial liver-directed therapy. The use of an eluting bead can be considered an improvement over conventional TACE. DEB are preformed, deformable microspheres that are loaded with doxorubicin (up to 150 mg per treatment). The pharmacokinetic profile of DEB significantly differs from that of conventional TACE; in particular, the peak drug concentration in the serum is lower for DEB-TACE compared with conventional TACE. An objective response rate of 70% to 80% according to the EASL criteria has been achieved[63]. One- and 3-year survival rates of 89.9% and 66.3%, respectively, have been reported in a heterogeneous cohort of patients with BCLC (stages A to C) treated with DEB-TACE[64].

Absolute contraindications for TACE are decompensated cirrhosis (Child-Pugh B ≥ 8, including jaundice, clinical encephalopathy and refractory ascites), extensive tumor with massive replacement of both lobes in their entirety, severely reduced portal vein flow (portal vein occlusion or hepatofugal blood flow), and a creatinine clearance < 30 mL/min[65].

Microwave ablation

Microwave ablation (MWA) is a potentially curative ablation procedure that has been proven to be safe in both percutaneous and intraoperative settings[66]. MWA can be utilized in patients with advanced liver disease and HCC, provides a more predictable ablation compared with RFA and requires fewer treatment sessions[21,67,68].

Microwave ablation creates an electromagnetic field in the tissues surrounding the ablation antenna with an extension of several centimeter, without flow of electrical current. Tissue within the MWA field heats rapidly to temperatures over 100 °C without the detrimental effects of tissue impedance, allowing a more rapid and consistent ablation[10]. Microwave ablation carries the risk of more severe injury to adjacent structures due to differences in energy delivery when compared with RFA; therefore, the operative approach is preferred over the percutaneous approach because it allows liver mobilization and protection of adjacent organs[66,69,70].

Radioembolization

Radioembolization is a newer hepatic transarterial technique that employs radioactive substances such as Iodine-131-labeled Lipiodol[71] or microspheres containing Yttrium-90[72]. This technique has been shown to be feasible and safe for the treatment of HCC in cirrhotic patients[73,74]. Microspheres are delivered to the tumor area for selective production of high energy and low penetration radiation. Radioembolization can be safely performed in patients with portal vein thrombosis due to the minimally embolic effect of 90Y microspheres[75]. The reported rate of complete tumor necrosis is 90% for patients with HCC < 3 cm[76], whereas the rate of complete necrosis after TACE varies widely in the literature, from 15% to 70%[77].

Radiation therapy

Radiation therapy is generally not considered an option in HCC consensus documents or national guidelines, primarily because of the lack of level 1 evidence[78]. However, experience with conformal radiation therapy (RT), intensity modulated RT, stereotactic body RT and particle therapy is rapidly increasing. RT should be considered as a treatment option in patients unsuitable for other established local therapies[78]. RT has also been used as a bridge to liver transplant and can be safely combined with locoregional therapies such as TACE[78,79].

SYSTEMIC TREATMENTS

Systemic treatment of HCC in cirrhotic patients is not effective due to the poor chemosensitivity of the tumor, and the impairment of hepatic function significantly increases the toxicity of chemotherapy.

Because the demonstrated benefits of systemic chemotherapy and hormonal treatments are lacking[80,81], molecular targeted therapies have recently been developed. Sorafenib, an inhibitor of multi-kinase, has antiproliferative and antiangiogenic activity, delays tumor progression and is currently the only agent with proven efficacy for the treatment of patients with advanced HCC[11,82-84]. This multitargeted tyrosine kinase inhibitor is a small molecule that inhibits vascular endothelial growth factor receptor, platelet-derived growth factor receptor, B-Raf, Fms-related tyrosine kinase and c-kit[85,86].

The use of sorafenib is currently recommended for patients with preserved liver function and advanced HCC who are not suitable for HR or LT and have failed to respond to locoregional treatments[87]. It is recommended that the treatment be continued until progression of the tumor is demonstrated. The main side effects associated with the use of sorafenib are diarrhea and hand-foot skin reaction; other possible side effects include anorexia, nausea, vomiting, weight loss, hoarseness of voice, asthenia and hypertension[52,88]. These effects can occasionally require dose reduction or treatment discontinuation. The potential benefit of sorafenib as adjuvant treatment after LT has not been demonstrated.

On the basis of a large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol[83], Sorafenib has been approved by the United States Food and Drug Administration for the treatment of patients with advanced HCC.

Studies are ongoing that aim to identify the best responders to Sorafenib; c-Jun N-terminal kinase (JNK) activity was positively correlated with the CD133 expression level and inversely correlated with the therapeutic response to Sorafenib. Accordingly, JNK activity may be considered as a new predictive biomarker for response to Sorafenib treatment[89].

To date, there is no second-line treatment for patients who are intolerant to Sorafenib or experience tumor progression while undergoing treatment.

COMBINED TREATMENTS

A combination of the different therapeutic approaches mentioned thus far is often required to address the different clinical peculiarities of HCC patients. For example, chemoembolization or RFA can be performed before radical surgery with curative intent (HR or LT) to allow effective tumor downstaging or reduce tumor growth. Different authors have proposed HR as a first-line therapy in patients who are candidates for LT[90]; however, the possible effect of previous surgery on the technical complexity of the liver transplantation procedure is a matter of debate[90,91]. One argument in favor of hepatic resection prior to LT is that histological analysis of the tumor can provide useful information regarding its oncological behavior: features such as the presence of a tumor capsule, the degree of differentiation or the presence of micro-vascular invasion can be precisely assessed in the surgical specimen and are well-known prognostic factors. However, there is no consensus among different authors regarding the influence that histological parameters should have on the therapeutic strategy; some authors suggest that LT should be contraindicated for patients with tumors that display poor prognostic histological criteria, whereas others recommend transplant priority in the presence of the same risk factors[23,92].

CONCLUSION

The treatment of HCC in cirrhotic patients has changed significantly over the past several decades and has become a major clinical issue. Patients with HCC on cirrhosis can benefit from several effective treatments that will improve their survival; however, the choice of the most appropriate options depends on several factors, namely: (1) severity of the underlying chronic liver disease; (2) stage of the tumor assessed viaimaging; (3) histological features of the tumor (when available); (4) availability of an active transplant program; (5) availability of a hepatobiliary surgical unit; and (6) availability of an experienced interventional radiology service.

Some of these variables may account for the different attitudes that are often observed. To ensure that the most effective treatment can be offered for a given case, a multidisciplinary approach is warranted, and professionals skilled in the administration of the different treatment types should be available. The increase in the incidence of HCC justifies the development of services related to the management of this tumor.

Footnotes

P- Reviewer: Scherubl H S- Editor: Gou SX L- Editor: A E- Editor: Zhang DN

References

Source

Ground-breaking scan may identify liver disease

Provided by MedicalXpress

November 26, 2013

A ground-breaking scan that can identify and help to treat liver disease, could make painful and invasive liver biopsies a thing of the past, thanks to a trial being led by the University of Birmingham.

Nearly 15 million people in the UK are affected by liver disease and this number is increasing. Most suffer from fatty liver disease which is linked to obesity, diabetes and alcohol excess and in severe cases can cause cancer or death. The Chief Medical Officer for England, Dame Sally Davies, identified it as a priority for the NHS in her report on the state of the nation's health and called for urgent action to reverse the trend.

Patients who are suspected of having liver disease will usually be sent for an invasive biopsy to assess the level of damage. But, as well as being painful and uncomfortable, biopsies have some drawbacks, including the fact that they cannot be used over and over again on the same patient. The new scan, called LiverMultiscan, could be used numerous times which means doctors will find it easier to monitor the progress of the disease and adapt the treatment plan accordingly for the individual.

The trial is a collaboration between clinicians and scientists at the NIHR Liver Biomedical Research Unit at the University of Birmingham, the University of Edinburgh and medical imaging company Perspectum Diagnostics. It is supported by a grant of £1.2 million from the UK's innovation agency, the Technology Strategy Board.

Until now, non-invasive tests such as blood tests and routine scans have been limited in detecting liver damage, especially in the early stages where patients have the most to gain from treatment. The only current accurate way to diagnose liver disease is through a liver biopsy where a needle is put into the liver and a sample of tissue is taken. This is uncomfortable and carries a small risk of serious complications.

Alex Morris, 40, from Birmingham, has had two liver biopsies. The first one, at Birmingham's Queen Elizabeth Hospital in 2012, confirmed she was suffering from liver disease.

She said that the ground breaking scan would be far preferable to a biopsy.

"Biopsies are not nice, not at all. They are a necessary evil, to diagnose you and to monitor whether you are getting any worse, but they are not nice," she said.

"The staff, the nurses, the doctors, they were all fantastic and explained what was happening the whole time. I was nervous and scared going in, and they really do everything they can to put you at your ease. But the anxiety of knowing you may be about to be diagnosed with a disease, together with undergoing a procedure does make it scary.

"If it comes down to a scan or a biopsy, and you can get the same result from both, I would choose a scan every time."

Miss Morris said that her biopsies took her about a week each to physically recover from.

If successful, LiverMultiscanTM, which uses a new type of MRI (magnetic resonance imaging) technology could be used throughout the UK to diagnose patients with liver disease without resorting to biopsies and could be available to patients in the NHS within three years.

Over the next two years the clinical study being undertaken will further assess LiverMultiscanTM and will also use the technology to monitor a group of patients with primary sclerosing cholangitis to see how well changes in the liver can be tracked over time.

Dr Peter Eddowes, Clinical Research Fellow in Hepatology at the University of Birmingham said:

"Liver disease often has no symptoms and people can go for years not knowing their liver is damaged. Current non-invasive tests lack the sensitivity to reliably pick up early liver disease"

Dr Gideon Hirschfield, the chief investigator on the study said:

"We are pleased to run this study in Birmingham alongside our partners in Edinburgh and Oxford. We hope LiverMultiscanTM will improve the care of liver patients and enable us to provide a quicker, cheaper and most importantly, safer diagnosis."

Explore further: Fast, painless alternative to liver biopsies for hepatitis patients proves accurate and reliable

Provided by University of Birmingham

Source

Will The New Hepatitis C Drugs Trigger A Battle Over Cost?

Provided by Forbes

Ed Silverman, Contributor

PHARMA & HEALTHCARE 11/11/2013 @ 5:39PM |7,160 views

As excitement mounts among physicians and investors over a new batch of drugs for treating hepatitis C, there is also concern that patients in developing countries may not have sufficient access due to high prices. But a recent poster presentation at a medical conference suggests that drugmakers can produce these new medicines for relatively little cost and should be compelled to do so.

The analysis, which was displayed at the American Association for the Study of Liver Diseases gathering last week in Washington, DC, concluded that large-scale production of direct acting antivirals may be possible for as little as $100 to $200 for 12 weeks of treatment. The estimate cited HIV drugs, which initially cost tens of thousands of dollar per patient but have since dropped significantly in price in developing nations, as a model framework.

This new group of drugs includes sofosbuvir, which is made by Gilead Sciences and was unanimously endorsed by an FDA panel last month. The treatment offers a higher cure rate with less toxicity and a shorter duration for treatment than a pair of medicines from Merck and Vertex Pharmaceuticals that was approved two years ago, which explains the enthusiasm on Wall Street, where sofosbuvir pricing is expected to reach $80,000 to $90,000 per patient in the US.

The FDA panel voted in favor of approving sofosbuvir for patients with hepatitis C genotypes 2 and 3 in combination with an older medicine called ribavirin. If approved, the drug will be the first all-oral treatment for these strains. The panel also endorsed the drug for combating genotypes 1 and 4 in combination with ribavirin and interferon in patients who have not already received therapy. And the vast majority of HCV cases involve genotype 1.

As a result, “Gilead does not expect to have high gross/net discounting in this segment, since they will not have a lot of competition initially and because the key driver of discounts is taking price increases over time,” Citi analyst Yaron Werber wrote in a recent investor note. The formal FDA approval date for this drug, by the way, is December 8 and there is anticipation the agency will endorse the panel recommendation.

These sorts of pricing estimates, however, are prompting worries that such medical advances will be out of reach for patients in poor countries – and perhaps some people in the US, as well - unless Gilead and the other drugmakers that are developing DAAs, a group that includes Bristol-Myers Squibb and AbbVie, agree to sell their drugs for much lower prices.

“It only takes a few grams of these drugs to cure hepatitis C,” says Andrew Hill of Liverpool University, one of the researchers. “Companies have a choice: continue treating a very small number of people with hepatitis C at a very high cost, or expanding access to these treatments, lowering treatment costs significantly, and working towards eradication of this disease” (here is the analysis).

A key issue is that there are no international agencies or groups that purchase hepatitis C drugs for distribution to poor countries. Meanwhile, there are anywhere from 130 million to 150 million people who are infected worldwide. In the US, there are approximately 3 million to 4 million people infected with hepatitis C in the US, but less than 60,000 are being treated, according to Gilead.

In other words, demand is expected to mushroom, setting up a potential clash over availability. Even in the US, the situation is expected to become exacerbated as physicians await FDA approval for the newest drugs before treating some patients, a practice known as warenhousing. Meanwhile, more people are likely going to be in need of treatment now that the US Preventive Services Task Force has recommended testing for hepatitis C.

“If the current high prices continue, it is likely that very few people will be treated and the overall epidemic of hepatitis C in the USA will continue unchecked,” Hill says. “It is only by lowering the prices, and treating more people, that there could be a real change in the USA.”

In the analysis, Hill and a colleague assumed that the production cost per gram of a hepatitis C drug was between one to 10 times higher than the equivalent HIV antiretroviral, depending on the complexity of chemical synthesis. The production cost of sofosbuvir, for instance, was estimated at $68 to $136 for a 400mg dose for 12 weeks. A Gilead spokeswoman declined to comment on the research and added that it is “premature” to comment on pricing.

In response, Doctors Without Borders, which hopes the oral DAAs can place the ease of treating hepatitis C on a par with treating HIV, issued a statement exhorting drugmakers to make their forthcoming medicines affordable on a large scale. If not, the advocacy group suggested that drugmakers may find themselves confronting countries willing to issue compulsory licenses, which is a path some countries have taken in response to prices for some AIDS and cancer medicines.

“We urge companies expected to bring these drugs to market soon to price new hepatitis C regimens at below $500 in developing countries, and for countries affected by the disease to consider ways to overcome patent barriers to allow the production of more affordable generic versions,” says Manica Balasegaram, who heads the group’s Access Campaign. The patents on the forthcoming crop of DAAs do not expire for a dozen years or more.

It is worth noting that a report issued earlier this year from the Global Commission on Drug Policy, which includes former Federal Reserve Chairman Paul Volcker and billionaire businessman Richard Branson, suggested that compulsory licenses should be pursued when pricing talks with drugmakers fail (back story).

Hill, meanwhile, acknowledged some limitations to the analysis. For instance, more precise estimates of production costs require pilot production batches and more detailed analysis of process chemistry, and access to DAAs at minimum prices in developing countries will depend on the level of enforcement of patent restrictions. And of course, some may argue that production costs do not cover the entire gamut of expenses, but pricing is likely to be debated, regardless

Source

PRESS RELEASE

Nov. 26, 2013, 9:21 a.m. EST

Nearly Half of Adults Living with HIV Are Women Who Face Unique Challenges Throughout Every Stage of Life

PR-Logo-Newswire

NORTH CHICAGO, Ill., Nov. 26, 2013 /PRNewswire via COMTEX/ -- In advance of World AIDS Day on December 1, 2013, AbbVie ABBV +0.85% today announced the launch of See Us: Women Take a Stand on HIV, an international awareness campaign focused on helping to address the unique challenges faced by women living with HIV. The campaign is being launched in collaboration with an expert steering committee, which includes representation from women living with and affected by HIV, the medical community, the International Association of Providers in AIDS Care (IAPAC), and NAM/aidsmap, the HIV information charity.

Women are the fastest-growing group within the population of people living with HIV globally.1 They face many challenges as a consequence of the compounding effects of HIV status, its associated stigmas and the status of women. These challenges range from lack of access to care to the experience of violence and discrimination.2 In addition, at each stage of life, from childhood through childbearing years to post-menopause, women living with HIV are confronted with unique care considerations, which include maternal and emotional health issues, and an increased risk for multiple disease complications.3

"As we recognize World AIDS Day this year, it is important to acknowledge and work to address the unique needs of women living with HIV, who make up nearly half of the global population of people living with HIV," said Jose M. Zuniga, PhD, MPH, President of IAPAC. "Because women living with HIV can face challenges around accessing health care resources, and as HIV prevalence increases among women, there is an urgent need for initiatives to raise awareness and respond to the unique needs of women living with HIV throughout all phases of their lives."

In the coming months, AbbVie and the See Us: Women Take a Stand on HIV steering committee will develop and launch an informational tool as a resource for women living with HIV and will continue to contribute to building a broader sense of community by helping to gain support from national and international organizations focused on both women and HIV.

"As a global leader in HIV, AbbVie has a long-standing commitment to providing support to people living with HIV through global initiatives that seek to increase knowledge and understanding of the effects of HIV on people living with the disease," said Marisol Martinez-Tristani, MD, Medical Director, Global Medical Affairs, AbbVie. "It's important that we recognize specifically the plight of women living with HIV. Through this campaign we will engage in efforts to reach the HIV community to collectively improve both emotional support and long-term care for these women."

About See Us: Women Take a Stand on HIV See Us: Women Take a Stand on HIV is an international awareness campaign created by AbbVie and the steering committee with representation from women living with and affected by HIV, the medical community, IAPAC, and NAM/aidsmap. The campaign seeks to assist in breaking down barriers, improving overall care and support, and ultimately helping encourage women living with HIV to create a cohesive community and advocate for their own needs. The campaign is made possible through funding provided by AbbVie and involves the participation of HIV community representatives from around the world.

Women: The New Face of HIVWomen are the fastest-growing group within the population of people living with HIV worldwide.1 Every minute, one woman is infected by HIV, mainly through sexual transmission.2 Globally, some 49 percent of all adults living with HIV are female.2 Infection rates among women aged 15-24 are twice as high as in young men.2 Women have different care considerations from men, including pregnancy, increased risk for cervical cancer, and premature menopause and osteoporosis.3 HIV is the leading cause of death in women of reproductive age around the world4, many of whom are diagnosed when they become pregnant.5

About AbbVieAbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

References1 AIDS Epidemic Update December 2004. UNAIDS and WHO. Accessed September 26, 20132 Women Out Loud. UNAIDS. Accessed September 26, 20133 Guide for HIV/AIDS Clinical Care, Health Care of HIV Infected Women through the Life Cycle. US Department of Health and Human Services. Accessed September 26, 20134 Women and Health. WHO. Accessed September 26, 20135 Global HIV/AIDS Response Epidemic Update and Health Sector Progress Towards Universal Access. Accessed September 26, 2013

SOURCE AbbVie

Copyright (C) 2013 PR Newswire. All rights reserved

Source

This study is not yet open for participant recruitment.

Verified November 2013 by AbbVie

Sponsor: AbbVie

Information provided by (Responsible Party): AbbVie

ClinicalTrials.gov Identifier:
NCT01995071
First received: November 21, 2013
Last updated: NA
Last verified: November 2013
History: No changes posted

Purpose

The purpose of this study is to evaluate the safety and antiviral effect of multiple doses of ABT-493 and ABT-530 in adults with genotype 1 HCV.

Condition Intervention Phase
Chronic Hepatitis C
Hepatitis C Virus
Compensated Cirrhosis

Drug: ABT-493
Drug: ABT-530
Drug: ABT-450/r/ABT-267
Drug: ABT-333
Drug: Ribavirin (RBV)

Phase 2

Study Type: Interventional

Study Design:

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Official Title: A Randomized, Open-Label, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Multiple Doses of ABT-493 and ABT-530 in Adult Subjects With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection

Resource links provided by NLM:

Genetics Home Reference related topics: North American Indian childhood cirrhosis

MedlinePlus related topics: Cirrhosis Hepatitis Hepatitis A Hepatitis C

Drug Information available for: Ribavirin Hepatitis A Vaccines

U.S. FDA Resources

Further study details as provided by AbbVie:

Primary Outcome Measures:

  • Maximal decrease in log10 hepatitis C virus ribonucleic acid levels from baseline [ Time Frame: 3 days after first dose of study drug ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • The percentage of subjects with sustained virologic response 12 weeks post-treatment [ Time Frame: 12 weeks after last dose of study drug ] [ Designated as safety issue: No ]

    Hepatitis C virus ribonucleic acid less than the lower limit of quantification

  • The percentage of subjects with on-treatment virologic failure during the treatment period [ Time Frame: Up to 87 days ] [ Designated as safety issue: No ]

    Percentage of subjects with quantifiable hepatitis C virus ribonucleic acid throughout the entire treatment period, confirmed quantifiable hepatitis C virus ribonucleic acid after previously having unquantifiable hepatitis C virus ribonucleic acid, or a confirmed increase of at least one log10 in hepatitis C virus ribonucleic acid during treatment

  • The percentage of subjects with post-treatment relapse [ Time Frame: Within 12 weeks after the last dose of study drug ] [ Designated as safety issue: No ]

    Percentage of subjects with confirmed quantifiable hepatitis C virus ribonucleic acid among subjects with unquantifiable hepatitis C virus ribonucleic acid at the end of treatment

  • Estimated Enrollment: 80
    Study Start Date: November 2013
    Estimated Study Completion Date: May 2015
    Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Arm 1
ABT-493 Dose A for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-493
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 2
ABT-493 Dose B for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-493
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 3
ABT-493 Dose C for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-493
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 4
ABT-493 Dose D for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-493
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 5
ABT-493 Dose E for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-493
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 6
ABT-530 Dose A for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-530
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 7
ABT-530 Dose B for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-530
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 8
ABT-530 Dose C for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-530
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 9
ABT-530 Dose D for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-530
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Experimental: Arm 10
ABT-530 Dose E for 3 days, followed by ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 12 weeks
Drug: ABT-530
tablet
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: Ribavirin (RBV)
tablet
Eligibility

Ages Eligible for Study: 18 Years to 70 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

  • Chronic HCV infection prior to study enrollment.
  • Screening laboratory result indicating HCV genotype 1-infection.
  • Subject has plasma HCV RNA level greater than 10,000 IU/mL at Screening.
  • Per local standard, subject is considered to be non-cirrhotic or to have compensated cirrhosis.

Exclusion Criteria:

  • History of severe, life-threatening or other significant sensitivity to any drug.
  • Positive test result for Hepatitis B surface antigen (HBsAg) or anti-Human Immunodeficiency Virus antibody (HIV Ab).
  • Prior therapy for the treatment of HCV.
  • Any current or past clinical evidence of Child Pugh B or C classification of clinical history of liver decompensation including ascites (noted on physical exam), variceal bleeding or hepatic encephalopathy.
  • Any cause of liver disease other than chronic HCV infection.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01995071

Contacts

Contact: Christian Naylor, BS
847-935-2492
christian.naylor@abbvie.com

Contact: Mary Santangelo, BS
847-938-6703
mary.santangelo@abbvie.com

Sponsors and Collaborators AbbVie

Investigators Study Director: Armen Asatryan, MD AbbVie

More Information

No publications provided

Responsible Party: AbbVie

ClinicalTrials.gov Identifier: NCT01995071 History of Changes

Other Study ID Numbers: M13-595

Study First Received: November 21, 2013

Last Updated: November 21, 2013

Health Authority: United States: Food and Drug Administration