April 1, 2014

Screening for liver cancer in patients with cirrhosis

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April 1, 2014

In a systematic review and meta-analysis of 47 studies with 15,158 patients, Amit Singal (University of Texas Southwestern Medical Center) and colleagues found that patients with cirrhosis who underwent surveillance (via liver ultrasound with or without measurement of serum alpha fetoprotein) for hepatocellular carcinoma (HCC) had cancers detected at an earlier stage, were more likely to receive curative instead of palliative treatment, and had longer survival. Across all the studies, the pooled 3-year survival rate was 50.8% among the 4735 patients who underwent HCC surveillance, compared to 27.9% among the 6115 patients without prior surveillance (p<0.001).

The finding of longer survival persisted after the authors limited their review to studies that took into account lead time bias. Lead time bias, as it applies to this study, is the time between when a disease would normally be diagnosed without screening and when the disease is diagnosed with screening. Detecting disease earlier through screening can sometimes appear to increase survival when instead it only prolongs the time the person has the diagnosis. However, in this case, studies that accounted for lead time bias statistically still found that screening increased survival. Among the 6 studies that adjusted for lead time bias, those who underwent HCC surveillance had 3-year survival rates of 39.7%, vs. 29.1% among those who did not (p<0.001).

The authors note that while screening for HCC in patients with hepatitis B virus (HBV) infection is supported by a large randomized trial, no such randomized trials exist for patients with cirrhosis. Therefore the authors systematically reviewed published research that evaluated whether screening was associated with improved patient outcomes. While guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver recommend surveillance with ultrasound every 6 months in high-risk patients (which includes those with chronic HBV infection and/or cirrhosis), the authors note that studies have shown that surveillance in the US is performed in less than 20% of these patients nationally, with lower rates among primary care physicians than gastroenterologists/hepatologists (physicians who specialize in caring for patients with liver disease).

A limitation of the study is that the studies were quite heterogeneous, suggesting benefits of surveillance may not be uniform among all patients, and studies did not include functional status, an important factor in determining appropriate treatment.

The authors conclude, "the preponderance of data that consistently demonstrate benefits should provide sufficient rationale to recommend HCC surveillance, even in the absence of a randomized controlled trial among patients with cirrhosis."

More information: Singal AG, Pillai A, Tiro J (2014) Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis. PLoS Med 11(4): e1001624. DOI: 10.1371/journal.pmed.1001624

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PUBLIC RELEASE DATE: 1-Apr-2014 Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Researchers report that low levels of sodium, known as hyponatremia, prior to transplantation does not increase the risk of death following liver transplant. Full findings are published in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

Medical evidence shows that low sodium concentration is common in patients with end stage liver disease (ESLD), with roughly half of those with cirrhosis having sodium levels below the normal range of 135-145 mmol/L. Moreover, previous research suggests that hyponatremia is linked to complications including bacterial infections, kidney failure and encephalopathy, and increases mortality in patients with ESLD. Following liver transplantation sodium levels will return to normal.

"There is much debate within the transplant community about whether to incorporate measures of serum sodium in the organ allocation system in the U.S.," explains lead author Dr. W. Ray Kim from Stanford University in Calif., and formerly with the Mayo Clinic where the research took place. "Understanding the impact of sodium concentrations in patients prior to and following liver transplantation is an important contribution to this debate."

Using data from the Organ Procurement and Transplantation Network (OPTN) researchers identified 19,537 patients 18 years of age or older who received a liver transplant in the U.S. between 2003 and 2010. Subjects were split into three groups: those with hyponatremia (sodium levels less than 130 mEq/L); normal sodium levels (serum sodium between131-145mEq/L); and hypernatremia (high sodium levels great than 145mEq/L).

"While our findings confirm that low sodium levels prior to transplant were a strong risk factor for waitlist mortality it was not associated with higher death risk following liver transplantation," concludes Dr. Kim. "Our data suggests that using serum sodium levels to determine organ allocation priority will not impact survival following a liver transplant."

###

This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact sciencenewsroom@wiley.com

Full citation: "The Effect of Pretransplant Serum Sodium Concentration on Outcome Following Liver Transplantation." Michael D. Leise, Byung Cheol Yun, Joseph J. Larson, Joanne T. Benson, Ju DongYang, Terry M. Therneau, Charles B. Rosen, Julie K. Heimbach, Scott W. Biggins and W. Ray Kim.Liver Transplantation; (DOI: 10.1002/lt.23860).

URL: http://doi.wiley.com/10.1022/lt.23860

About the Journal

Liver Transplantation is published by Wiley on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit http://wileyonlinelibrary.com/journal/lt.

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Clinical Liver Disease Volume 3, Issue 3 March 2014 Pages 65–68

M. Valerie Lin M.D., Raymond Chung M.D.

First published: March 2014 Full publication history

DOI: 10.1002/cld.332

Citing literature

From the Gastrointestinal Unit, Liver Center and Gastroenterology Division, Massachusetts General Hospital, Boston, MA.

Potential conflict of interest: Nothing to report.

Raymond T. Chung, Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Blake 4, Boston, MA 02114. E-mail: rtchung@partners.org.

Abstract

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Direct-Acting Antiviral Agents

NS3/NS4A Protease Inhibitors

NS3/NS4A protease inhibitors block the hepatitis C virus (HCV) NS3/NS4A protease enzymatic cleavage of the HCV C-terminal polyprotein into discrete nonstructural proteins. Telaprevir and boceprevir represent the first wave of HCV protease inhibitors. The second wave (simeprevir, ABT-450, asunaprevir) have improved pharmacokinetics and allow once-daily dosing with more tolerable side effects. Each of these agents has similar genotype and subtype coverage (less efficacious against 1a than 1b because of a lower barrier to selection for resistance) and resistance profiles. The true second-generation protease inhibitors (MK-5172) are in earlier stages of development and likely provide close to pan-genotypic antiviral activity and a higher genetic barrier to resistance.

NS5A Inhibitors

NS5A inhibitors block viral production at two steps: the HCV replication complex and the virion assembly stage. Representative drugs in development include daclastavir, ledipasvir, ABT-267, and MK-8742.

Nucleos(t)ide NS5B Polymerase Inhibitors

Nucleos(t)ide NS5B polymerase inhibitors inhibit HCV RNA-dependent RNA-polymerase activity by binding to the active site and causing early chain termination. These agents (sofosbuvir) have broad potency and a very high barrier to resistance. Because of the critical function of the highly conserved active site, mutations in this site result in crippled replication fitness. This barrier to resistance stands in stark contrast to the nonnucleoside NS5B inhibitors, which bind to the enzyme outside the active site (allosteric inhibitors) and induce conformational changes that limit access of nucleotides to the growing viral RNA.

Figure 1 shows the HCV genome, which is a small, positive-sense, single-stranded RNA virus with a 9.6-kb genome. The virus circulates as a highly lipidated molecule that closely resembles host lipoproteins. Once inside the cell, the viral genome is exposed and translated into a polypeptide of about 3000 amino acids. This polypeptide is cleaved by a combination of host and viral proteases into 10 viral proteins. These include 3 structural proteins (C, E1, E2) and 7 non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).[1]

cld332-fig-0001

Figure 1. Open in figure viewer   Download Powerpoint slide

The HCV RNA genome (upper line) is translated into a single long polyprotein (middle line), which is cleaved by host and viral proteases into 10 mature peptides (lower line). From reference 1.

Host Targeting Agents

Cyclophilin Inhibitors

Cyclophilin inhibitors inhibit cyclophilin A and disrupt its interaction with NS5A and the HCV replication complex, which results in impaired replication.

MicroRNA Antagonists

MicroRNA antagonists exert inhibitory effect on HCV replication by blocking a key microRNA essential for HCV RNA replication.

Sofosbuvir

Mechanism of Action

Sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase, targeting the HCV NS5B polymerase active site and becoming incorporated into the growing viral RNA, causing early chain termination.[2] It exerts potent antiviral activity against HCV genotypes 1 through 6.

Approved Indications

The US Food and Drug Administration (FDA) approved the use of sofosbuvir in patients with HCV genotype 1 to 4 infections. It is also approved for use in human immunodeficiency virus (HIV)/HCV coinfection and patients with hepatocellular carcinoma awaiting liver transplantation who are within Milan criteria and have a Model for End-Stage Liver Disease (MELD) score of <15.

In HCV genotype 1 treatment-naïve patients, the combination of sofosbuvir, pegylated interferon (PEG-IFN) and ribavirin (RBV) for 12 weeks yielded a sustained virologic response (SVR) of 89%; in those with multiple unfavorable baseline factors, the SVR was 71%.[3] Patients with genotype 2 who were treated with sofosbuvir and RBV for 12 weeks had a SVR of 95%-97% in treatment-naïve patients and 82%-90% in treatment-experienced patients. In patients with genotype 3, an extended duration of 24 weeks with sofosbuvir and RBV produced a SVR rate of 93% in treatment-naïve populations and 77% in treatment-experienced populations.[3-5]

The PHOTON-1 study, in which HCV/HIV-1-coinfected patients were treated with sofosbuvir and RBV for 12-24 weeks, yielded a SVR of 76% in genotype 1, 88% in genotype 2, and 92% in genotype 3 with a good safety profile and minimal drug interaction with highly active anti-retroviral therapy (HAART).[6]

Table 1 summarizes the approved uses of sofosbuvir.

Table 1. Recommended Sofosbuvir Regimens
HCV Medications Duration

Sofosbuvir is given orally at 400 mg daily with or without food. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75 kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.

Genotypes 1 and 4 Sofosbuvir + PEG-IFN/RBV 12 weeks
Genotype 2 Sofosbuvir + RBV 12 weeks
Genotype 3 Sofosbuvir + RBV 24 weeks
Hepatocellular carcinoma awaiting liver transplantation Sofosbuvir + RBV Up to 48 weeks (or until time of liver transplantation)
Use Outside the Approved Indications

Patients with HCV genotype 1 who are ineligible for or intolerant of PEG-IFN-based regimens should consider 1) sofosbuvir and simeprevir for 12 weeks, particularly in patients with compensated cirrhosis, or 2) sofosbuvir and ribavirin for 24 weeks.

Patients with mild to moderate renal impairment and/or anemia should consider sofosbuvir and simeprevir for 12 weeks.

Patients who failed first-generation protease inhibitors and who are therefore not candidates for simeprevir-based therapy and require immediate treatment should consider sofosbuvir and PEG-IFN/RBV therapy for 12 weeks.

Patients with posttransplantation-recurrent HCV infection may be considered for sofosbuvir and simpeprevir for 12 weeks in genotype 1; sofosbuvir and RBV with or without PEG-IFN for 24 weeks in genotypes 2, 3, and 4; or sofosbuvir and RBV for up to 48 weeks in decompensated disease or fibrosing cholestatic hepatitis C.

Simeprevir

Mechanism of Action

Simeprevir is a macrocyclic NS3/4A protease inhibitor that inhibits the HCV NS3/4A protease's cleavage of the HCV polyprotein, preventing viral replication in infected cells.[7]

Approved Indications

The FDA approved the use of simeprevir in combination with PEG-IFN and RBV for HCV genotype 1 infection in treatment-naïve and treatment-experienced patients with noncirrhotic and compensated cirrhotic disease.

A pooled analysis of phase 3 studies of HCV treatment-naïve patients treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks showed a SVR of 80%. This was reduced to 61% and 60% in patients with interleukin−28B TT genotype and cirrhosis, respectively. The efficacy was also significantly lower among those with genotype 1a who harbor the Q80K polymorphism (SVR 58%).[8, 9]

Prior PEG-IFN/RBV relapsers treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks had a SVR of 79%.[10] Prior partial- and null-responders treated with simeprevir for 12 weeks and PEG-IFN/RBV for 48 weeks had a SVR of 65% and 53%, respectively.[11]

Table 2 summarizes the approved uses of simeprevir.

Table 2. Recommended Simeprevir Regimens for HCV Genotype 1 Patients
Prior Treatment Status Medications and Duration SVR 12

Simeprevir is given orally at 150 mg daily. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.

Naïve Simeprevir 12 weeks + PEG/RBV 24 weeks 80%
Relapser Simeprevir 12 weeks + PEG/RBV 24 weeks 79%
Partial Simeprevir 12 weeks + PEG/RBV 48 weeks 65%
Null Simeprevir 12 weeks + PEG/RBV 48 weeks 53%

Use Outside the Approved Indications and Conditions

The “Use Outside the Approved Indications” section for sofosbuvir discusses combination therapy of simeprevir with sofosbuvir for patients who are ineligible for PEG-IFN-based therapy, who have renal impairment, or who have recurrent allograft HCV.

Patients who have HIV/HCV coinfection, have genotype 1b, have genotype 1a without Q80K polymorphism, and are on compatible HAART regimens (permitted antiretroviral therapy with simeprevir: raltegravir, rilpivirine, maraviroc, tenofovir, emtricitabine, lamivudine, and abacavir) may consider the following: 1) if no cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for 12 or 36 weeks based on response-guided therapy criteria; or 2) if cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by 36 weeks of PEG-IFN/RBV.

Challenges

The challenges associated with the use of these agents include cost of treatment, third-party reimbursement for off-label use, use in special populations, and drug resistance.

Combining direct-acting antiviral agents (DAAs) in an off-label manner may be an attractive option for patients who are unwilling or unable to undergo PEG-IFN-based therapy. While the sofosbuvir/simeprevir strategy relies on phase 2 data supporting safety and efficacy compared with the FDA-approved regimen, these data were derived from exactly those patients who necessitate more urgent treatment (patients with either cirrhosis and bridging fibrosis). It will be of great interest to assess the willingness of third-party payers to support this regimen, especially in the setting of the most recent American Association for the Study of Liver Diseases-Infections Diseases Society of America HCV guidance document, http://www.hcvguidelines.org/ which supports its use.

The optimal use of these medications in special populations such as patients with decompensated cirrhosis, first-generation protease inhibitor failures, recipients of solid organ transplants, and patients with end-stage kidney disease is not clear, because data are much more limited and may be challenging to obtain. Thus, use of these and other DAAs in these populations will likely be off-label and will require justification based on their risk/benefit comparison.

Resistance issues will be clarified as different drugs and combinations are evaluated. One case of sofosbuvir resistance (S282T) was reported in the LONESTAR trial with sofosbuvir and ledipasvir. Although the resistant variant persisted during the retreatment phase with sofosbuvir/ledipasvir/RBV, the patient nonetheless achieved SVR with longer duration of therapy.[12] The efficacy of simeprevir/PEG-IFN/RBV is significantly diminished in patients with genotype 1a who had a baseline Q80K polymorphism; thus, routine baseline Q80K testing should be performed and alternative treatment offered to those with the polymorphism. For those patients treated in the COSMOS trial with sofosbuvir/simeprevir, the baseline Q80K had an insignificant impact on SVR.[13]

Will Sofosbuvir and/or Simeprevir Replace the Previous Generation of Antiviral Agents?

Although there is no head-to-head trial comparison, it appears that simeprevir is at least as effective as telaprevir and boceprevir. Simeprevir has the advantage of once-daily dosing, more tolerable side effects, shorter treatment duration, less intense monitoring, and no requirement to be administered food or a high-fat meal, and this has led to the American Association of the Study of Liver Diseases advising against the use of the first-generation protease inhibitors. In addition, simeprevir is a weak inhibitor of P-glycoprotein and CYP3A4 in the gut; thus, no dose adjustment is required for cyclosporine or tacrolimus, making it a useful treatment agent in the liver transplant recipient.

Sofosbuvir is a potent NS5B polymerase inhibitor that is effective across all HCV genotypes and in difficult-to-treat populations. It is given once daily and is associated with minimal adverse effects. These drugs have the highest barrier to resistance among the current classes and are effective both with and without PEG-IFN. Sofosbuvir has also been associated with promising treatment outcomes as part of an all-oral regimen with other DAAs (e.g., ledipasvir) now completing phase 3 trials.

Overall, sofosbuvir and simeprevir represent a major advance in HCV treatment and will undoubtedly supplant telaprevir and boceprevir based on their efficacy, safety, tolerability, and convenience. While the earliest such drugs are still approved as add-ons to PEG-IFN-based therapy in genotype 1 HCV, all-oral PEG-IFN-free regimens will become available within the next year and will advance HCV treatment even further. (See Table 3 for a summary of key points.)

Table 3. Key Points

  • Sofosbuvir and simeprevir, each approved as add-on therapy with PEG-IFN/RBV, have surpassed the previous generation of direct antiviral agents (telaprevir, boceprevir) based on their effectiveness, safety, convenience, and resistance profiles.
  • Sofosbuvir is a nucleotide NS5 polymerase inhibitor with pan-genotypic activity and a very high barrier to viral resistance. It has been shown to be effective in treatment-naïve, treatment-experienced, and difficult-to-treat populations such as those with HCV/HIV coinfection, cirrhosis, and patients with mild to moderate impaired renal function and anemia.
  • Sofosbuvir is not recommended in patients with severe renal impairment/ESRD or hemodialysis, because no dosing data are currently available for this patient population.
  • Simeprevir is a second-wave, macrocyclic NS3/4A protease inhibitor and is effective against HCV genotype 1; however, its clinical efficacy is limited by the Q80K polymorphism in genotype 1a patients.
  • Based on phase 2 data, strong rationale exists for the use of sofosbuvir and simeprevir in genotype 1 treatment-naïve or experienced patients with advanced fibrosis who are intolerant of or ineligible for PEG-IFN.
  • Sofosbuvir and simeprevir each have minimal to no interaction with cyclosporine and tacrolimus; thus, a combination of sofosbuvir and simeprevir may be considered in the setting of recurrent allograft HCV.
  • Given the overall effectiveness and safety of the new HCV therapies, treatment should be strongly considered in each patient to mitigate long-term risks such as disease progression, change in health status making future treatment impossible, and risk of HCV transmission.

References

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Gastroenterologists Would Prescribe Sovaldi plus Daclatasvir plus Ribavirin to 60 Percent of Their Genotype-3 Patients, According to Findings from Decision Resources Group

BURLINGTON, Mass., April 1, 2014 /PRNewswire/ -- Decision Resources Group finds that surveyed gastroenterologists in the United States and Europe agree that the percentage of hepatitis C virus (HCV) genotype-3 infected patients with cirrhosis of the liver achieving a sustained virologic response (SVR) is one of the attributes that most influences their prescribing decisions. Clinical data and interviewed experts indicate that interferon-free regimens containing Gilead's Sovaldi (sofosbuvir) and Bristol-Myers Squibb's NS5A inhibitor daclatasvir have convenience and efficacy advantages over currently available regimens for HCV genotype-3 infections. However, competition from other NS5A inhibitors, such as Gilead's GS-5816, may constrain uptake of daclatasvir.

Other key findings from the DecisionBase report entitled Hepatitis C Virus Genotype 3: What Untapped Opportunities Remain for Treatment of Genotype-3 Infections:

  • Payer receptivity to new HCV genotype-3 therapies: Almost half of surveyed U.S. managed care organization pharmacy directors would not reimburse a new HCV genotype-3 therapy offering a 6-week duration if priced at $100,000 per course, with a notable share citing price and insufficient clinical benefit as the reasons. This suggests that, assuming comparable efficacy, payers are unwilling to accept a premium for a shorter course of therapy.
  • The importance of cost in treatment decisions for HCV genotype-3 infections: Conjoint analysis of drug attributes influencing prescribing behavior revealed that surveyed gastroenterologists perceive the cost of treatment as important as SVR rate in treatment decisions for HCV genotype-3 infected patients. This suggests that the cost of sofosbuvir plus ribavirin is a key barrier to prescribing and that physicians and payers will favor a lower-cost alternative with comparable efficacy and safety.
  • Estimated prescribing of the sofosbuvir and daclatasvir combination: Surveyed U.S. gastroenterologists indicated that they would prescribe sofosbuvir and daclatasvir plus ribavirin to 60 percent of their HCV genotype-3 patients.

Comments from Decision Resources Group Analyst Seamus Levine-Wilkinson, Ph.D.:

  • "Gilead's interim phase two data for their pangenotypic interferon- and ribavirin-free combination of Sovaldi and the NS5A inhibitor GS-5816 indicates that up to 100 percent of genotype-3 infected patients achieved SVR4. If these impressive results are confirmed in planned phase three studies, likely including evaluation of a coformulated sofosbuvir and GS-5816 one-pill, once-daily regimen, then this combination will provide a highly effective, safe, pangenotypic, and convenient single-tablet regimen for HCV infections. In other words, this could be one pill to rule them all."
  • "Cost of HCV therapies is a serious concern among both payers and physicians. Given the high price for a 24-week course of Sovaldi, the new standard of care for HCV genotype-3 infections, it is likely that payers and physicians will be very skeptical of any new HCV genotype-3 therapy priced at a premium to Sovaldi. Conversely, a drug developer that is able to offer a lower-cost interferon- and ribavirin-free regimen for HCV genotype-3 that achieves high SVR rates, will be very well positioned to compete in this market segment."

About Decision Resources Group
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