Abbvie at AASLD 2013

Provided by NATAP

AASLD: Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects With Ribavirin Dose Reductions - (11/06/13)

AASLD: High Medication Adherence in HCV-Infected Patients Taking a Triple-DAA Regimen for 12 Weeks - (11/06/13)

AASLD: Low Relapse Rate Leads to High Concordance of SVR4 and SVR12 With SVR24 After Treatment With ABT-450/r, ABT-267, ABT-333 + Ribavirin in Patients With Chronic HCV Genotype 1 Infection in the AVIATOR Study - (11/06/13)

AASLD: Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and Prior Null Responders - (11/04/13)
64rd Annual Meeting of the American Association for the Study of Liver Diseases Washington, DC Nov 1-5 2013

SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY - (04/25/13)

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First FDA Authorization for Next-Generation Sequencer

Perspective

Francis S. Collins, M.D., Ph.D., and Margaret A. Hamburg, M.D.

November 19, 2013DOI: 10.1056/NEJMp1314561

This year marks 60 years since James Watson and Francis Crick described the structure of DNA and 10 years since the complete sequencing of the human genome. Fittingly, today the Food and Drug Administration (FDA) has granted marketing authorization for the first high-throughput (next-generation) genomic sequencer, Illumina's MiSeqDx, which will allow the development and use of innumerable new genome-based tests. When a global team of researchers sequenced that first human genome, it took more than a decade and cost hundreds of millions of dollars. Today, because of federal and private investment, sequencing technologies have advanced dramatically, and a human genome can be sequenced in about 24 hours for what is now less than $5,000 (see graph),  This is a rare example of technology development in which faster, cheaper, and better have coincided: as costs have plummeted and capacity has increased, the accuracy of sequencing has substantially improved. With the FDA's announcement, a platform that took nearly a decade to develop from an initial research project funded by the National Institutes of Health will be brought into use for clinical care. Clinicians can selectively look for an almost unlimited number of genetic changes that may be of medical significance. Access to these data opens the door for the transformation of research, clinical care, and patient engagement.

To see how this technology could be used, consider cancer. Comprehensive analysis of the genome sequence of individual cancers has helped uncover the specific mutations that contribute to the malignant phenotype, identify new targets for therapy, and increase the opportunities for choosing the optimal treatment for each patient. For instance, lung adenocarcinoma can now be divided into subtypes with unique genomic fingerprints associated with different outcomes and different responses to particular therapies. More broadly, recent work from the Cancer Genome Atlas demonstrates that the tissue of origin of a particular cancer may be much less relevant to prognosis and response to therapy than the array of causative mutations.1 As a result, patients diagnosed with a cancer for which there are few therapeutic options may increasingly benefit from drug therapies originally aimed at other cancers that share common driver mutations. The new technology allows us go from our current approach of targeted searches for specific mutations in individual cancers to widespread use of approaches that survey the entire genome.

A major area of opportunity that has yet to be fully exploited is pharmacogenomics — the use of genomic information to identify the right drug at the right dose for each patient. More than 120 FDA-approved drugs have pharmacogenomics information in their labeling, providing important details about differences in response to the drug and, in some cases, recommending genetic testing before prescribing.2

But the full potential of pharmacogenomics is largely unrealized, because of the logistic challenges in obtaining suitable genomic information in a timely enough fashion to guide prescribing. Placing genomic information in the electronic medical record would facilitate this kind of personalized medicine. If the patient's entire genome were part of his or her medical record, then the complexities of acquiring a DNA sample, shipping it, and performing laboratory work would be replaced by a quick electronic query.

Although this scenario holds great promise, the utility of genomic information for drug prescribing must be documented with rigorous evidence. For example, three recently published clinical trials raise questions about the clinical utility of using pharmacogenetic information in the initial dosing of vitamin K anatagonists.3

The FDA based its decision to grant marketing authorization for the Illumina instrument platform and reagents on their demonstrated accuracy across numerous genomic segments, spanning 19 human chromosomes. Precision and reproducibility across instruments, users, days, and reagent lots were also demonstrated.

The marketing authorization of a sequencing platform for clinical use will probably expand the incorporation of genetic information into health care. But even the most promising technologies cannot fully realize their potential if the relevant policy, legal, and regulatory issues are not adequately addressed. Already, key policy advances have helped smooth the way and address many of the public's concerns about the potential misuse of genetic information.4 For example, the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and the Genetic Information Nondiscrimination Act (GINA) prohibit health insurers from considering genetic information as a preexisting condition, as material to underwriting, or as the basis for denying coverage. GINA also protects against use of genetic information by employers. These protections do not, however, extend to the disease manifestations of genetic risks. Although genomic information showing a predisposition to cancer would be protected under GINA, other clinical signs or symptoms indicative of cancer are not protected. Provisions of the Affordable Care Act set to go into effect in 2014 go a step further and will preclude consideration of all preexisting conditions, whether genomic or not, in establishing insurance premiums. Current federal laws, however, do not restrict the use of genomic information in life insurance, long-term care insurance, or disability insurance.

The legal landscape for the use of genomics in personalized medicine grew brighter in June of this year when the Supreme Court ruled (in Association for Molecular Pathology v. Myriad Genetics) that isolated naturally occurring DNA cannot be patented. This decision was a breakthrough for access to individual genetic tests but also, even more important, for the integration of genome sequencing into clinical care. Before the Myriad decision, there were substantial concerns that in order to offer whole genome sequencing, clinical laboratories would have to pay royalties to a long list of gene patent holders. The decision has opened the creative doors to an as yet unimaginable set of products that may benefit the public health.

The FDA has also been active in addressing other regulatory issues surrounding personalized medicine.5 Along with authorizing the Illumina technology for marketing, the FDA recognized the need for reference materials and methods that would permit performance assessment. As a result, the FDA collaborated with the National Institute for Standards and Technology (NIST) to develop reference materials consisting of whole human genome DNA, together with the best possible sequence interpretation of such genomes. The first human genome reference materials are expected to be available for public use in the next 12 months.

This marketing authorization of a non–disease-specific platform will allow any lab to test any sequence for any purpose. Thus, putting in place an appropriate risk-based regulatory framework is now critical to ensure the validation and quality of tests (called laboratory-developed tests, or LDTs) developed in-house by clinical laboratories.

The marketing authorization for the first next-generation genome sequencer represents a significant step forward in the ability to generate genomic information that will ultimately improve patient care. Yet it is only one step. There are many challenges ahead before personalized medicine can be considered truly embedded in health care. We need to continue to uncover variants within the genome that can be used to predict disease onset, affect progression, and modulate drug response. New genomic findings need to be validated before they can be integrated into medical decision making. Doctors and other health care professionals will need support in interpreting genomic data and their meaning for individual patients. Patients will want to be able to talk about their genetic information with their doctor. With the right information and support, patients will be able to participate alongside their doctors in making more informed decisions. Reimbursement issues need to be resolved to assure that patients have access to the best tests and that manufacturers have incentives to develop them.

The arrival of next-generation sequencing at this regulatory landmark is only the beginning. We need to work together to ensure that research progresses, that regulatory policies are developed, that patients' rights and needs are addressed, and that clinical use of genomic information is based on rigorous evidence.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on November 19, 2013, at NEJM.org.

SOURCE INFORMATION

From the Office of the Director, National Institutes of Health, Bethesda, MD (F.S.C.); and the Office of the Commissioner, Food and Drug Administration, Department of Health and Human Services, Silver Spring, MD (M.A.H.).

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Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

Journal of Hepatology

Volume 59, Issue 6, Pages 1323-1330, December 2013

Manuel Romero-Gómez, Marina Berenguer, Esther Molina, José Luis Calleja

Received 6 May 2013; received in revised form 20 June 2013; accepted 8 July 2013. published online 17 July 2013.

Summary
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Abbreviations: BMI, body mass index, ITPA, inosine triphosphate pyrophosphatase, HCV, hepatitis C virus, GWAS, genome-wide association study, SNP, single nucleotide polymorphisms, sRfT, transferrin soluble receptor, EPO, erythropoietin

Keywords:Hepatitis C virus, Anemia, Boceprevir, Telaprevir, Pegylated interferon, Ribavirin, Epoietin, Protease inhibitor

Introduction

Anemia is a major complication of antiviral therapy in chronic hepatitis C. With dual therapy, and despite its negative impact on quality of life, it was a desirable effect due to its association with higher sustained viral response rates. In patients treated with triple therapy, the impact of anemia on outcome is controversial; its incidence though is significantly higher and the management in this scenario is more complex, frequently requiring ribavirin dose reduction, epoetin and, in some cases, blood transfusions, jeopardizing the final efficacy of triple therapy.

In this review, we will try to answer the questions that physicians face regarding the management of anemia among patients treated with telaprevir or boceprevir triple therapy. We highlight the most relevant aspects with regards to the incidence of anemia, its clinical course, factors implicated in its development, characterization, and management.

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Mathematical modeling: A tool for selecting agents with complementary modes of action?

Journal of Hepatology

Volume 59, Issue 6 , Pages 1346-1348, December 2013

Sylvie Deuffic-Burban, Yazdan Yazdanpanah

Received 24 June 2013; received in revised form 14 July 2013; accepted 15 July 2013. published online 29 July 2013.

Keywords: Direct-acting antiviral agents, Mathematical modeling, Viral dynamics

COMMENTARY ON:

Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, Layden TJ, Uprichard SL, Perelson AS. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3991–6. Copyright © 2013. Abstract reprinted with permission from the National Academy of Sciences.

http://www.ncbi.nlm.nih.gov/pubmed/23431163

Abstract. The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir’s mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6–9h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.

Chronic hepatitis affects nearly 3% of the world population [1]. The landscape of therapy for hepatitis C virus (HCV) infection, where treatment was still suboptimal until recently, is changing rapidly. Specific proteins involved in the replication of the virus have been identified and targeted by drug development. Among these, we can enumerate non-structural (NS) viral proteins with known enzymatic functions, such as the NS3/4A protease [2], [3], and the NS5B polymerase [4], [5] but also non-enzymatic targets such as NS5A proteins [6]. The mode of action of HCV drugs targeting these proteins is not always understood. For example, the mode of action of Daclatasvir (BMS-790052), one of the most promising and expected molecules identified as a potent NS5A inhibitor, is not known [6], [7]. This is related to the uncertain nature of the molecular mechanisms by which NS5A functions and the absence of direct screening assays for NS5A function.

One means of uncovering an antiviral agent’s mode of action is to analyze the kinetics of the response it generates using mathematical modeling. This approach was initiated by Perelson et al. in HIV by characterizing the decline in HIV during antiretroviral therapy [8], [9] and it was then successfully applied to understand HCV kinetics during therapy [10]. In these models, the infected cell is treated as a “black box” that produces/secretes virus particles, which then either are cleared or infect new target cells, and the effect of treatment is to block virus production from infected cells [10]. Clearly, one limitation of these models is that it does not take into account the stages of the (intracellular) viral lifecycle that are yet the main target of DAAs. In a recent study published in PNAS, Guedj et al. introduced a novel generation of models, called “multiscale models” that, in contrast to the standard model, takes into account the dynamics of the intracellular viral RNA and identifies some essential stages of viral replication that can be affected by treatment, namely virion assembly/secretion, viral RNA production, and vRNA degradation (Fig. 1) [11].

Fig. 1. Presentation of the standard and multi-scale model of HCV dynamics, and parameter estimates obtained to fit data from patients treated with daclatasvir[11]. In both models, T and I represent target and infected cells, respectively, and V represents virus. Target cells are created and die with constant rates, s and d, respectively, and are infected by virus, V, with constant rate β. Infected cells, I, are lost with constant rate δ, and virus, V, is cleared from serum with constant rate c. (A) The standard model considers only the level of cell infection and virus in the serum. Treatment (parameters in red) acts by reducing the average number of virions produced by infected cells from p to (1−ε)p. Thus, ε represents a global measure of antiviral effectiveness that does not distinguish the stages of intracellular viral replication that are blocked by treatment. The main estimates are c=23.3d⁻¹, ε=0.997, δ=1.06d⁻¹. (B) The multi-scale model was designed to account for essential features of intracellular HCV RNA replication, R, i.e., production, degradation, and assembly/secretion with rates α, μ, and ρ, respectively. The HCV RNA level within an infected cell (dashed circle) is assumed to increase with time since infection and reach a steady state. Treatment (parameters in red) may block HCV RNA production with effectiveness ε_α and/or virion assembly/secretion with effectiveness ε_s, and/or enhance the degration rate of HCV RNA by a factor κ. The main estimates after fixing δ=0.14d⁻¹, μ=1d⁻¹, α=40d⁻¹ are c=22.3d⁻¹, ε_α=0.99, ε_s=0.998, ρ=8.18d⁻¹, κμ=1.46d⁻¹. Figure reprinted from [11], Copyright © 2013, National Academy of Science.

This model was applied to the comparison of the viral kinetics observed after initiation of three different classes of agents, namely IFN, telaprevir (a protease inhibitor) and daclatasvir (a NS5A inhibitor) and allowed to puzzle out the mode of action of these drugs. The authors showed that the kinetics observed were dependent on the stages of the viral lifecycle where these drugs acted. While all three agents were found to have a high effectiveness in blocking vRNA production, the reason why HCV RNA declines so rapidly with daclatasvir was due to the fact that daclatasvir, unlike IFN and telaprevir to a lower extent, was extremely effective in blocking viral assembly/secretion, with an effectiveness estimated to 99.8% (vs. 39.0% in IFN-treated patients, p<10⁻¹⁰; and 0.94 in telaprevir-treated patients, p<10⁻⁶). As a consequence, the number of viruses newly secreted after initiation of daclatasvir is minimal and thus the viral decline observed in serum provides a good model to estimate HCV half-life in serum. Using this approach, Guedj et al. could demonstrate that the current estimate of 2.7h derived from the analysis of viral kinetics during IFN-based treatment were not accurate and now estimate the mean serum half-life of HCV at 45min. Of note, if HCV half-life is about four times shorter than previously thought, it implies that, in order to maintain a given level of virus, HCV production is also four times larger than initially thought. Thus the risk of generating mutations conferring drug resistance is also larger than previously thought.

The dual mechanism of action of daclatasvir provides a basis to explain why NS5A inhibitors may be good candidates for combination with drugs with complementary mode of actions, such as protease or polymerase inhibitors. Yet, these modeling efforts were based on the analysis of viral kinetics after one single dose of daclatasvir, and important questions on the implications of this dual mode of action remain to be solved. In particular, it is still unclear whether that plays any role in improving the genetic barrier to resistance and how this rapid initial viral decline translates into the long-term viral decline. Clearly, further studies with repeated doses of daclatasvir will be needed to study whether blocking assembly/secretion accelerates only the initial viral decline or also contributes to a faster elimination of the virus in the long run that may allow for shorter treatment duration.

The speed of development of drugs to treat HCV infection is unprecedented and new drugs with high potency, low side effects and requiring short treatment duration are emerging. In this context, mathematical modeling as the one performed by Guedj et al. is a promising tool to better understand the mechanism of action of new DAAs, such as NS5A and NS5B inhibitors, or a new generation of antiprotease inhibitors [12], rationalizing the combination of these agents and eventually selecting agents with complementary modes of action.

Conflict of interest 

Yazdan Yazdanpanah received travel grants, honoraria for presentations at workshops and consultancy honoraria from Abbott, Bristol-Myers Squibb, Gilead, Merck, Roche, Tibotec and ViiV Healthcare.

Sylvie Deuffic-Burban received grants from Roche, Janssen Pharmaceuticals, and Merck, and consultancy honoraria from Merck, GlaxoSmithKline, and AbbVie.

References

1. World Health Organization. Hepatitis C. Fact sheet N°164. July 2012. [cited May 8, 2013]; Available from:http://www.who.int/mediacentre/factsheets/fs164/en/. View In Article

2. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416 View In Article CrossRef

3. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206 View In Article CrossRef

4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878–1887 View In Article CrossRef

5. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867–1877 View In Article CrossRef

6. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100 View In Article CrossRef

7. Suk-Fong Lok A. HCV NS5A inhibitors in development. Clin Liver Dis. 2013;17:111–121 View In Article Abstract Full Text Full-Text PDF (208 KB) CrossRef

8. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996;271:1582–1586 View In Article MEDLINE

9. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997;387:188–191 View In Article MEDLINE CrossRef

10. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103–107 View In Article MEDLINE CrossRef

G11. uedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A. 2013;110:3991–3996 View In Article CrossRef

12. Rong L, Guedj J, Dahari H, Coffield DJ, Levi M, Smith P, et al. Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model. PLoS Comput Biol. 2013;9:e1002959 View In Article CrossRef

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Sofosbuvir-based interferon-free therapy for patients with HCV infection

Journal of Hepatology
Volume 59, Issue 6 , Pages 1342-1345, December 2013

Tarik Asselah

Received 23 May 2013; received in revised form 8 July 2013; accepted 10 July 2013. published online 26 July 2013.

Abbreviations: DAA, direct-acting antivirals, IFN, interferon, PegIFN, pegylated interferon, RBV, ribavirin, SVR, sustained virological response, eRVR, extended rapid virological response, RVR, rapid virologic response

Keywords: Direct-acting antivirals, Sustained virological response, Chronic hepatitis C, NS5A inhibitors, Gilead, Safety, Resistance

COMMENTARY ON:

Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953. Copyright © 2013. Abstract reprinted with permission from Massachusetts Medical Society.

http://www.ncbi.nlm.nih.gov/pubmed/23281974

Abstract: Background: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection.

Methods: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400mg once daily) plus ribavirin for 12weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24weeks after therapy.

Results: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12weeks and interferon for 4, 8, or 12weeks had a sustained virologic response at 24weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8weeks had a sustained virologic response at 24weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.

Conclusions: Sofosbuvir plus ribavirin for 12weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350).

For the treatment of HCV infection, several direct-acting antivirals (DAAs), including NS3 protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors, are under development [1]. Among them, sofosbuvir is a potent HCV-specific nucleotide analog (chain terminator). It is given orally, once daily, without food effect. So far, no safety signal in preclinical/clinical studies has been observed with this compound. Sofosbuvir has a high barrier to resistance with no virologic breakthrough to date. It has a pangenotypic antiviral effect, although it might be less efficient in genotype 3 (G3).

The ELECTRON study goal was to evaluate the safety and efficacy of sofosbuvir as a backbone of combination antiviral therapy in patients with chronic HCV genotype 1, 2, and 3 infections, including both treatment-naïve and treatment-experienced patients [2]. The design of the trial and the results are provided in Fig. 1. Sofosbuvir combined with ribavirin (RBV) for 12weeks was associated with sustained virological response (SVR) in 100% of G2/G3 HCV infected patients. For G1 HCV infected patients, 12-week sofosbuvir plus RBV provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders. For G2/3, when sofosbuvir was given alone, SVR rate was 60%.

Fig. 1. Electron trial design and results [2]. ELECTRON is an open-label study with eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400mg once daily) plus ribavirin for 12weeks. Three of these groups also received PegIFNα-2a for 4, 8, or 12weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12weeks or sofosbuvir plus PegIFNα-2a and ribavirin for 8weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. The rate of sustained virologic response 24weeks after therapy is reported.

The authors concluded that sofosbuvir plus RBV may be an effective treatment in all previously untreated patients with G2 or G3 HCV infections and also in the majority of G1 HCV naïve infected patients.

What have we learned and what are the questions raised?

First, can we predict relapse with early viral kinetics with sofosbuvir based regimen? No, unfortunately. Previous studies with pegylated-interferon (PegIFN) based therapy demonstrated that early kinetics may help predict SVR [3]. However, in this sofosbuvir plus RBV trial, HCV RNA levels in all patients declined rapidly after the initiation of treatment (Fig. 2). By week-2 of treatment, the majority of patients from all groups had an undetectable level of HCV-RNA. By week-4 of treatment, all 95 patients in the study had an undetectable level of HCV RNA, which was maintained until the end of treatment.

Fig. 2. Mean change from baseline in hepatitis C virus (HCV) RNA level during treatment. All patients with HCV genotype 2 or 3 infection completed the 12weeks of treatment. All patients had an HCV RNA level below the limit of detection (i.e., <15IU/ml) from week 4 until the end of treatment. Reprinted from [2].

Second, is RBV useful? Yes. Results from the 10 patients with G2 or G3 HCV infection who received sofosbuvir alone strongly suggest a role for RBV in the maintenance of an antiviral response. The exact mechanism by which RBV acts remains unknown.

Third, can we extrapolate these data to phase 3 data or real-world practice?

No, we still have to be cautious for several reasons: the number of patients is limited; they are selected as they have no cirrhosis, no comorbidities. We have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response.

For G1, since sofosbuvir and ribavirin are not a reasonable option, two strategies have been developed: (1) 12-week sofosbuvir, PegIFN/RBV and (2) new IFN-free regimens with sofosbuvir and ledipasvir (NS5A inhibitor).

Interestingly, several phase 3 studies with sofosbuvir based regimen have been published since then.

The NEUTRINO trial was a single-group, open-label study of sofosbuvir plus PegIFN/RBV in 327 patients infected with HCV genotype 1, 4, 5, or 6 [4]. All patients received sofosbuvir, PegIFNα-2a for 12weeks. Most of the patients who were included in the study had HCV G1 (89%); 9% had G4, and 2% had G5 or 6. Sofosbuvir was given orally at a dose of 400mg, once a day, along with RBV, also given orally in a dose based on body weight. Patients who weighed less than 75kg received 1000mg/d, and heavier patients received 1200mg/d. Patients received PegIFNα-2a subcutaneously once a week at a dose of 180μg.

A total of 295 of the 327 patients (90%) reached SVR after 12weeks of treatment. According to the HCV genotype: 89% of patients with G1 (92% for G1a and 82% for G1b) and 96% (27/28) of those with G4 had SVR. The single patient with G5 and all six patients with G6 in this trial had an SVR.

The FISSION trial was a randomized, open-label, active-control study of sofosbuvir plus RBV in patients with G2 or G3 HCV infection; patients with the two genotypes were enrolled in an approximately 1:3 ratio, respectively [4]. Patients were randomly assigned to a 1:1 ratio to receive either 12weeks of sofosbuvir plus RBV or 24weeks of PegIFN/RBV. The doses of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose of RBV for patients in the PegIFN/RBV group was 800mg daily. Sofosbuvir–RBV was shown to be non-inferior to PegIFN/RBV. At 12weeks, the rates of SVR for patients receiving 12weeks of sofosbuvir–RBV and those receiving 24weeks of PegIFN/RBV were each 67%. An SVR occurred in 97% of patients with G2 and in 56% of those with G3 in the group receiving sofosbuvir–RBV, as compared with response rates of 78% and 63%, respectively, in the group receiving PegIFN/RBV. Among patients with cirrhosis at baseline, 47% of those receiving sofosbuvir–RBV had an SVR, as compared with 38% of those receiving PegIFN/RBV.

The POSITRON trial was a double blinded, placebo-controlled study that compared 12weeks of treatment with sofosbuvir and RBV with matching placebo in patients who had previously discontinued IFN-therapy owing to unacceptable adverse events, who had a concurrent medical condition precluding therapy with an IFN-containing regimen, or who had decided against treatment with an IFN-containing regimen [5]. The most common reasons that IFN treatment was not an option were clinically significant psychiatric disorders (in 57% of patients) and autoimmune disorders (in 19%).

The rate of SVR at 12weeks after treatment was 78% among patients receiving sofosbuvir-RBV, as compared with 0% among those receiving placebo (p<0.001). Among patients who received sofosbuvir-RBV, 93% of patients with G2 HCV infection had an SVR, as compared with 61% of those with G3 HCV infection. Likewise, 81% of patients without cirrhosis (92% of patients with G2 HCV infection and 68% of those with G3 HCV infection) had an SVR, as compared with 61% of patients with cirrhosis (94% of patients with G2 HCV infection and 21% of those with G3 HCV infection).

The FUSION study was a blinded, active-control study involving patients who had not had a response to prior treatment with an IFN-containing regimen [5]. Approximately 75% of the previously treated patients enrolled had either virologic breakthrough during the prior treatment or virologic relapse afterward; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the 12-week group and 73% in the 16-week group (p<0.001 for each comparison). Rates of SVR between the groups showed that patients receiving 16weeks of treatment had a significantly higher rate of SVR than patients receiving 12weeks of treatment (p<0.001). The rates of SVR among patients with G2 HCV infection who received 12weeks of treatment and those who received 16weeks of treatment were 86% and 94%, respectively, as compared with 30% and 62% for 12 and 16weeks of treatment, respectively, among patients with G3 HCV infection.

Cirrhosis was associated with a decreased rate of SVR, particularly among patients with G3 HCV infection who received 12weeks of treatment. Among patients with cirrhosis who received 12weeks of treatment, the rate of SVR was 31% (60% with G2 HCV infection and 19% with G3 HCV infection), as compared with 61% among patients without cirrhosis (96% with G2 HCV infection and 37% with G3 HCV infection). Among patients with cirrhosis who received 16weeks of treatment, the rate of SVR was 66% (78% with G2 HCV infection and 61% with G3 HCV infection) as compared with 76% among patients without cirrhosis (100% with G2 HCV infection and 63% with G3 HCV infection).

So can we summarize these data? Yes, we can (Table 1). What are the key messages?

P/R, PegIFN/RBV; sof, sofosbuvir.

First, for G1 HCV naïve patients, sofosbuvir with PegIFN-RBV triple therapy appears a reasonable option. Of course, we will need to increase the number of patients with cirrhosis; and also data from genotype 1 experienced patients. There are ongoing phase 3 studies to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination with or without RBV for 8 or 12weeks in treatment-naive G1 HCV chronic infection. Ledipasvir is an NS5A replication complex inhibitor ledipasvir (previously GS-5885).

Second, for G4 naïve patients, the data are excellent but limited (n=28 patients) and we need larger studies for this specific G4 HCV population. There is a major medical need since standard of care remains PegIFN-RBV for 48weeks with low SVR in “difficult-to-cure” patient populations (IFNL3 non CC; patients with cirrhosis, experienced patients, etc.) [6]. We urge for studies in G4 HCV, naïve but also experienced patients.

Third, for G2 HCV naïve patients, sofosbuvir-RBV provides excellent results. We have to recall obvious evidence: G2 HCV is not G3, and we need separate studies. In past PegIFN/RBV dual therapy, for statistical issues, HCV G1 and G4, and HCV G2 and G3, were respectively pooled [6]. For DAAs, we need an individual study for each genotype. For G2 HCV treatment experienced and cirrhosis, we need more data.

Four, data were disappointing regarding G3 HCV naïve patients, in particular those with cirrhosis. The question is how to treat HCV G3 infected patients in the near future. There will be several options:

(1)PegIFN plus RBV, with satisfactory results, but with IFN side effects.

(2)Sofasbuvir plus RBV for 16weeks: (better tolerated, possible in case of IFN contra-indication, but not better than PegIFN plus RBV, and even worse in cirrhotics).

(3)Sofosbuvir plus RBV for 24weeks; however, SVR results will be given by the ongoing VALENCE study.

(4)Triple therapy (Sofosbuvir plus PegIFN-RBV) with a short duration of 12weeks, using the neutrino regimen, but without data with G3!

Moreover, it is believed that clinical trials provide best evidence when they are randomized to controlled arms with large number of patients [7]. Several of the trials discussed here lack controlled arms or large number of patients. It may be argued that controlled arms are not necessary when they expose patients to side effects. Furthermore, we need data for «difficult-to-cure» patients, those with cirrhosis, previous non response, comorbidities, etc.

Impressive data have been reported with sofosbuvir based therapy, with high SVR rates and a favorable safety profile so far. A pilot study demonstrated that addition of ledipasvir increased efficacy of sofosbuvir plus RBV, without additional safety issues, and without virologic failures. Gilead recently initiated the first Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and lepidasvir in treatment-naïve G1 HCV infected patients. This four-arm study is evaluating the fixed-dose combination with and without RBV for 12-and 24-week durations in 800 patients, 20 percent of whom have evidence of cirrhosis.

Finally, there is a realistic hope for patients with HCV infection, since several IFN-free trials are ongoing with promising early data [8], [9], [10], [11]. We do hope that the majority of patients with HCV infection will become «easy-to-cure», and there will be increase in access to treatment.

Conflict of interest

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen, Gilead, Roche and MSD.

References

1. Asselah T, Marcellin P. Interferon-free therapy with direct acting antivirals for HCV. Liver Int. 2013;33(Suppl. 1):93–104 View In Article

2. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34–44  View In Article CrossRef

3. Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol. 2012;57:1110–1125 View In Article Abstract Full Text Full-Text PDF (1930 KB)  CrossRef

4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–1887 View In Article CrossRef

5. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment option. N Engl J Med. 2013;368(20):1867–1877 View In Article CrossRef

6. Asselah T, De Muynck S, Broet P, Masliah-Planchon J, Blanluet M, Bieche I, et al. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol. 2011;56:527–532 View In Article Abstract Full Text Full-Text PDF (698 KB)  CrossRef

7. Sacks H, Chalmers TC, Smith H. Randomized vs. historical controls for clinical trials. Am J Med. 1982;72:233–240 View In Article Abstract Full-Text PDF (945 KB)  CrossRef

8. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45–53 View In Article CrossRef

9. Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson D, Zeuzem S, et al. Safety and efficacy of interferon-free regimens of ABT-450/R, ABT-267, ABT-333 ± ribavirin in patients with chronic HCV GT1 infection: results from the Aviator study. J Hepatol.2013;58(Suppl. 1):A3 View In Article

10. Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, et al. Efficacy of the protease inhibitor BI201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047–2055 View In Article Abstract Full Text Full-Text PDF (914 KB)  CrossRef

11. Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Mullhaupt B, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369(7):630–639 View In Article CrossRef

PII: S0168-8278(13)00534-5
doi:10.1016/j.jhep.2013.07.023
© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

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Ending the Silent Epidemic of Viral Hepatitis in the U.S. - Ronald Valdiserri MD HHS

Provided by NATAP

Reported by Jules Levin
AASLD Nov 1-4 2013 Wash DC

Ronald O. Valdiserri, M.D., M.P.H.
Deputy Assistant Secretary for Health, Infectious Diseases Director, Office of HIV/AIDS & Infectious Disease Policy American Association for the Study of Liver Diseases November 5, 2013

"The CHeCS investigators examined 1.2 million people who used the four integrated medical care systems during 2006 through 2008, and 57% of the number estimated to have HCV infection had actually been tested and identified as infected. In the broader population from which the 30,140 NHANES participants were drawn, 50% of persons who had tested positive for antibodies to HCV and provided information during in-depth telephone interviews were aware of their HCV-infection status before being notified of that infection by the NHANES.3 The CHeCS researchers are currently examining reasons why the people who were found to be infected in their study had or had not been tested previously. In the population on which the CHeCS draws, less than half of people who had had two or more abnormal alanine aminotransferase results were subsequently tested for HCV infection.2......(38%) had no follow-up HCV RNA testing documented in the electronic database1......From these data it seems reasonable to deduce that 63 to 77% of people who have tested positive for HCV antibodies - 32 to 38% of all HCV-infected people in the United States - received follow-up hepatitis care......Among those receiving care, such as the 8810 who were initially examined in the CHeCS, 5540 (63%) had had at least one HCV RNA measurement between 2001 and 2010.....Of the HCV-infected people in the CHeCS - people who are more likely than average to be receiving specialist care for HCV - 3380 (38%) had undergone a liver biopsy between 2001 and 2010.1 In the NHANES, of 66 persons who said they received care for their HCV infection, 31 (47%) said they had undergone a biopsy. These proportions translate to about 12 to 18% of the total HCV-infected population......In the CHeCS, 36% of people who knew they were infected - about 18% of the estimated total infected population who had been identified as infected - had evidence in their electronic or hard-copy chart of any treatment for HCV.1 In the NHANES, 22 of the 170 HCV-infected persons who answered follow-up surveys (13%) said they had received treatment for HCV infection.3.....It is more difficult to determine whether treatment has been successful, but in the CHeCS the most recent test results indicated that HCV RNA was "undetectable" in 21% of patients, and 80% of patients with such results had documentation of having received antiviral therapy1 - that is, about 17% of the total CHeCS cohort, or about 5 to 6% of all HCV-infected people......resulting estimates may actually be high.....there is also a need to do a better job of getting HCV-infected persons who know their HCV status into care, evaluated, and, as appropriate, treated. It is past time to address more vigorously what Assistant Secretary for Health Howard Koh has called the silent epidemic of viral hepatitis."

Hepatitis C in the United States Perspective (screening/care) - Natap www.natap.org/2013/HCV/051613_02.htm

Continue here to view full slide presentation …..

Low Vitamin D Predicts Death in HIV-Positive

Medscape Medical News > Conference News

Daniel M. Keller, PhD
November 19, 2013

BRUSSELS — Among patients infected with HIV, current levels of 25-hydroxyvitamin D are associated with the risk for death but not for other adverse events, a new study suggests.

"Earlier levels of 25-hydroxyvitamin D failed to predict death, suggesting the association diminishes with time," Jean-Paul Viard, MD, from the Hôtel-Dieu, Université Paris Descartes in France reported here at the 14th European AIDS Conference.

The study included patients from a previous study of the EuroSIDA cohort, in which severe vitamin D deficiency at baseline was associated with the risk for progression to death in a 5-year follow-up period.

The aim of the current study was to further assess the short- and long-term prognostic value of vitamin D deficiency for AIDS-defining and non-AIDS-defining events and death and to study the association of vitamin D deficiency with inflammatory markers.

The work used a 1:1 case-control design nested within the EuroSIDA cohort for each of the outcomes of AIDS events (n = 50 pairs), non-AIDS events (n = 63 pairs), and death (n = 42 pairs). Control individuals were matched with cases on the basis of age, sex, region of residence, CD4 count, and HIV RNA level at baseline and on the dates of the final samples.

Vitamin D was lower in cases of death than in controls, but only for the latest sample.Dr. Jean-Paul Viard

Measurements of vitamin D and inflammatory markers were done on stored plasma from the time of study entry, at the time of an event, and at a midpoint of follow-up, if available. The time from the first to last samples averaged 44.6 months (interquartile range, 22.7 - 72.3 months).

Of 50 deaths, 88% were from chronic conditions and 12% were sudden events such as heart attack, stroke, suicide, lung embolism, gastric hemorrhage, or violent death.

Although the odds of death were not associated with the baseline vitamin D level, they "decreased significantly by 46% for a 2-fold higher level of 25-hydroxyvitamin D," Dr. Viard reported. There was no association of the baseline, latest measurement, or annual percentage change in the level of vitamin D on AIDS-related or non-AIDS-related events.

"Vitamin D was lower in cases of death than in controls, but only for the latest sample, while interleukin-6 [IL-6] was higher in cases than in controls for all items," Dr. Viard said.

"Similarly, CRP [C-reactive protein] was higher in cases than in controls at the latest sample for AIDS-events and death, and it was also higher at baseline for people who were going to die. CD14 levels were higher in cases and in controls for AIDS events and death."

The percent change in the level of inflammatory biomarkers and the CD4 cell count reflected the vitamin D status. If patients were severely vitamin D deficient (<10 ng/mL), high-sensitivity IL-6, and high-sensitivity CRP increased by 4.66% per year and by 8.35% per year after adjustment for several variables, including season, sex, age, and region of residency. There was no change in these markers if patients had normal or moderately deficient vitamin D levels.

Soluble CD14 increased regardless of vitamin D status. CD4 counts increased by 7.00% per year for people deficient in vitamin D and by 11.14% per year for people nondeficient in vitamin D (both P < .01), but not at all for patients who were severely deficient.

Asked for perspective on these findings, session cochair Andrea Antinori, MD, from the National Institute for Infectious Disease in Rome, Italy, who was not involved with the study, told Medscape Medical Newsthat he found the results interesting because "probably we don't have much information about the role of vitamin D, and more interestingly, not only its role in bone mineral density and fracture in the long term but even in immune activation inflammatory pathways" that can increase other risks, for example, for cardiovascular disease.

His recommendation is "monitoring vitamin D in all types of patients before treatment in the first phase of induction by drugs for long-term treatment," with eventual supplementation for patients found to be vitamin D deficient.

This study was supported by grants from the European Commission and the Swiss National Science Foundation and unrestricted grants from BMS, Janssen R&D, Merck, Pfizer, and GSK. Dr. Viard reports no relevant financial relationships. Dr. Antinori reports financial ties to BMS, Gilead, ViiV; Abbvie, BMS, Gilead, and Janssen-Cilag.

14th European AIDS Conference: Abstract BPD1/2. Presented October 17, 2013.

Source

Prevention of hepatitis B virus infection and liver cancer

Recent Results Cancer Res. 2014;193:75-95. doi: 10.1007/978-3-642-38965-8_5.

Chang MH.

Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan, changmh@ntu.edu.tw.

Abstract

Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world, particularly in areas prevalent for HBV infection such as Asia, Africa, southern part of Eastern and Central Europe, and the Middle East. Risk factors of HBV-related HCC include (1) viral factors-persistent high viral replication, HBV genotype C or D, pre-S2 or core promoter mutants; (2) host factors-older age (>40 years old) at HBeAg seroconversion, male gender; (3) mother-to-infant transmission; and (4) other carcinogenic factors-smoking, habitual use of alcohol, etc. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective. Its cancer preventive efficacy supports it as the first successful example of cancer preventive vaccine in human. This experience can be extended to the development of other cancer preventive vaccine. Careful basic and clinical research is needed to develop ideal vaccines to induce adequate protection. Understanding the main transmission route and age at primary infection may help to set the optimal target age to start a new cancer preventive vaccination program. Besides timely HBV vaccination, the earlier administration of hepatitis B immunoglobulin immediately after birth, and even antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are possible strategies to enhance the prevention efficacy of HBV infection and its related liver cancer.

PMID: 24008294 [PubMed - in process]

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The oncogenic role of hepatitis C virus

Recent Results Cancer Res. 2014;193:97-111. doi: 10.1007/978-3-642-38965-8_6.

Koike K.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, kkoike-tky@umin.ac.jp.

Abstract

Persistent infection with hepatitis C virus (HCV) is a major risk toward development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV whether the virus plays a direct or an indirect role. The observation that chronic hepatitis C patients with sustained high levels of serum alanine aminotransferase are prone to develop HCC suggests the significance of inflammation in hepatocarcinogenesis in hepatitis C. However, the rare development of HCC in patients with autoimmune hepatitis, which is accompanied by robust inflammation, even after the progress into cirrhosis, implies a possibility of the direct role of HCV in HCC development. What is the role of HCV, a simple plus-stranded RNA virus, whose genome is never integrated into the host genome, in hepatocarcinogenesis? The studies using transgenic mouse and cultured cell models, in which the HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activities. In particular, the core protein of HCV induces overproduction of oxidative stress by impairing the mitochondrial electron transfer system, through insulting the function of molecular chaperon, prohibitin. HCV also modulates the intracellular signaling pathways including mitogen-activated protein kinase, leading to the acquisition of growth advantage by hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolisms, thereby accelerating the progression of liver fibrosis and HCC development. These results would provide a clue for further understanding of the role of HCV in pathogenesis of persistent HCV infection including hepatocarcinogenesis.

PMID: 24008295 [PubMed - in process]

Source

HCV Infection Ups Risk Of Chronic Kidney Disease In People With HIV

Provided by The International AIDS Society

Author: Mark Mascolini

18 November 2013

Both viremic and aviremic HCV infection independently raised the risk of moderate, advanced, and progressive chronic kidney disease (CKD) in a large study of North Americans with HIV infection.

Because the impact of HCV infection on CKD in people with HIV is poorly understood, NA-ACCORD investigators conducted this study of three HIV-positive groups: 52,602 HCV-seronegative people, 9508 HCV-viremic people (HCV seropositive with detectable HCV RNA), and 913 HCV-aviremic people (HCV seropositive but undetectable HCV RNA).

The researchers defined stage 3 CKD as two or more glomerular filtration rates (GFRs) below 60 mL/min separated by at least 90 days; they defined stage 5 CKD as two or more GFRs below 15 mL/min separated by at least 90 days; and they defined progressive CKD as a sustained 25% GFR decrease from baseline to below 60 mL/min.

Median ages of the HCV-negative, HCV-viremic, and HCV-aviremic groups were 41, 47, and 44. Proportions of blacks were 38%, 58%, and 37%. Proportions taking antiretroviral therapy were 43%, 45%, and 42%. Median GFR in the three groups measured 102, 103, and 100 mL/min.

Compared with HCV-seronegative people, HCV-viremic people and HCV-aviremic people ran higher risks of stage 3 CKD, stage 5 CKD, and progressive CKD at the following adjusted hazard ratios (aHR) (and 95% confidence intervals):

HCV-viremic people:
• Risk of stage 3 CKD: aHR 1.36 (95% CI 1.26 to 1.46)
• Risk of stage 5 CKD: aHR 1.95 (95% CI 1.64 to 2.31)
• Risk of progressive CKD: aHR 1.31 (95% CI 1.19 to 1.44)

HCV-aviremic people:
• Risk of stage 3 CKD: aHR 1.19 (95% CI 0.98 to 1.45, not significant)
• Risk of stage 5 CKD: aHR 1.69 (95% CI 1.07, 2.65)
• Risk of progressive CKD: aHR 1.31 (95% CI 1.02 to 1.68)

The study found no statistically significant differences in risk of CKD outcome between HCV-viremic and HCV-aviremic people. The NA-ACCORD team determined that “factors other than chronic HCV replication appear to account for most of the observed association between HCV infection and CKD.”

The researchers conclude that, compared with HCV-negative people, “both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.”

Source: Gregory M. Lucas, Yuezhou Jing, Mark Sulkowski, Alison G. Abraham, Michelle M. Estrella, Mohamed G. Atta, Derek M. Fine, Marina B. Klein, Michael J. Silverberg, M. John Gill, Richard D. Moore, Kelly A. Gebo, Timothy R. Sterling, Adeel A. Butt, for the NA-ACCORD of the IeDEA. Hepatitis C viremia and the risk of chronic kidney disease in HIV-infected individuals. Journal of Infectious Diseases. 2013; 208: 1240-1249.

For the study abstract

(Downloading the complete article requires a subscription to the Journal of Infectious Diseases or an online payment; the abstract is free.)

For a report on this study at the 2013 CROI

Source

HIV Virus Spread And Evolution Studied Through Computer Modeling

Published: November 19, 2013. By Los Alamos National Laboratory
http://www.lanl.gov

LOS ALAMOS, N.M., November 19, 2013—Researchers at Los Alamos National Laboratory are investigating the complex relationships between the spread of the HIV virus in a population (epidemiology) and the actual, rapid evolution of the virus (phylogenetics) within each patient's body.

"We have developed novel ways of estimating epidemics dynamics such as who infected whom, and the true population incidence of infection versus mere diagnoses dates," said Thomas Leitner, principal investigator. "Obviously, knowledge about these things is important for public health monitoring, decision making and intervention campaigns, and further to forensic investigations."

The team models the uninfected population using traditional differential equations on the computer; this is done for computational speed, because an agent-based component is much more demanding. Once a person is infected, he/she becomes an "agent" in computer modeling terms, and the model starts following their behavior individually, as well as the viral HIV evolution within the person.

Agent-based Modeling Clarifies Infection History

This new modeling approach distinguishes between susceptible and infected individuals to capture the full infection history, including contact tracing data for infected individuals. The uninfected individuals are modeled at a population level and stratified by transmission risk and social group. The social network in this model forms – and can change – during the simulation. Thus, the model is much more realistic than traditional models.

The advantage of this epidemiological model, Leitner said, is that "it allows us to simulate many possible outcomes of epidemics with known parameters of human interactions, where social networks form as part of the agent interactions. It is a flexible system that has the ability to describe realistic human populations."

Within a National Institutes of Health-supported project "Reconstructing HIV Epidemics from HIV Phylogenetics," the team has published 10 papers describing new mathematical models and results from real data addressing these issues. Most recently, they published aNature correspondence on the limitations of HIV forensics and the need for better standards.

Who Infected Whom

A key question is on the fundamental limitations to the inference of who infected whom, based on a concept known as the pre-transmission interval (which this group first described back in 1999). Another publication, published in Epidemics, developed a new hybrid model to simulate and analyze the spread of HIV or other pathogens spread in a human population. The work also appeared in PLOS ONE Public Library of Science online publication.

As an example, the team modeled a Latvian HIV-1 epidemic, and they showed that injecting drug users fueled the heterosexual population, thereby sustaining the overall epidemic. The researchers are now expanding this hybrid model to also include HIV genetic evolution, which occurs in every infected individual.

The researchers have shown that in fast HIV epidemics – such as among individuals injecting themselves with drugs – HIV viral evolution is slow, resulting in little diversification at the population level. Meanwhile, slower-spreading epidemics display more HIV evolution over the same amount of time.

New Field of Phylodynamics Evolves

Understanding HIV's genetic evolution will soon allow investigations of how accurately researchers can reconstruct different epidemiological scenarios using pathogen genetic materials, an important and growing field called phylodynamics.

The team also has developed a new mathematical model that facilitates estimation of when a person was infected with HIV based on a previously used biomarker (BED IgG).

"This is important because most HIV infected persons are not discovered shortly after infection rather, they are often discovered long after, often years after infection, said Leitner. "Thus, to estimate true incidence, that is when infections actually occurred, cannot be done based on diagnosis dates."

Using Swedish surveillance data, the team has shown that the common assumption that infection occurred on average half way between last negative test and first positive test, is wrong. Instead, the actual infection is strongly skewed towards the first positive sample.

This finding should have large impact on epidemiological models used worldwide by public health organizations, Leitner says. "Currently, we have further developed this model to also correct for unknown cases, such as infected people not yet discovered but who contribute to new infections and thereby the true incidence of the disease."

The Team Behind the Insights

Researchers include Frederik Graw, Thomas Leitner, Ruy M. Ribeiro, and Helena Skar (Los Alamos National Laboratory) and Jan Albert (Karolinska Institute and Karolinska University Hospital). The National Institutes of Health funded the research.

About Los Alamos National Laboratory

Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Company, and URS Corporation for the Department of Energy's National Nuclear Security Administration.

Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.

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Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment

Antimicrob Agents Chemother. 2013 Dec;57(12):6097-105. doi: 10.1128/AAC.00608-13. Epub 2013 Sep 30.

Brennan BJ, Wang K, Blotner S, Magnusson MO, Wilkins JJ, Martin P, Solsky J, Nieforth K, Wat C, Grippo JF.

Hoffmann-La Roche, Nutley, New Jersey, USA.

Abstract

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

PMID: 24080649 [PubMed - in process]

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Development and validation of a nomogram based on clinical factors and standard laboratory tests for prediction of clinically significant liver fibrosis in chronic hepatitis C virus infection

Eur J Gastroenterol Hepatol. 2013 Dec;25(12):1385-95. doi: 10.1097/MEG.0b013e328363e29d.

Sagrini E, Ardoino I, Marano G, Gianstefani A, Orlandini A, Sebastiani G, Donati G, Cucchetti A, Pelosi G, Ferrari C, Alberti A, Biganzoli E, Piscaglia F,Bolondi L.

aDepartment of Digestive Diseases and Internal Medicine, Division of Internal Medicine bDivision of Surgery and Liver Transplantation, S. Orsola-Malpighi University and General Hospital, Bologna cDepartment of Clinical Sciences and Community Health, University of Milan dUnit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS National Cancer Institute Milan, Milan eUnit of Infectious Diseases and Hepatology, University Hospital, Parma fVenetian Institute of Molecular Medicine (VIMM), University of Padova, Padova gDivision of Internal Medicine, Ospedale di Rimini, Rimini, Italy.

Abstract

OBJECTIVES: Staging liver fibrosis in chronic viral hepatitis C (HCV) patients is essential for prompting surveillance and treatment. The aim of this study was to develop a nomogram, on the basis of simple clinical and laboratory variables, to predict three clinically significant stages of fibrosis (nil-mild, moderate, advanced/cirrhosis), using histology as reference, and to compare its performance with that of FibroTest, a widely used noninvasive fibrosis score.

MATERIALS AND METHODS: Nomograms are graphical representations of a mathematical formula, used as predictive tools. The study retrospectively recruited 406 HCV patients undergoing liver biopsy. Nomogram was developed in a training set of 252 patients and tested in a validation set of 154 patients. Histology was staged according to the Metavir system. Fibrosis stages were subgrouped as follows: advanced fibrosis/cirrhosis (F3/F4, 24%), nil-mild (F0/F1, 36%), and moderate (F2, 40%). Age at biopsy, aspartate aminotransferase, γ-glutamyl transpeptidase, albumin, platelet count, and prothrombin activity formed the basis for the so-called Fibro-Nomogram, which, in one graphical representation, estimates probability for different stages of fibrosis.

RESULTS: Areas under the receiver-operating characteristic curves for advanced fibrosis/cirrhosis were similar for training (0.86) and validation sets (0.87). For nil-mild fibrosis, area under the receiver-operating characteristics were 0.81 and 0.79. Compared with FibroTest, Fibro-Nomogram performed slightly better at predicting severe fibrosis (F3/F4) with positive likelihood ratio (LR+) 5.07 (95% confidence interval 3.08-8.37) versus LR+ 3.82 (95% confidence interval 2.56-5.71) for FibroTest. For nil-mild fibrosis, the two tests showed limited but comparable performances.

CONCLUSION: In HCV patients, Fibro-Nomogram, an inexpensive and readily available predictive tool, could enable clinicians to interpret patients' profile, concurrently stratifying patients into three clinically relevant probability categories with good overall performance.

PMID: 23839163 [PubMed - in process]

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