New Antiviral Agents for Hepatitis C

Jean-Michel Pawlotsky^1,2

1. National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Henri Mondor Hospital, University of Paris-Est, France
2. INSERM U955; 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France

Corresponding author

F1000 Biol Reports2012, 4:5 (doi: 10.3410/B4-5)

Published: 01 Mar 2012

© 2012 Faculty of 1000 Ltd

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/4/5

The PDF of this article can be found at: http://f1000.com/reports/b/4/5/pdf

Abstract

Approximately 120-130 million individuals are chronically infected with hepatitis C virus (HCV) worldwide, although it is curable by therapy. Until recently, treatment of chronic hepatitis C was based on the combination of pegylated interferon-α and ribavirin. A number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors. They led to the development of antiviral agents that specifically target a viral function (direct acting antivirals), and host-targeted agents that inhibit HCV replication. Direct acting antivirals in clinical development include NS3-4A protease inhibitors (two of which, telaprevir and boceprevir, have recently been approved for treatment of HCV genotype 1 infection in combination with pegylated interferon-α and ribavirin), nucleoside/nucleotide analogue and non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, and NS5A inhibitors. Host-targeted agents include cyclophilin inhibitors. This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α.

Introduction

Hepatitis C virus (HCV) was discovered in 1989 [1]. It was found to be responsible for the vast majority of so-called chronic non-A, non-B hepatitis and cryptogenetic liver diseases [2-4]. In adults, acute HCV infection leads to chronic infection in approximately 80% of cases. Chronic HCV infection is responsible for chronic hepatitis, which is complicated by cirrhosis in approximately 20% of cases. Patients with cirrhosis are exposed to life-threatening complications, including end-stage liver disease, esophageal varices hemorrhage and the development of hepatocellular carcinoma, which occurs at an incidence of 4%-5% per year in these patients [5]. Approximately 120-130 million individuals are chronically infected with HCV worldwide [6]. Chronic HCV infection has become the leading cause of hepatocellular carcinoma (primary liver cancer) and the first indication of liver transplantation in industrialized countries [5]. Six genotypes (1 to 6) and a number of subtypes have been described. Genotype 1 (subtypes 1a and 1b) is by far the most frequent genotype worldwide [7].

Unlike other known chronic viral infections, HCV infection is curable by therapy. Cure of infection is characterized by the “sustained virological response”, defined as undetectable HCV RNA in peripheral blood by means of sensitive molecular biology-based techniques. Until recently, treatment of chronic hepatitis C was based on the combination of a pegylated form of interferon (IFN)-α (pegylation improves the pharmacokinetic and pharmacodynamic properties and enhances the antiviral potency of IFN) and ribavirin [8-10]. This combination cures approximately 80% of infections in patients infected with HCV genotypes 2 or 3, but only 40%-50% in patients infected with genotypes 1 or 4. This emphasizes the need for more efficient antiviral strategies.

Over the past 10 years, a number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors [11]. These models include cell-free enzyme assays for the HCV NS3-4A protease and RNA-dependent RNA polymerase, hepatoma cell lines harboring subgenomic and genomic replicons (nucleic acids capable of autonomous replication), an infectious cell culture system (limited to genotype 2a), and humanized mouse models infectable by HCV. They led to the development of antiviral agents that specifically target a viral function, now collectively termed “direct acting antivirals”. In addition, “host-targeted agents” that inhibit HCV replication are also in development. This article describes the direct acting antivirals that have recently been approved and direct acting antivirals and host-targeted agents that have been tested in HCV-infected patients and discusses their current paths of clinical development: with or without IFN-α.

New HCV drugs in development

In principle, every step of the HCV lifecycle, including receptor binding, endocytosis, fusion, uncoating, translation, polyprotein processing, RNA replication, virion assembly, maturation, transport and release, can be a target for new anti-HCV drugs [12]. Thus far, drugs targeting two major steps of the HCV lifecycle have reached clinical development. They include inhibitors of the HCV NS3-4A protease that block polyprotein processing and several drug families that block viral replication, including nucleoside/nucleotide inhibitors of the HCV RNA-dependent RNA polymerase, non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase, and inhibitors of the NS5A viral protein which plays a regulatory role in replication. Host-targeted agents that inhibit the host cell protein cyclophilin A, a protein required to interact with the replication complex for efficient viral genome production, are also in clinical development. Table 1 summarizes the drugs that have been tested in clinical trials and for which results have been published or presented at medical meetings as of November 2011.

Table 1. New drugs that have reached clinical development for treating chronic hepatitis C (/r means boosted by ritonavir)

Barrier to resistance of HCV drugs

Like antiretroviral drugs, HCV direct acting antivirals have been shown to select drug-resistant viral variants, the outgrowth of which is responsible for virological breakthrough and disease progression [13]. In vivo, the “barrier to resistance” of an HCV drug is influenced by three parameters: (a) the “genetic barrier to resistance” of the drug, defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question (if a single substitution is sufficient to confer high-level resistance, the drug is considered to have a low genetic barrier to resistance, while the need for three or more substitutions represents a high genetic barrier); (b) the “in vivo fitness” of the resistant viral variant population, defined as its ability to survive and grow in the replicative environment; and (c) drug exposure, defined as the drug concentration achieved in vivo relative to the 50% and 90% inhibitory concentrations (in enzyme assays) and efficient concentrations (in cellular assays) [13]. HCV drugs in development can be split into two groups according to their barrier to resistance, including drugs with a low barrier to resistance, and drugs with a high barrier to resistance.

HCV drugs with a low barrier to resistance

HCV drugs with a low barrier to resistance include the following direct acting antivirals: first-generation NS3-4A protease inhibitors, non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase and NS5A inhibitors.

A large number of NS3-4A protease inhibitors have reached clinical development, including two drugs, telaprevir and boceprevir (Table 1), that have recently been approved for use in combination with pegylated IFN-α and ribavirin in patients infected with genotype 1. NS3-4A protease inhibitors have closely related chemical structures. They inhibit viral replication by 3.5 to 4.5 Log international units (IU)/mL when administered alone for a few days (one log reduction means that the viral level has been divided by 10, 2 log by 100, etc). Telaprevir and boceprevir are active against genotypes 1 and 2 only, whereas other protease inhibitors have broader genotype coverage; however, none of the first-generation NS3-4A protease inhibitors are active against genotype 3. A large number of amino acid substitutions conferring resistance to protease inhibitors have been shown to pre-exist at generally low levels in infected patients and are selected within a few days to weeks on drug monotherapy [13]. Different resistance profiles have been reported for subtypes 1a and 1b. Second-generation NS3-4A protease inhibitors, such as MK-5172 or ACH-2684 (Table 1), are expected to have broader genotypic coverage and higher barriers to resistance.

In contrast to protease inhibitors, non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase are a heterogeneous group of drug families targeting one of four allosteric sites at the surface of the viral enzyme (Table 1). Their antiviral action is thus far restricted to HCV genotype 1. Different non-nucleoside inhibitors may have different antiviral potencies and select amino acid substitutions conferring resistance that is generally, but not always, located in close vicinity to their target site. Extensive cross-resistance has been reported between drugs targeting the same site, and cross-resistance can also occur between drugs targeting different sites.

NS5A inhibitors are potent antiviral drugs that block the function of the NS5A protein through an, as yet, unclear mechanism (Table 1). They have broad genotypic coverage, but a low barrier to resistance, with the highest levels of resistance conferred by single amino acid substitutions in subtype 1a.

New HCV drugs with a high barrier to resistance

HCV drugs with a high barrier to resistance include nucleoside/nucleotide analogues and host-targeted agents, such as cyclophilin inhibitors. Nucleoside/nucleotide analogues target the catalytic site of the RNA-dependent RNA polymerase. Several nucleoside and nucleotide analogues have reached clinical development, including purine and pyrimidine analogues. They are effective on all known genotypes and subtypes. Although these drugs have a low “genetic barrier” to resistance (as one single amino acid substitution is sufficient to confer resistance to the drug), these amino acid substitutions alter the conformation of the enzyme catalytic site. Thus, resistant variants exhibit low fitness and are not clinically meaningful. In this respect, nucleoside/nucleotide analogues have a high “barrier” to resistance in vivo, as resistant viral populations on single drug administration grow very slowly with virological breakthrough eventually occurring after months of treatment.

Cyclophilin A plays an important role in the HCV replication cycle by binding to both NS5A and the RNA-dependent RNA polymerase within the viral replication complex. Blocking cyclophilin peptidyl-prolyl cis-trans isomerase enzyme activity results in a significant inhibition of HCV replication both in vitro and in vivo, through molecular mechanisms that remain unclear. Because their target is a host protein, cyclophilin inhibitors have broad genotypic coverage and a favorable resistance profile. Amino acid substitutions in the NS5A protein can be selected by these drugs, but they confer low-level resistance and the corresponding variants exhibit low fitness.

Newly approved NS3-4A protease inhibitors

The first available direct acting antivirals for clinical development in patients infected with HCV genotype 1 were the NS3-4A protease inhibitors telaprevir and boceprevir. Due to their low barrier to resistance, it soon appeared that they could not be used alone and should be combined with other compounds with potent antiviral properties and no cross-resistance with the protease inhibitors. Only pegylated IFN-α and ribavirin were available for combination in Phase II and III clinical trials. It soon became apparent that ribavirin was also needed to improve the cure rates in combination with pegylated IFN-α and a protease inhibitor [14]. In 2011, the results of several Phase III trials have led to the approval of both telaprevir (Incivek, Vertex Pharmaceuticals, in the US; Incivo, Janssen, in Europe) and boceprevir (Victrelis, Merck) in combination with pegylated IFN-α and ribavirin [15-18]. Complex treatment algorithms have been issued in the US Food and Drug Administration and European Medicines Agency labels, which substantially differ between the two protease inhibitors (Tables 2 and 3). Treatment duration must be tailored to the severity of liver disease, prior virological response to pegylated IFN-α and ribavirin in previously treated patients, and the virological response during therapy (response-guided therapy). Sustained virological response rates in the range of 66% to 75% have been achieved in treatment-naïve patients in Phase III trials, significantly higher than with pegylated IFN-α and ribavirin alone [16,18]. In previously treated patients, the results strongly depended on the prior response to pegylated IFN-α and ribavirin, with sustained virological response rates of the order of 30% in prior null responders and up to approximately 85% in prior responder-relapsers [15,17].

Table 2. Telaprevir label (US and Europe)

Table 3. Boceprevir labels (US and Europe)

In addition to the complexity of the approved treatment regimens, the new triple combination therapies raise a number of issues.

1. They are restricted to HCV genotype 1.
2. The addition of a third drug to pegylated IFN-α and ribavirin is associated with additional, and eventually severe, side effects. The principal adverse reactions associated with telaprevir are anemia, pruritus and rash [17,18]. Rash is observed in approximately half of cases. It is generally benign and responds well to topical corticosteroids; however, severe cases have been reported in clinical trials, including occasional cases of Stevens-Johnson syndrome and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. These complications can be life-threatening and impose rapid treatment interruption. Therefore, telaprevir therapy requires strict adherence to the rash management plan, in close collaboration with experienced dermatologists. Boceprevir administration is associated with anemia that aggravates hemolytic anemia due to ribavirin and dysgueusia [15,16].
3. Selection of viral variants that are resistant to the protease inhibitor is an inevitable consequence of treatment failure, i.e. the failure to eradicate the virus on triple combination therapy. Such failure is due to an inadequate response to pegylated IFN-α and ribavirin, which does not prevent outgrowth of resistant variants selected by the protease inhibitor [13]. After treatment cessation, resistant viral populations progressively decrease in proportion and are no longer detectable with population sequencing after a period of a few months to two years [19-21]. Selection of resistant HCV variants does not appear to have a negative impact on the outcome of liver disease. Theoretically, it should not compromise the chance for a subsequent cure with another drug regimen.
4. The addition of a protease inhibitor substantially increases the cost of therapy, raising issues regarding screening policies and access to care.

Two paths of clinical development of HCV direct acting antivirals

Issues raised by the recent approval of telaprevir and boceprevir in combination with pegylated IFN-α and ribavirin emphasize the need for alternative therapeutic strategies that ensure broader genotypic coverage, better efficacy, better tolerance and limited selection of resistant HCV variants. The clinical development of new HCV drugs currently follows two paths, according to whether or not pegylated IFN-α is included in the drug combination.

IFN-based regimens

Most of the new direct acting antivirals and host-targeted agents in development are currently tested as part of triple combinations with pegylated IFN-α and ribavirin. The results of Phase II trials have been encouraging with other NS3-4A protease inhibitors, such as TMC435 or BI201335 (currently in Phase III evaluation), the NS5A inhibitor daclatasvir (BMS-790052), or the cyclophilin inhibitor alisporivir (DEBIO-025, currently in Phase III evaluation), with sustained virological response rates of the same order as those with telaprevir and boceprevir [22-25]. Results of trials with two non-nucleoside inhibitors, filibuvir and tegobuvir, have been disappointing. However, this result cannot be generalized to the wider group of non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, as it seems to be essentially the result of the modest antiviral efficacy of the two individual compounds. Results are awaited with other drugs, tested in ongoing clinical trials. As with telaprevir and boceprevir, the response to IFN and ribavirin is a key determinant of the final outcome of therapy. It is too early to say whether the effect of IFN responsiveness will be attenuated when drugs with a high barrier to resistance are used in combination with pegylated IFN-α and ribavirin.

Interest was recently raised about quadruple combination treatment regimens that combine pegylated IFN-α, ribavirin, and two direct acting antivirals belonging to different drug classes without cross-resistance. In a study in patients who previously experienced a null response to pegylated IFN-α and ribavirin, 10 out of 10 patients receiving a quadruple combination including both daclatasvir (an NS5A inhibitor) and asunaprevir (an NS3-4A protease inhibitor) showed a sustained virological response [26]. The number of patients in this study was too small to draw firm conclusions, and it also remains to be established whether two drugs with a low barrier to resistance do better in combination with pegylated IFN-α and ribavirin than one drug with a high barrier to resistance, or whether quadruple combinations may be further improved by including at least one drug with a high barrier to resistance.

All-oral, IFN-free regimens

Enthusiasm about IFN-free regimens has recently risen dramatically with reports of sustained virological response rates of the order of 100% in small groups of patients treated with one or two direct acting antivirals alone, with or without ribavirin. What is known about IFN-free regimens can be summarized as follows: (a) the combination of two oral drugs with a low barrier to resistance results in early virological breakthroughs due to the selection of viral populations that are resistant to both drugs [26-28]; (b) ribavirin accelerates HCV clearance in combination with direct acting antivirals in the absence of IFN and is useful for shortening treatment duration and preventing post-treatment relapses [27]; (c) the use of a nucleotide analogue (PSI-7977) with ribavirin in patients infected with HCV genotypes 2 and 3 [29], or of a combination of an NS3-4A protease inhibitor (asunaprevir) and an NS5A inhibitor (daclatasvir) in patients infected with genotype 1b [30], a population in which daclatasvir has a reasonably high barrier to resistance, yielded 100% sustained virological response rates in small groups of patients.

Overall, these results provide a proof-of-concept that HCV infection can be cured by an all-oral IFN-free treatment regimen within 12 to 24 weeks and that very high sustained virological response rates can be achieved with drugs or drug combinations that have a high barrier to resistance. They strongly suggest that the IFN era is coming to an end in hepatitis C therapy, although this end cannot yet be precisely dated. Further results are awaited that will allow the establishment of an ideal all-oral IFN treatment regimen for patients with chronic HCV infection.

Conclusion

A new standard-of-care is now available for patients infected with HCV genotype 1, based on the triple combination of pegylated IFN-α, ribavirin, and either telaprevir or boceprevir. However, these new therapies are associated with increased costs, additional side effects and more complex treatment strategies, whereas pegylated IFN-α and ribavirin remain the standard treatment for all other genotypes, as well as in resource-limited settings where the cost of these new therapies cannot be afforded. A universal, cost-effective, well-tolerated all-oral first-line treatment regimen is needed and will most likely be available within a few years, when more is known about the ideal combination of drugs and the optimal doses and duration. Nevertheless, antiviral therapy is not the solution to definitively eradicate HCV infection, most of the 120-130 million chronic carriers live in areas where screening, cost and access to care preclude the use of these novel therapies. An efficient prophylactic vaccine is still urgently needed. This will be the next, and probably last, challenge of the HCV story.

Abbreviations

HCV, hepatitis C virus; IFN, interferon.

Competing Interests

The author has received research grants from Gilead and Roche/Genentech. He has served as an advisor for Abbott, Achillion, Anadys, Biotica, Boehringer-Ingelheim, Bristol-Myers Squibb, DebioPharm, Gen-Probe, Gilead, Glaxo-SmithKline, Idenix, Inhibitex, Janssen-Cilag, Madaus-Rottapharm, Sanofi-Aventis, Schering-Plough/Merck, Novartis, Pfizer, Roche/Genentech, Vertex and Virco.

References

1 Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989, 244:359–62.PubMed | CrossRef

2 Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, Kuo G: Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med. 1989, 321:1494–1500.PubMed | CrossRef

3 Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M: Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet. 1989, 2:1006–8.PubMed | CrossRef

4 van der Poel CL, Reesink HW, Lelie PN, Leentvaar-Kuypers A, Choo QL, Kuo G, Houghton M: Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in The Netherlands. Lancet. 1989, 2:297–8.PubMed | CrossRef

5 Seeff LB: Natural history of chronic hepatitis C. Hepatology. 2002, 36:S35–46.PubMed | CrossRef

6 Global Burden Of Hepatitis C Working Group: Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004, 44:20–29.PubMed | CrossRef

7 Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, Halfon P, Inchauspé G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin-I T, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A: Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology. 2005, 42:962–73.PubMed | CrossRef

8 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002, 347:975–82.PubMed | CrossRef

9 Hadziyannis SJ, Sette HJ, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM; PEGASYS International Study Group: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2002, 140:346–55.PubMed

10 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001, 358:958–65.PubMed | CrossRef

11 Lindenbach BD, Rice CM: Unravelling hepatitis C virus replication from genome to function. Nature. 2005, 436:933–8.PubMed | CrossRef

12 Pawlotsky JM, Chevaliez S, McHutchison JG: The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007, 132:1979–98.PubMed | CrossRef

13 Pawlotsky JM: Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology. 2011, 53:1742–51.PubMed | CrossRef

14 Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S; PROVE2 Study Team: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009, 360:1839–50.PubMed | CrossRef

15 Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators: Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011, 364:1207–17.PubMed | CrossRef

16 Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators: Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011, 364:1195–206.PubMed | CrossRef

17 Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M; REALIZE Study Team: Telaprevir for retreatment of HCV infection. N Engl J Med. 2011, 364:2417–28.PubMed | CrossRef

18 Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011, 364:2405–16.PubMed | CrossRef

19 Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang E, Spanks J, Tigges A, Adda N, Martin EC, Jacobson IM, Sherman KE, Zeuzem S, Picchio G, Kieffer TL: Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. J Hepatol. 2011, 54(Suppl. 1):S4.CrossRef

20 Sherman KE, Sulkowski MS, Zoulim F, Alberti A, Wei LJ, Sullivan J, Martin EC, Kieffer TL., De Meyer S, Gaston P, Graham CS.; Stefan Zeuzem on behalf of the EXTEND Study Team: Follow-up of SVR durability and viral resistance in patients with chronic hepatitis C treated with telaprevir-based regimens: interim analysis of the EXTEND study. Hepatology. 2011, 54(Suppl):485A.

21 Zeuzem S, Barnard RJ, Howe JA, Ogert RA, Ralston R, Boparai N, Brass CA, Albrecht J, Burroughs M., Sniukiene V., Poordad F., Gordon S, Jacobson I: Boceprevir resistance-associated variants (RAVs) are observed more frequently in HCV (GT1)-infected patients with poor response to peginterferon alfa-2b/ribavirin. J Hepatol. 2011, 54(Suppl. 1):S4.CrossRef

22 Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson IM, Marcellin P, Manns MP, Nikitin I, Poordad FF, Sherman M, Zeuzem S, Lenz O, Peeters M, Sekar V, De Smedt GD: TMC435 in combination with peginterferon and ribavirin in treatment-naive HCV genotype 1 patients: final analysis of the PILLAR Phase IIb study. Hepatology. 2011, 54(Suppl):1429A.

23 Dieterich D, Asselah T, Guyader D, Berg T, Ceausu E, Preotescu L, Schuchmann M, Mauss S, Ratziu V, Ferenci P, Larrey G, Maieron A, Biermer M, Stern JO, Scherer J, Kubiak R, Boecher WO: SILEN-C3: treatment for 12 or 24 weeks with BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naive patients with chronic genotype 1 HCV infection. Hepatology. 2011, 54(Suppl):378A.

24 Hezode C, Hirschfield GM, Ghesquiere W, Sievert W, Rodriguez-Torres M, Shafran SD, Thuluvath PJ, Tatum HA, Waked I, Esmat GE, Lawitz E, Rustgi VK, Pol S, Weis N, Pockros P, Bourliere M, Serfaty L, Vierling JM, Fried MW, Weiland O, Brunetto MR, Everson GT, Zeuzem S, Kwo PY, Sulkowski MS, Yin PD, Diva UA, Hughes EA, Wind-Rotolo M, Scnittman SM: BMS-790052, a NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naive HCV genotype 1 or 4 patients: phase 2b AI444010 study interim week 12 results. Hepatology. 2011, 54(Suppl):474A.

25 Flisiak R, Pawlotsky JM, Crabbé R, Calistru PI, Kryczka W, Haussinger D, Mazzella G, Romero M, Purcea D, Vuagniaux G, Bao W, Avila C, Zeuzem S: Once daily alisporivir (DEB025) plus PegIFN alfa-2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naive patients. J Hepatol. 2011, 54(Suppl. 1):S2.CrossRef

26 Lok AS, Gardiner GF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C: Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med.. 2012, 366:216–24.PubMed | CrossRef

27 Zeuzem S, Buggisch P, Agarwal K, Manns MP, Marcellin P, Foster GR, Sereni D, Klinker H, Moreno C, Zarksi JP, Horsmans Y, Shelton M, West S, Zong J, Harris J, McHutchison J, Lee W, Delaney W, Oldach D: Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment-naïve, genotype 1 HCV subjects. Hepatology. 2010, 52(suppl):400A.

28 Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib RH, Reindollar R, Rustgi V, Wendelburg P, Zhu K, Shah V, Sherman D, McPhee F, Wind-Rotolo M, Bifano M, Eley T, Guo T, Persson A, Hindes R, Grasela D, Pasquinelli C: Combination therapy with BMS-790052 and BMS-650032 alone or with PegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. Hepatology. 2010, 52(Suppl):877A.

29 Gane EJ, Stedman CA, Hyland RH, Sorensen RD, Symonds WT, Hindes R, Berrey MM: Once daily PSI-7977 plus RBV: pegylated interferon alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. Hepatology. 2011, 54(Suppl. 1):377A.

30 Chayama K, Takahashi S, Kawakami Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Ohmura T, Ishikawa H, Watanabe H, Guo T, McPhee F, Hughes EA, Kumada H: Dual oral combination therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 achieved 90% sustained virologic response (SVR12) in HCV genotype 1b-infected null responders. Hepatology. 2011, 54(Suppl):1428A.

Source

Hepatitis B Vaccinations Increasing for At-Risk Infants

From Medscape Medical News

Jenni Laidman

March 26, 2012 — A greater percentage of infants at risk for hepatitis B are being successfully vaccinated against the virus, but almost half of all at-risk infants slip through the healthcare system unnoticed. This puts them at risk for chronic liver disease and premature death, according to an article published online March 26 in Pediatrics.

Despite a 33% increase in the number of infants at risk for hepatitis B (from 19,208 in 1994 to 25,600 in 2008; P < .001) the percentage of infants managed for hepatitis B risk increased even more (from 40.8% to 50.5%; P < .001) in those years.

Emily A. Smith, MPH, from the Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, and colleagues examined data from 1994 to 2008 to determine the success of the National Perinatal Hepatitis B Prevention Program (PHBPP), established in 1990 by the CDC to decrease perinatal hepatitis B virus (HBV) transmission.

Although CDC guidelines call for hepatitis B (HepB) vaccination before hospital discharge for all newborns, infants born to mothers who test positive for the hepatitis B surface antigen (HBsAG) are to receive HepB, as well as hepatitis B immune globulin (HBIG), within 12 hours of birth, followed by 2 to 3 more HepB doses during infancy, with a goal of 90% series completion by 6 to 8 months of age. PHBPP protocol calls for these at-risk infants to be tested for the infection after the vaccination series is complete.

At-risk infants who fail to complete the vaccine series or who delay completion have a significantly higher risk for chronic HBV. In a study of 426 children at risk for HBV, incomplete vaccination increased risk for chronic infection almost 8-fold. Another study showed that receiving HBIG more than 12 hours after birth was associated with increased risk for HBV infection among at-risk infants.

The new analysis covered 49 states (excluding Alaska), as well as Chicago, Illinois; Houston, Texas; New York City; Philadelphia, Pennsylvania; San Antonio, Texas; and Washington, DC. "The PHBPP achieved substantial progress in preventing perinatal hepatitis B virus infection in the United States," the authors note.

Among the case-managed infants, 94.4% received HepB and HBIG within a day of birth, and a smaller proportion of children completed the vaccine series within a year, falling from 86.0% to 77.7% (P = .004). However, testing for HBV increased among children who completed the vaccination series, rising from 25.1% to 56.0% (P < .001). This testing showed a decline in chronic HBV infections, from 2.1% in 1999 to 0.8% in 2008 (P = .001).

However, the authors acknowledge, "Significant gaps remain in identifying HBsAG-positive pregnant women, and completing management and assessment of their infants to ensure prevention of perinatal hepatitis B virus transformation."

Children born to mothers with the hepatitis B surface antigen have a 90% risk of developing chronic hepatitis, which could lead to liver failure or liver cancer. However, proper prophylaxis prevents 85% to 95% of infections.

Although fewer infants were lost to follow-up in 2008 (13.0%) than in 2004 (26.4%), the difference was not significant (P = .126) The most common reason for lack of follow-up was failure to locate the child, at 33.1%, followed by "moved out of country," at 24.4%. Family refusal was a growing reason children did not complete testing, rising from 10.8% in 2005 to 17.9% in 2008 (P = .020). The authors termed this "problematic."

Even with timely vaccines, risks remain for some portion of at-risk children. An estimated 1% to 10% of infants born to hepatitis-positive mothers develop chronic or breakthrough hepatitis infection. Breakthrough infection is strongly associated with the mother's viral load, with transmission rates as high as 32% for mothers with HBV DNA concentrations greater than 10⁸ copies/mL.

The authors have disclosed no relevant financial relationships.

Pediatrics. 2012;129:609-616.

Source

Detection and treatment for hepatic encephalopathy prevents car accidents, reduces costs

Posted On: March 27, 2012 - 3:00pm

A late stage liver condition, known as minimal hepatic encephalopathy (MHE), is associated with impaired driving skills and greater risk of motor vehicle accidents. Cost analysis of management strategies for detection and treatment of MHE are published in the April issue of Hepatology, a journal of the American Association for the Study of Liver Diseases. Findings report that MHE diagnosis using the inhibitory control test followed by treatment with lactulose was the most cost-effective approach--preventing the most car accidents and reducing societal cost by up to $3.6 million over a 5-year period.

In cirrhosis, as the liver fails, the build-up of toxic substances normally removed by the liver can lead to MHE—a reversible condition that causes cognitive impairment and loss of consciousness. Medical evidence reports that MHE is present in 55% of cirrhotic patients tested, and is associated with higher risk of motor vehicle collisions due to attention and visuomotor coordination deficits. The Inhibitory control test measures an individual's attention and experts suggest it could be cost-effective in diagnosing MHE and correlates with driving impairments.

Previous research estimates vehicular accidents cost more than $200 billion per year in the U.S. in terms of lost productivity, medical costs, automobile damage, and insurance expenses. "Detection and treatment of MHE has potential to reduce costs and morbidity related to car accidents," explains lead study author Dr. Jasmohan Bajaj with McGuire VA Medical Center and Associate Professor at Virginia Commonwealth University School of Medicine. "Our study analyzes the cost-effectiveness of various strategies for diagnosing and treating MHE to reduce vehicular accidents and the societal cost burden."

Researchers compared five strategies for managing MHE that included presumptive treatment of all cirrhotic patients; diagnosis by neuropsychological exam with therapy; psychometric diagnostic testing with treatment; diagnosis using inhibitory control test with treatment; and no MHE diagnostics or treatment. Analysis was conducted on a simulated group of 1,000 cirrhotic patients treated for MHE with lactulose or rifaximin, and followed for 5 years. Researchers estimated the societal cost of a single car accident to be $42,100.

Results show the cost per motor vehicle accident prevented by diagnosing MHE with the inhibitory control test was $24,454; standard psychometric tests was $25,470; with presumptive treatment it was $30,469; and with neuropsychological exam the cost was $33,742. "Our findings provide strong evidence that detection of MHE, particularly the inhibitory control test, and subsequent treatment with lactulose reduces societal costs by preventing motor vehicle accidents in patients with MHE," concludes Dr. Bajaj.

The authors of a related editorial also published in this month's issue cite previous research that reports driving errors account for 71% to 98% of all motor vehicle accidents. They suggest that the high percentage of traffic accidents involving driver error makes the assessment of driving abilities crucial for patients with MHE. The study by Bajaj et al. provides evidence which may encourage further real-life effect of MHE on accident rates, and according to the authors, raise awareness of the implications for patients with liver disease and the whole of society.

Source: Wiley-Blackwell

Source

Over 20 million individuals infected with hepatitis E in Asia and Africa

Public release date: 27-Mar-2012

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

 

70,000 deaths and 3,000 stillbirths caused by infections

New research funded by the World Health Organization (WHO) estimates that 20.1 million individuals were infected with hepatitis E virus (HEV) genotypes 1 and 2 across 9 world regions in 2005. According to findings available in the April issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, there were 3.4 million symptomatic cases, 70,000 deaths, and 3,000 stillbirths from HEV that year in countries throughout Asia and Africa.

Unlike hepatitis virus B and C strains that lead to chronic disease states, HEV causes acute illness. Previous studies show HEV genotypes 1 and 2 specifically infect humans, and are associated with large outbreaks in developing countries where sanitation conditions are poor. There is evidence that HEV increases mortality risk among pregnant women. While a safe and effective HEV vaccine has been developed, it has not been widely implemented.

"Our study represents the first attempt to estimate the annual global impact of hepatitis E," said lead author Dr. David Rein of the social science research organization NORC at the University of Chicago. Estimates were created by modeling the disease burden of HEV genotypes 1 and 2 in the 9 regions, representing 71% of the world's population. Based on published evidence the team—a collaboration between researchers from NORC, WHO and RTI International—also estimated annual incidence of infection to determine symptomatic, asymptomatic, and mortality cases.

The team determined that the prevalence pattern of HEV was consistent across the regions, with the largest incident increase occurring in those between the ages of 5 and 20 years. The average age of infection was 17 years with the lowest age of infection in North Africa (8 years) and highest in East Asia (21 years).

Of the more than 20 million people infected with HEV, 61% of the cases occurred in East and South Asia, two regions which also accounted for 65% of deaths from HEV. Researchers also noted that North Africa accounted for 14% of all global HEV infections, but only 8.3% of symptomatic cases and 8% of deaths, which the authors attribute to the younger average age of infection in that region.

The authors caution there are limitations to the study which only estimated incidence of HEV genotypes 1 and 2, leaving out genotype 3 that prevalently occurs in Europe and the U.S., and genotype 4. "Future HEV estimates should include genotypes 3 and 4 to provide a complete picture of the global burden of HEV," concludes Dr. Rein.

###

Full Citation: "The Global Burden of Hepatitis E Virus Genotypes 1 and 2 in 2005." David B. Rein, Gretchen Stevens, Jordan Theaker, John S. Wittenborn and Steven T. Wiersma. Hepatology; Published Online: November 26, 2011 (DOI: 10.1002/hep.25505); Print Issue Date: April 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25505/abstract.

Author Contact: To arrange an interview with Dr. Rein, please contact Raymond Boyer at raymondcboyer@gmail.com or at 312-330-6433.

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

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com or our new online platform, Wiley Online Library (http://www.wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

Source

ICVH 2012: Eliminating HIV/HCV Among Injection Drug Users Is Possible

From Medscape Medical News

Megan Brooks

March 27, 2012 (New York, New York) — Scaling up prevention and treatment programs will help control and possibly eliminate the transmission of HIV and hepatitis C virus (HCV) among people who inject drugs, according to a poster abstract presented here at the International Conference on Viral Hepatitis 2012.

"With prevention efforts like syringe exchange, drug dependence treatment, and treatment for hepatitis C and HIV, we really have the potential to either eliminate transmission of those viruses among people who inject drugs or get it down to close to trivial levels," study author Don C. Des Jarlais, PhD, noted in an interview with Medscape Medical News. Dr. Des Jarlais is director of research at the Rothschild Chemical Dependency Institute, Beth Israel Medical Center, in New York City.

"People who inject drugs are at very high risk of infection with HIV and hepatitis C," Dr. Des Jarlais explained. "Is it going to be possible to eliminate HIV and HCV in people who inject drugs? We did a literature review and meta-analysis looking specifically at combined prevention and treatment and concluded that yes, it is certainly conceivable to eliminate transmission of those viruses among people who inject drugs," he said.

Moving in the Right Direction

Current estimates put the number of injection drug users at 16 million. Of these, 10 million are HCV-seropositive and 3 million are HIV-seropositive. Most live in low/middle-income countries; however, there has been a recent increase in new injectors in the United States, the researchers report. The estimated incidence of HCV infection ranges from 10 to 40 per 100 person-years; for HIV, it ranges from approximately 0.5 to 10.0 per 100 person-years.

On the basis of their analysis, Dr. Des Jarlais and colleagues estimate that combined prevention programs — particularly needle-exchange programs, drug dependence treatment, counseling, and testing — should be able to reduce HIV incidence to less than 0.5 per 100 person-years.

If this were the case, it would be "providing effective control," he said. The same programs applied to HCV could reduce incidence to 2.5 to 5.0 per 100 person-years, they report.

They also say that treatment for HCV infection, including new direct-acting antivirals, "might substantially reduce HCV transmission below these levels, but would be required on a large-scale basis, with 70% or more of currently infected persons treated."

"It's going to take prevention efforts like syringe exchange, pharmacy sales of syringes, and providing treatment for drug dependence," Dr. Des Jarlais said. "We are moving in that direction; certainly the new direct-acting antivirals are a huge advance. Without them, one wouldn't really consider the likelihood of treating large numbers of people who are infected with hepatitis C because the old treatments were really not that good," he told Medscape Medical News.

He also noted that although "many more people are getting screened, there are still a lot of gaps in getting someone screened, evaluated, and successfully treated. There is a big fall off at each of those steps."

Dr. Des Jarlais has disclosed no relevant financial relationships.

International Conference on Viral Hepatitis (ICVH) 2012: Poster abstract 79359. Presented March 26, 2012.

Source

Transplant technique opens door to patients forgoing anti-rejection drugs

Northwestern trials involve manipulation of donor stem cells to trick recipient's immune system

By Steven Ross Johnson, Special to the Tribune

March 28, 2012

Since she was first diagnosed with polycystic kidney disease at age 19, Lindsay Porter, now 47, has had to face the reality that she would someday need a kidney transplant.

"It really didn't affect me very much at all until my early 30s, when I developed high blood pressure," said Porter, who lives on Chicago's Northwest Side. "In my 40s, I started feeling really tired, and my abdomen just started growing huge by leaps and bounds. Eventually, my function declined to the point where I knew I was going to have to have a transplant."

Scheduled for June 2010, Porter's surgery was delayed until July, which she said turned out to be a stroke of good fortune.

"I knew that Northwestern (Memorial Hospital) was doing these trials. But at the time that (a friend) offered to donate the kidney, the trial wasn't open," Porter said. "The trial opened again on July 1, and I ended up being the first person in the trial."

The trial Porter referred to was the testing of a new kidney transplant method that has the potential to someday allow organ recipients to live a life free of anti-rejection medication.

The method, published this month in the journal Science Translational Medicine, suggested that through the manipulation of donor stem cells, the recipient's immune system might be tricked into accepting the new organ as a natural part of the body, thereby eventually eliminating the need for immunosuppressant drugs.

Study co-author Dr. Joseph Leventhal said the procedure has marked the first success at making a recipient's immune system accept a mismatched organ — one with a high rate of rejection — or from those donors who are unrelated, which made up the majority of the roughly 28,000 organ transplants conducted in the U.S. last year.

"We think this approach has very broad applicability to the larger number of patients receiving a solid organ transplant by virtue of the fact that it has been successful in mismatched, unrelated individuals, which is the usual scenario when you're doing a solid organ transplant," said Leventhal, a transplant surgeon at Northwestern Memorial Hospital.

Transplant recipients often must take a number of medications for the rest of their lives in order to prevent the body's immune system from rejecting their new organ.

As a result, the immune system is left susceptible to viruses and bacteria that it could easily fight off prior to surgery, which in turn requires the need to take a number of anti-viral drugs along with immunosuppressants.

But prolonged exposure to such drugs can have serious side effects, including high blood pressure, diabetes, cancer and damage to the new organ. That damage often requires the patient to eventually undergo another transplant.

On average, kidneys that are transplanted from living donors can last up to 15 to 20 years, with kidneys from deceased donors lasting anywhere from 5 to 10 years, Leventhal said. He felt the new procedure could prolong the life span of the new organ, eliminating the need for additional transplants.

"Many of the individuals who are coming onto the transplant waiting list — be it for a kidney, or for a heart, or for a liver — are people who have received a previous transplant and that transplant is failing," Leventhal said. "By achieving better control of the immune system without the need for drugs that can have negative side effects, we think that this is going to further prolong how the organs will last."

Dr. Suzanne Ildstad, a co-author of the study, said the process, which she called immune system tolerance, requires the kidney donor to also donate part of his or her immune system. The bone marrow stem cells that are collected are then enriched for "facilitating cells," which is believed to help transplants succeed.

During the monthlong process, the recipient undergoes radiation and chemotherapy to suppress his or her own bone marrow in order to provide enough space for the donor's stem cells to grow once they have been transplanted, said Ildstad, who is director of the University of Louisville's Institute of Cellular Therapeutics.

Conditioning of the stem cells takes about two days, which makes it possible to use only kidneys that come from living donors because bone marrow taken out of the body has already begun to degrade after such time, Ildstad said.

Ildstad and Leventhal said they hope the new transplant procedure might become a standard alternative in three to five years. For now, additional trials were needed to see whether the process could be used to treat patients who receive organs from deceased donors.

For physicians such as Dr. Dorry Segev, an associate professor of surgery at Johns Hopkins University School of Medicine, such a discovery has been what many in his field have waited to become a reality for years.

"Organ transplantation without anti-rejection medication is the holy grail that transplant folks have been dreaming about for decades," Segev said. "So if this can work, this would be a major breakthrough in our field."

Now two years removed from her surgery, Porter has remained drug-free and said living free of medications has vastly improved her quality of life.

"I feel great, I feel fantastic," Porter said. "I kind of feel like I got into a time machine, and it suddenly took me back about 10 or 15 years."

Source

How Much Aspirin Is Too Much of a Good Thing?

March 26, 2012, 6:20 pm

By RONI CARYN RABIN, Reporter

More than 40 million American adults already take an aspirin a day to prevent heart disease. Now many more are weighing the pros and cons of daily aspirin use in light of new studies finding that it also may reduce the risk of many cancers and stop the spread of tumors.

Six months ago Vanessa Brannan, a 31-year-old Seattle mother of two, learned she had colon cancer and Lynch syndrome, an inherited condition that increases risk of the disease and other cancers. Some of the best data on aspirin’s effectiveness against cancer has been found in patients like Mrs. Brannan. In one British study, patients with Lynch syndrome who took aspirin for two years cut their risk of colon cancer in half.

Yet doctors still don’t know how much aspirin these patients — or anyone else — should take. So Mrs. Brannan is taking 325 milligrams daily, though patients in the British study received nearly twice that amount. Her oncologist, though, recommended just an 81-milligram baby aspirin. “We kind of decided to split the difference and get as much aspirin into me as we can, knowing that higher amounts have been proven to work,” she said.

She is not the only cancer patient grappling with uncertainty. The science about daily aspirin and its effect on cancer is still in its infancy. In research studies, subjects have received doses ranging from 75 milligrams a day to 1,200 milligrams a day.

Now some scientists think low doses may work if they’re taken every day; American clinical trials of every-other-day aspirin had no effect on cancer rates at all.

Renewed interest in aspirin was set off by studies by researchers at Oxford, published last week in The Lancet, that found that after just three years of daily aspirin use, the risk of developing cancer was reduced by almost 25 percent when compared with a control group not taking aspirin.

Over six and a half years on average, daily aspirin reduced the risk of metastatic cancer by 36 percent and the risk of adenocarcinomas — common solid cancers including colon and prostate cancer — by 46 percent.

The studies found large reductions in colon and esophageal cancers, and hinted at benefits for the prevention of breast, uterine, ovarian and pancreatic cancers and lung cancer in smokers. The mechanism is believed to be aspirin’s suppression of inflammation, which is believed to play a role in cancer, and its inhibition of COX-2, an enzyme that helps tumors grow.

Critics say the new analyses may not be reliable because they are based on data from studies that were designed to assess aspirin’s effect on vascular disease, not cancer.

“The data with regard to breast cancer is interesting, but it is not actionable — period,” said Dr. Clifford A. Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer CenterinNew York City.

But he does not dismiss aspirin altogether, saying it may help a specific subgroup of people at high risk for breast cancer because of changes related to obesityand inflammation. “That is far different than saying everybody should take it,” he said.

Public health experts worry about widespread use of aspirin, because the drug increases the risk of gastrointestinal bleeding, ulcers and hemorrhagic strokes that can be fatal. An analysis in Archives of Internal Medicine in January found that for every 162 people who took aspirin, the drug prevented one nonfatal heart attack but caused about two serious bleeding episodes.

Aspirin may be a household staple, but it is also a potentially toxic drug, said Dr. Khosrow Kashfi, an associate medical professor at the City College of New York, who is working to develop a safer but more potent form of aspirin. “If you are telling healthy people that they should take a drug for a long period of time, for years — at what dose we don’t even know, but for a long time — then safety becomes of paramount importance,” he said.

It may be necessary to treat as many as 2,000 patients with daily aspirin to prevent a single case of colon cancer a year, said Dr. Alfred Neugut, a professor of cancer research, medicine and epidemiology at Columbia University. “The question is: what does aspirin do on a daily basis to 2,000 people?” If 20 or more of those patients suffer bleeding episodes, then taking aspirin to prevent cancer isn’t worthwhile, he added.

But if research were to uncover significant reductions in other common cancers, “you could start to argue, for general cancer prevention, the cumulative benefit may make it worthwhile.”

Other researchers are more enthusiastic about aspirin’s prospects as a cancer treatment.

“These studies may not be perfect, but do we say, ‘Wait, and we’ll do a 15-year study to answer this’?” said Dr. Scott Kopetz, who treats gastrointestinal cancers at M.D. Anderson Cancer Center in Houston. “Or do we say, ‘This is really good, compelling data, and we need to start taking this into consideration for the individual who may be at cancer risk’?”

So what’s a consumer to do? The best evidence on aspirin’s potential as a cancer preventive has been found in clinical trials of patients at increased risk for colon cancer because of a strong familial or personal history of colon cancer.

“In that case, the benefit of long-term aspirin is likely to outweigh the risks,” said Dr. Peter M. Rothwell, the Oxford professor who led the recent Lancet studies. Dr. Rothwell said research indicates that a low 75-milligram dose of aspirin a day mitigates risk, but he urged patients to seek individualized guidance from a physician.

Those who use blood thinners or have stomach ulcers, blood clot disorders, liver or kidney disease, uncontrolled blood pressure or risks for hemorrhagic stroke should not take aspirin, said Dr. Asad Umar, chief of the gastrointestinal cancers research group in the National Cancer Institute’s Division of Cancer Prevention.

If you already take aspirin, don’t stop suddenly without telling your physician. Don’t take it on an empty stomach, and avoid alcohol and other anti-inflammatory drugs.

Source

Researchers unravel genetic mechanism of fatty liver disease in obese children

Public release date: 26-Mar-2012

Contact: Karen N. Peart
karen.peart@yale.edu
203-432-1326
Yale University

Obese youths with particular genetic variants may be more prone to fatty liver disease, a leading cause of chronic liver disease in children and adolescents in industrialized countries, according to new findings by Yale School of Medicine researchers.

The study, which focused on three ethnic groups, is published in the March issue of the journal Hepatology.

Led by Nicola Santoro, M.D., associate research scientist in the Department of Pediatrics at Yale School of Medicine, the authors measured the hepatic, or liver, fat content of children using magnetic resonance imaging. The study included 181 Caucasian, 139 African-American and 135 Hispanic children who were, on average, age 13.

"We observed that a common genetic variant known as Patatin-like phospholipase domain containing protein-3 (PNPLA3) working with a regulatory protein called glucokinase (GCKR), was associated with increased triglycerides, very low-density lipoproteins levels, and fatty liver," said Santoro.

Santoro explained that his observations could help unravel the genetic mechanisms that contribute to liver fat metabolism. "This may drive the decisions about future drug targets to treat hypertriglyceridemia and non-alcoholic fatty liver disease," he said.

Childhood obesity is a global health concern. Experts say nonalcoholic fatty liver disease is now the leading cause of chronic liver disease in children and adolescents in industrialized countries.

"Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease," said Santoro, who is cautious about automatically extending this observation to the overall population.

"Our data refer to a population of obese children and adolescents," he said. "I think that further studies in a larger sample size involving lean subjects and adults may help to further define in more details these associations."

###

Other authors on the study included Clarence K. Zhang, Hongyu Zhao, Andrew J. Pakstis, Grace Kim, Romy Kursawe, Daniel J. Dykas, Allen E. Bale, Cosimo Giannini, Bridget Pierpont, Melissa M. Shaw, Leif Groop, and Sonia Caprio.

The work was also funded, in part, by the Yale Clinical and Translational Science Award grant from the National Center for Research Resources at the National Institutes of Health.

Citation: Hepatology Vol. 55, No. 3 (March 2012)
http://onlinelibrary.wiley.com/doi/10.1002/hep.24806/abstract.

Source

Achillion Pharmaceuticals: Hope, Hype, And Hep C

March 27, 2012

Stephen Simpson

I've followed biotech for a long time now, and I have a hard time thinking of an example of another addressable market like hepatitis C (HCV) where investor interest has just exploded in the space of about a year. Like antisense, monoclonal antibodies, RNAi, genomics, stem cells and every other hot property in biotech, there has been no end of hope, hype, and hucksterism. Although HCV is likely to grow into a very financially significant drug target in the coming years, it's worth wondering just how much of the frenzy today can be justified in long-term valuations.

In particular, I'm curious about Achillion Pharmaceuticals (ACHN) these days. I've watched this stock for a while now and came close to buying on multiple times in the pre-2010 pre-$2 level. I underestimated just how fast this market would heat up, though, and had to re-learn a painful lesson - sometimes, you snooze and you lose.

Achillion jumps out as the only serious HCV play I'm aware of with a market cap below $1 billion (while Idenix (IDIX) is hardly a giant at $1.1 billion). Not only is it relatively small, but it also may be one of the relatively few players with its own home-grown effective combination therapy.

Of course everything Achillion is working on in HCV is still in the clinic and as Gilead (GILD) showed so clearly recently, "surprising" clinical results are not always positive surprises. The end result, then, is that this may be the next Pharmasset or just another biotech destined to flame out.

The Good - Interesting Compounds All Their Own

Achillion has at least two HCV antivirals well worth watching - ACH-1625 and ACH-3102.

ACH-1625 is a potentially pangenotypical NS3 protease inhibitor (PI) that has shown both solid efficacy and encouraging safety in early studies. Showing both strong efficacy and safety thus far, it could perhaps be the backbone for future combination therapies. That said, pangenotypical efficacy is not yet established and the compound still has not gone through a pivotal Phase 3 study.

The good news with antivirals is that, unlikely oncology and anti-inflammatory drugs, efficacy signals in early pilot studies often hold up through pivotal studies. What's more, these studies are relatively easy to enroll and can be completed expeditiously. What that all means for investors is that ACH-1625 could have a relatively quick path to market.

Achillion is also developing ACH-3102, a NS5a inhibitor, and expects to put it in human studies soon. This drug looks like it should be less subject to resistance and the company (as well as bulls) seem more excited about this drug than the more advanced ACH-2928 (also a NS5a inhibitor). Coupled with ACH-1625, this could be a very interesting combo therapy, but it's worth mentioning that almost every drug is interesting to bulls going into Phase 2 studies.

These aren't the only drugs in Achillion's HCV pipeline, and the company does have identified experimental compounds targeting bacterial infections and HIV. It should be noted too that Achillion's HCV pipeline is wholly-owned.

The Bad - Competition, And Expectations, Left Right And Center

Achillion is very definitely not going to be the first company to market with new HCV drugs, and there is apt to be extensive competition in the market. That is not only going to place a premium on the SVR efficacy data and safety profile, but also potentially on the marketing muscle of the company in question.

Since its acquisition of Pharmasset, Gilead was put in the pole position in the race to develop blockbuster HCV drugs. That is, until the company reported Phase 2 data on the superstar-to-be '7977 that showed it is not 100% perfect. Specifically, this Phase 2 study indicated that '7977 may not be effective in null responders (patients who have failed to respond to earlier treatments), and may give new hope to alternate approaches that include a NS5a inhibitor or NS3 protease inhibitor.

That said, a little perspective is in order. Maybe '7977 isn't flawless, but SVR-12 rates of 91% in genotype 1 and 100% in genotypes 2 and 3 in a thus far safe drug is still pretty impressive. Moreover, Gilead is looking at a variety of combination possibilities and while the company would certainly love to have "the one antiviral to rule them all", being a part of a blockbuster combination therapy is not a bad consolation prize.

Along Gilead and Achillion is a host of companies developing therapies and a sea of drugs known more by number than by name.

Bristol-Myers Squibb (BMY) has its NS5a inhibitor daclatasvir well along in studies, a PI ('032), and the NS5b inhibitor it acquired with the Inhibitex deal, as well as other earlier stage compounds. The NS5a inhibitor has shown solid efficacy, and its PI/NS5 combo showed 100% SVR without PEG-interferon or ribavarin.

Of course there are many more. Abbott (ABT) has its own all-oral combination (NS5a and PI), as does Roche (RHHBY.PK), although the efficacy in the Roche compounds has not been as encouraging. Johnson & Johnson (JNJ) has its TMC435 PI that it in-licensed from Medivir, and Boeringher Ingelheim has its PI as well. Indenix has a nucleotide inhibitor and NS5a inhibitor in trials and a non-nuc in preclinical development.

Last and not least are Vertex (VRTX) and Merck (MRK). These companies have brought the two newest HCV drugs to market (Incivek and Victrelis, respectively). Vertex has a PI in trials and two nucleotide inhibitors licensed in from Alios, while Merck's PI has seen a significant setback tied to safety issues.

A Quick Rundown On The Market, Prospects, And Deals

The oft-repeated statistic on HCV says that there are between 130 million and 170 million infected persons around the world. Approximately 4 million of those are in the U.S., with another 5 million the EU. By way of comparison, Brazil is thought to have at least 7 million HCV patients, India at least 10 million, and China 43 million.

Untreated HCV offer leads to severe chronic liver disease (including cirrhosis), but the long-used PEG-interferon and ribavirin therapy (dominated by Roche and Merck) has had success rates of below 50% in long-term usage.

That efficacy underlies a lot of the market expectation on HCV drugs. While the pre-Incivek/Victrelis HCV market was estimated to be about $3 billion (with $2.5 billion of that going to PEG-inteferon), analysts believe better efficacy could drive that figure close to $10 billion in 2016.

Admittedly, that's a large number. It may not be completely out of line, though, if these 90%+ SVR rates hold up in pivotal studies. Offer people with a serious lifelong illness a safer, more effective drug that is also easier to take and you can almost always charge a premium for it. Also, think about it this way - the U.S. and European insurance/payer systems are willing to pay several tens of thousands of dollars for cancer therapies that offer a few extra months of median survival benefit, so there's clearly a willingness to pay for better clinical outcomes.

What's this all mean for Achillion?

I could see ACH-1625 garnering perhaps up to a billion in sales if the early results hold all the way through studies. Moreover, there's the potential to be had from the combo therapy; whether that's in combination with another Achillion drug or a rival compound (like, say, Gilead's '7977). If Achillion could garner $1 billion in sales, that would translate into a fair value of $13 to $18 per share today based upon your forward multiple estimate (6x or 8x).

I'm sure $1 billion in sales will sound too small to Achillion bulls. Fair enough; if the early results hold up, maybe it's an even bigger blockbuster, but it looks like there are going to be a lot of competing therapies on the market and good marketing is going to deliver sales even in inferior compounds.

It may well be the case, though, that Achillion never makes it to the point where its sales matter. I would be quite surprised to see Achillion partner its drugs, but I think a buyout could well happen. Certainly there have been plenty of chatter on that subject, what with Gilead and Bristol-Myers paying up for HCV compounds (and Roche also making some deals of its own).

So how does the M&A scene break out? I don't think Bristol-Myers would need Achillion, and I don't think Gilead would go that route either unless a '7977/ACH-1625 really showed something special. Johnson & Johnson may think it needs non-PI partner compounds and may not want to pay for the overlap between their PI programs.

That said, I think there are a lot of names left that could be interested. Merck arguably needs a better protease inhibitor, and likewise Roche, Abbott, and Vertex may find that they need better compounds than they presently have. Companies like Sanofi (SNY) and GlaxoSmithKline (GSK) aren't doing much here today, but could find Achillion to be a ready-made HCV platform. Odds are, though, that Achillion holds out a bit for a desperate buyer - not because there's anything wrong with its pipeline, but because a desperate Merck or Roche may pony up a better deal if they feel pressure.

The Bottom Line

Taking a midpoint of that earlier $13-$18 range, I'd say Achillion may be worth about $15.50 a share today. Annoyingly, that's almost spot on with the current consensus number. I do believe there could be more upside as its pipeline matures and rivals run into problems, but I usually want more than 50% undervaluation before buying into a new biotech story.

Disclosure: I am long RHHBY.PK.

Source

VICTRELIS™ Now Available for Eligible Patients in British Columbia

PRESS RELEAE

March 26, 2012, 4:42 p.m. EDT

MONTREAL, March 26, 2012 /PRNewswire via COMTEX/ -- Province to reimburse new chronic hepatitis C treatment

BC PharmaCare recently announced the reimbursement of VICTRELIS™ (boceprevir) for eligible British Columbians living with chronic hepatitis C.

Boceprevir is a first-in-class oral hepatitis C virus (HCV) protease inhibitor for the treatment of chronic hepatitis C genotype 1 infection. It is to be used in combination with peginterferon alpha and ribavirin (peg/riba) in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.1 When added to peg/riba, boceprevir can significantly increase a patient's chance of clearing the virus from the body.2,3 The treatment was authorized for use in Canada in July 2011.

"This is most welcome news as British Columbia has one of the heaviest burdens of chronic hepatitis C in Canada," says Dr. Eric Yoshida, hepatologist and Professor of Medicine at the University of British Columbia. "Boceprevir represents a major advance in the treatment of this infection. We now have the ability to cure this disease for a majority of patients, and therefore reduce the risk of premature mortality from end-stage cirrhosis and liver cancer. British Columbia is the third province to offer patients with chronic hepatitis C infection public access to this potentially life-saving treatment."

Eligibility criteria for boceprevir can be accessed through the following link: http://www.health.gov.bc.ca/pharmacare/sa/criteria/restricted/boceprevir.html

Hepatitis C in Canada and British Columbia An estimated 250,000 individuals in Canada are infected with HCV and there are 3,200 to 5,000 newly infected individuals each year.4 About 2,500 new cases of HCV are identified in British Columbia each year.5 HCV damages the liver and may lead to serious complications, including death, when left untreated.6 It is the leading cause of liver transplants in Canada.7

About Merck Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit www.merck.ca .

Forward-Looking Statement This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships.

Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2011 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site ( www.sec.gov ).

TM Trademark of Schering Corporation, a subsidiary of Merck & Co., Inc. Used under license.

1VICTRELIS™, Product Monograph, July 27, 2011, p. 3. 2Poordad, F., et al., for the SPRINT-2 Investigators. Boceprevir for Untreated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1195-1206, page 1195. 3Bacon, B.R., et al., for the HCV RESPOND-2 Investigators. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364:1207-1217, p. 1207. 4Canadian Institutes of Health Research. About the Hep C Research Initiative. http://www.cihr-irsc.gc.ca/e/38855.html . Accessed November 2, 2011. 5 HealthLinkBC. http://www.healthlinkbc.ca/dietitian/hfile40a.stm . Accessed March 15, 2011. 6Public Health Agency of Canada. http://www.phac-aspc.gc.ca/hepc/pubs/multiling-hepc/index-eng.php . Accessed November 2, 2011. 7Canadian Liver Foundation. http://www.liver.ca/Liver_Disease/ . Accessed November 2, 2011.

SOURCE MERCK

Source

Hepatitis C: From Bed to Book

Lucinda K. Porter, RN

Thinking about hepatitis C as a journey may be a metaphor that is overused, but it best describes my experience of living with this disease. My journey is from bed to book, how at my lowest, a virus brought me to this amazing life.

For more than 20 years, mental illness gripped me like a straightjacket (and yes, I know all too well, what a straightjacket feels like). In 1988, unable to bear another moment, I made my final suicide attempt. I had multi-organ failure, including liver failure, and told to say my good-byes, as I would not live another 24 hours.

A miracle, the kindness of others, and a blood transfusion gave me back my life. Why it took this much drama to wake me up to life, I don’t know. What I do know is that my life began in 1988 in that hospital bed. Here is where I slowly emerged from mental illness, physical decay, and soul-sickness. Here is where I started to put back my life, cell by cell, moment by moment.

Hepatitis C virus (HCV) was part of the deal, an unintended consequence of the life-saving transfusion. This virus has been a great gift to me. It reminds me to take care of myself. It is like a mantra, whispering, “Don’t drink. Meditate. Eat well. Go to bed early. Have fun. Help others. Be grateful. Trust the process.”

I went to nursing school, later working at a needle exchange site while undergoing interferon treatment. In 1998, I started writing for the Hepatitis C Support Project (www.hcvadvocate.org) and then landed a job as a hepatology nurse at Stanford Medical Center. I lectured across North America, continued to write and underwent peginterferon plus ribavirin treatment in 2003, but relapsed after treatment ended.

I know HCV inside and out; it is my life’s work. HCV binds me to others, and walking through treatment with patients is a deep privilege. This connection inspired me to write a book, Freedom from Hepatitis C. This guide focuses on helping patients through treatment. I wrote it because it seemed the most expedient way to pass along the knowledge I’ve compiled from my personal experience and what I learned from patients.

I know that some people can’t or don’t want to go through HCV treatment. This does not mean giving up. In fact, having HCV is an argument for doing more to take care of ourselves. Freedom from Hepatitis C suggests ways to maximize one’s health while living with this virus.

I fully intend to undergo treatment again. The “let’s get this taken care of” side of me wants to start now, but my medical team advised me to wait to see what is around the bend. Waiting is hard for me, but since I trust my advisors, I will take their advice. Waiting is a good spiritual practice for me.

The most radical change that I’ve experienced since 1988 is that I don’t let fear rule me. I still feel fear from time to time, but I deal with it. If I could give one thing to people who have HCV,

it would be this: Don’t let fear stop you from anything—from treatment, from joy, or from living a full life.

Free from Hepatitis C is my belief that just about anyone can endure hepatitis C and its treatment. If I, mentally ill, damaged, and hopeless, can go from bed to book, then so can you. You don’t have to be strong or special, you just have to be supported and informed. You don’t have to be especially brave, you just need to be honest and willing. Help is here, for anyone willing to accept it.

Breakthrough could lead to cure for chronic liver disease

By Steve Connor

Monday March 05 2012

MEDICAL scientists have taken an important step towards understanding how the diseased liver can repair itself in a breakthrough that could eventually lead to the development of new treatments for chronic liver illnesses, which at present can only be cured by organ transplants.

The researchers have worked out how to stimulate the production of vital liver cells known as hepatocytes which are lost when the liver is attacked by potentially fatal conditions such as cirrhosis or chronic hepatitis.

Liver disease is the fifth biggest killer in Britain and is the only major cause of death that has seen a continual year-on-year increase over the past 40 years – more than twice as many people die of liver disease now compared with 20 years ago.

About 16,000 people in the UK died last year of liver disease, and the number of people on the waiting list for organ transplants has increased from about 300 five years ago to nearly 500 now.

The latest research, published in the journal Nature Medicine, has unravelled the network of complex biochemical signals that trigger the regeneration of cells within the liver, the body's main organ for filtering harmful toxins from the bloodstream.

Although the human liver has remarkable powers of natural regeneration, this often results in the replacement of the wrong kind of liver cells. Instead of hepatocytes, the damaged liver tends to make to many bile duct cells, the scientists said.

The scientists were able to shift the balance towards making more hepatocytes by altering the expression of certain genes at the earliest stages of liver cell development. The discovery could lead to the development of drugs that perform the same function in patients, they said.

Luke Boulter of the Medical Research Council's Centre for Regenerative Medicine at Edinburgh University, and lead author of the study, said that understanding how new liver cells are regenerated is key to finding ways of repairing damaged liver tissue.

"This research helps us to know how to increase numbers of cells that are needed for healthy liver function and could pave the way to finding drugs that help liver repair," Dr Boulter said.

Professor Stuart Forbes, associate director of the Centre for Regenerative Medicine, said such studies are needed to tackle the increase in demand for liver transplants. "But the supply of donated organs is not keeping pace with the demand. If we can find ways to encourage the liver to heal itself then we could ease the pressure on waiting lists."

- Steve Connor

Source

A Mother's Heartbreaking Story About Pediatric AIDS

Suzan Stirling

Ambassador, Elizabeth Glaser Pediatric AIDS Foundation

Posted: 03/23/2012 3:29 pm

My name is Suzan. I'm an ambassador for the Elizabeth Glaser Pediatric AIDS Foundation, where I advocate for people to join the fight of mothers around the world to protect their children from HIV. I'm also the author of The Silence of Mercy Bleu -- a story about a young woman who grows up harboring the secret of AIDS.

When people ask me what propelled me to write a novel about HIV/AIDS, they're often surprised to learn that I am a 26-year survivor of the disease. But unlike my character, Mercy, who grows up with the disease and later strives to have a healthy baby, I didn't learn the truth until it was almost too late.

I met and married the love of my life in 1988, and a couple of years later we decided to start a family. In 1990, our wish came true and we welcomed a beautiful baby girl into our lives. In those early years, everything was perfect.

But then in 1996, shortly after the birth of our second child, something began to go terribly wrong. In the matter of a few months, both of our children became very sick.

Alee, our then 5 year-old daughter, began to rapidly lose weight. At the same time, our newborn baby, Mitch, had to be put on a respirator in the ICU, where he would spend weeks fighting a respiratory virus his young body couldn't fend off.

The doctors were candid -- things weren't looking good. There were numerous tests and long hospital stays, but still we had no answers. It was a parent's worst nightmare. We were losing both of our children and no one could tell us why.

I'll never forget the phone call that saved my children's lives. It was a new doctor. She was quick to the point. She said, "Something in your son's blood work warrants an AIDS test. I suggest your whole family be tested."

I was in complete shock. I just remember thinking, "I'm going to have to watch my children die." I didn't think I was strong enough to handle that.

We took our HIV tests, and tragically, our doctor was dead on. I tested positive for HIV. So did Alee and Mitch. We were very lucky in that my husband was negative.

Almost overnight, my family became just another face of AIDS.

It wasn't hard to trace where I'd contracted the virus. Before I'd met my husband, I'd been engaged to a young man who I was later told had died of cancer, but who I now believe died of AIDS. I had carried the virus for nearly 10 years without ever knowing it.

My husband and I nearly lost Alee and Mitchell that year, but 1996 -- the year we were diagnosed -- was also the same year that protease inhibitors became available. My husband and I would crush the blue pills into pudding, clap and cheer, and somehow our children would manage to swallow the brown, sticky mess.

Daily, we saw improvements. This new medicine, in combination with two others, literally brought our children back to us. It was and still is the most miraculous thing that I have ever witnessed.

People often ask me how HIV has changed me, and I almost want to say, "How has it not changed me?" To be completely honest, you can't go through what I've been through -- any life-threatening illness really -- and not come out a completely changed person. HIV is even more difficult because it's a disease that many people suffer with in silence, myself included, for many years.

There were so many things that my family and I had to work through to get to where we are today. HIV forced me to be a much braver, more open person, and I'm thankful for that.

It's never easy for me to share my story, but I think it's important for me -- especially as a mother -- to do so. Today, with medicines that drive the virus to undetectable levels, there is now more hope than ever of staying healthy and stopping HIV transmission. This means being able to protect your partner from the virus, and being able to have a child born free of HIV.

My husband and I were fortunate. We didn't lose our children. The same can't be said for families in other parts of the world, like Africa where our youngest son Yonas was born.

Every day around the world, one thousand mothers -- many of them unaware that they carry HIV-transmit the virus to their own babies in utero, during labor, or through breastfeeding. Without access to the right medicines, they are helpless to protect their own health and that of their babies. Being a mother with three children who are all positive, yet remarkably healthy, I can only imagine what that feels like.

The hardest part of my having HIV was never that I might die -- the hardest part was that I had given this terrible disease to my children. No mother should have to carry that burden. Not today, not ever. Especially when mother-to-child transmission of HIV is completely preventable. With preventative services, the chances of a mother passing the virus on to her children are extremely low -- less than 2 percent. Those are some pretty terrific odds.

We can stop mothers and their children from dying. Really, we can. I know because I've seen it with my own eyes, with my own family.

It's been 16 years now since my children's health was restored. I will get to see my children grow up, and I know that for a parent, there's no greater gift.

As an ambassador for the Elizabeth Glaser Pediatric AIDS Foundation, I get the privilege of joining in the fight to eliminate pediatric AIDS. The work done by the Foundation and its partners around the world is saving children's lives and sparing families unimaginable heartache.

The Foundation has made huge strides to help mothers like me, and lifesaving medicines are now reaching more people than ever. You can be a part of that progress.

Join the fight of mothers around the world, and help us get closer to a new generation born free of HIV.

Source

The Affordable Care Act: Our Second Most Important Tool for Combating HIV and Ending AIDS

Posted: 03/23/2012 7:49 pm

As the nation turns its eyes toward the Supreme Court and its review of the Patient Protection and Affordable Care Act (the "ACA") this coming week, people living with HIV and their advocates will be among those watching carefully and most anxiously awaiting the outcome. For many of the approximately 1.2 million people with HIV in this country, the Court's decisions will directly affect access to quality care and life-saving treatment. Though not by any means the only group with a great deal at stake here, those affected by HIV present an exceptionally strong example of the positive impact the ACA will have, and a particularly compelling argument for the statute's constitutionality.

People living with HIV have been systematically excluded from the health-care insurance and health-care markets. Only 17 percent of people living with HIV have private health insurance, compared with 67 percent of the general population. While some of the remaining 83 percent have insurance through public programs (e.g., Medicare, Medicaid, the VA, etc.), nearly 30 percent are forced to rely exclusively upon the often spotty benefits provided through the overburdened and underfunded Ryan White programs, or to go without care altogether.

The consequences of this patchwork quilt of health care for people living with HIV are devastating: they discover their status later, go longer without lifesaving care and treatment, suffer greater complications and poorer health outcomes, and continue to die at frustratingly high and unnecessary rates. These negative consequences are more pronounced and concentrated in already marginalized populations, such as low-income communities; the gay, bisexual, and transgender communities; and communities of color -- most acutely, the black community.

We have at our disposal the means to avoid many of these consequences. Antiretroviral medications (ARVs) provide us with the opportunity to seriously impede progression of the disease, especially when it is discovered in a timely fashion, to prevent most of the complications and poor health outcomes associated with an AIDS diagnosis, and to dramatically reduce the number of AIDS-related deaths each year. For those with access to consistent, quality care and treatment, HIV can now be a chronic, manageable condition -- akin to diabetes or high blood pressure.

What's more, quality care and effective treatment for those currently living with HIV will significantly curtail the further spread of HIV. ARVs work by reducing the level of virus in a person's blood to extremely low levels -- and the less virus in the blood, the lower the chances of transmitting the disease. Recent studies show that the already-lower-than-generally-realized risk of contracting HIV sexually is reduced by up to 96 percent when a person's viral load is suppressed to undetectable levels. Not only is near-universal access to quality health care good for people living with HIV, but it is also one of the best prevention tools we have.

The positive effects of the ACA and the near-universal access to health care it will provide to people living with HIV by 2015 are not just theoretical. Massachusetts, where health-care reform similar to the ACA was enacted years ago, experienced a 37-percent reduction in new HIV infections from 2005 to 2008, while the rest of the country experienced an 8-percent increase. And Massachusetts's age-adjusted HIV/AIDS death rate is almost half the national average (2 percent vs. 3.7 percent). These statistics, and the improved circumstances they describe, foretell what the nation can expect when the ACA is fully implemented.

When viewed through the prism of the HIV/AIDS epidemic, the argument for the constitutionality of the ACA's minimum coverage requirement (or "individual mandate") is relatively simple. Congress has the power to address the exclusion of a particular group -- specifically people living with HIV, but more broadly anyone with a pre-existing condition -- from a market that operates in interstate commerce. But the ban on preexisting condition exclusions will not work without the accompanying individual mandate, which requires every American to become a part of the health-care insurance pool regardless of their current health status. For that reason, the individual mandate is a necessary and proper means by which Congress can effectuate its clearly constitutional power to regulate an interstate market under the Commerce Clause.

Full implementation of the ACA is absolutely critical in our battle against HIV/AIDS. Public health authorities are already talking about the "end of AIDS," meaning the ability to prevent a person's progression from HIV-positive to an AIDS diagnosis and the most detrimental effects of the disease. Let's hope the Supreme Court recognizes the constitutionality of the action Congress took when it passed the ACA, which will similarly prevent our nation's broken health-care system from going from bad to worse -- not just for people living with HIV but for all of us.

For a more detailed explanation of the legal arguments discussed above, read the friend-of-the-court brief submitted by Lambda Legal on behalf of 16 HIV advocacy groups, which was subsequently endorsed by 130 more groups.

Source

9 Simple Ways to Boost Your Liver

Michelle Schoffro Cook June 23, 2011 3:01 pm

The liver is the body’s main fat-digesting and detoxification organ. Every molecule of fat that you eat must pass through your liver, but if your liver is overburdened by its more than 500 other essential activities, it can become sluggish. Here are ways to boost your liver function:

1. Since the liver requires high amounts of vitamins and minerals to perform its many functions, your diet should be high in fruits and vegetables and nutrient-rich foods.

2. Because food additives and preservatives need to be filtered by your liver, your diet should be free of processed foods, artificial food additives, colors, and preservatives to take the load off your liver. Additionally, choose to eat a diet low in refined sugar and synthetic sweeteners.

3. You should definitely be avoiding margarine, shortening, commercial oils (choose unrefined oils from the refrigerator section of your local health food store). Avoid eating animal fat and fried foods as well.

4. Drink between eight to ten glasses of pure, filtered water every day. This is the only way your liver can flush toxins out of your body.

5. Better yet, start every day with a large glass of water with the fresh juice of one-half to one lemon added. Lemon helps bolster you liver’s detoxification abilities.

6. Eat plenty of liver-rebuilding foods, including: carrots, beets, leafy greens, and other green vegetables.

7. Eat lots of garlic, onions and broccoli since these foods contain sulfur that is required to increase the liver’s detoxification ability.

8. Detoxification in the liver requires considerable amounts of nutrients to function properly so be sure to take a high quality multivitamin and mineral supplement. Even a single nutrient deficiency can seriously disrupt natural detoxification processes.

9. While lying flat on your back, you can gently massage the liver/gallbladder area, which is located along the lower rib area on the right side of your body. This helps improve circulation to the area.

Always consult your physician prior to making dietary changes or taking nutritional supplements.

Source

Hepatitis C Treatment for Drug Users

March 23, 2012

The stigma surrounding addiction may discourage Hepatitis C treatment for drug users - but the evidence encourages these individuals to do triple therapy.

By Nicole Cutler, L.Ac.

Across a variety of cultures, the ability to receive quality medical treatment is not uniform. Unfortunate for some with chronic Hepatitis C, access to the latest drugs can be unjustly withheld. Having health insurance coverage, being considered a good candidate for treatment and assumption of a low relapse risk can be determining factors in who gets the most advanced medications for fighting the Hepatitis C virus. Despite being a population particularly inundated by this viral infection of the liver, intravenous drug users are often excluded from the latest approved Hepatitis C drug regimen.

Clinically acknowledged as a disabling disease, drug addiction is found in every socioeconomic class, within every ethnic group and gender. Addicts typically have extremely strong physiological and psychological cravings to use drugs despite their negative effects. The cravings can be as strong as a human's desire for food and water. Society imposes stigma on addicts because many still believe that addiction is a character flaw or weakness that is incurable. Despite addiction being a treatable disease, the stigma against addicts remains deeply rooted.

Click here to continue reading full article …

AASLD Grant Supports Hepatitis Projects in Mongolia

AASLD News: March 22, 2012

AASLD recently provided a grant in support of the Flagstaff International Relief Effort’s (FIRE) hepatitis related projects in Mongolia.

FIRE is dedicated to providing resources and support to individuals and communities in need, from poverty, political instability, or natural disasters. Their programs are currently focused in Mongolia, an area of the world that a recent article in the Lancet concluded "…has the world's highest rate of liver cancer (deaths) - six times the global average - and the number is increasing..." According to the World Health Organization, "…one of every ten deaths in the country is due to HCC (hepatocellular carcinoma or liver cancer) or its frequent precursor, cirrhosis. In the absence of a solid understanding of this epidemiology, the country's hepatitis C prevalence continues to rise…" Seldom do we hear about these silent tragedies. One of FIRE's missions is to get the message out to the world and to make a change.
With funding from AASLD and other organizations, FIRE has since August been able to:

• Test 400 health care workers for hepatitis B
• Send 300 samples to NIH for testing and epidemiological study of hepatitis B, C and D
• Facilitate the vaccination of 400 selected health care workers for hepatitis B
• Facilitate the distribution of 20,000 sharps containers

FIRE’s goals for the spring and summer of 2012 are to:

• Complete a training video for health care workers on health safety practices and hepatitis prevention
• Facilitate the distribution of 40,000 sharps containers
• Train 200 health care workers on hepatitis prevention
• Send 500 blood samples to NIH to conduct testing and epidemiological study of hepatitis B, C, and D
• Continue the development of a new project with the National Cancer Institute (NCI), a division of NIH, addressing liver cancer

To learn more about FIRE’s hepatitis related projects in Mongolia visit www.fireprojects.org

Source

Studies see link between HIV and abuse among women

Steptoe now sees her medication regimen as prolonging her life

Liz Hafalia / The Chronicle

Erin Allday

Friday, March 23, 2012

Diagnosed with HIV in the late 1980s, Cassandra Steptoe didn't tell anyone for years, and she didn't get any treatment.

She was depressed and hopeless after a lifetime of physical and sexual abuse. She assumed the infection would kill her. But, somehow, she survived - not just the HIV infection, but far more.

During the past decade, she's received help overcoming the trauma from the years of abuse, and in turn, she's finally faced her HIV diagnosis. And she is far healthier for it, she says.

"I'm a stronger person, a better person, than I was before," said Steptoe, who started treatment in 2003 at the Women's HIV Program at UCSF. "Now when I look at my pills, it's like another day of life."

Steptoe's story - especially her history of trauma and abuse - is hardly unique among women with HIV and AIDS, say doctors and public health experts. In fact, trauma and post-traumatic stress syndrome are closely tied both to the risk of becoming infected with HIV and lower rates of successful treatment, according to two recent UCSF studies.

Address the trauma

And health care providers could better serve many of their female HIV patients if they tackled trauma at the same time as the infection, said Dr. Edward Machtinger, director of the Women's HIV Program and lead author of the studies.

"Screening and responding to trauma needs to be a core element of health care for HIV-positive women, alongside medication and CD4 counts and viral load," Machtinger said.

Machtinger's studies were published this month in the journal AIDS and Behavior. The first study, an analysis of 29 previous reports, found that HIV-positive women were two to six times more likely to have suffered trauma or post-traumatic stress than women without HIV.

According to the study, roughly 30 percent of women with HIV have PTSD - six times the rate of PTSD in the general population of women. More than 60 percent of HIV-positive women have experienced sexual abuse in their lives, compared with 12 percent of women overall, and 55 percent of women with HIV have been a victim of domestic violence, compared with 25 percent of women overall.

The second study looked at patients in UCSF's Women's HIV Program. Based on surveys given to 113 patients, women who had suffered a recent trauma were four times more likely than women who hadn't suffered a trauma to have detectable levels of virus in their blood - meaning that their drug treatment wasn't working.

Those women were also nearly four times more likely than their peers to have unprotected sex with someone who wasn't infected with HIV - or whose status was unknown.

"It appears to us that trauma fuels the HIV epidemic among women," Machtinger said.

A common thread

Health care providers who work with HIV-positive women said physical and sexual abuse is without question common. And when women have experienced a very recent trauma or are in an abusive relationship, the effect on their HIV treatment can be disastrous.

These women may suffer depression or self-esteem issues that make it difficult for them to seek treatment, health care providers said. Or women in an abusive relationship may have partners who won't let them see doctors or pick up their medications.

In many cases, women haven't told their partners that they are HIV-positive, which makes it more difficult to get treatment, said Mary Lawrence Hicks, a nurse practitioner at San Francisco General Hospital who works in the women's HIV clinic there.

"These (HIV) meds must be taken at least on a once-a-day basis, and that's hard for anyone to maintain," Hick said. "But with the chaotic lifestyles that some folks end up in when there's a lot of trauma, it's very, very difficult."

Like many health care providers who treat HIV patients, Hicks said that working with HIV-positive women requires as much focus on mental health care as traditional medical treatment. Many women-centered HIV clinics have social workers and psychiatrists on staff.

"We can't just say here's the prescription and I'll see you in six months," said Dr. Deborah Cohan, director of the Bay Area Perinatal AIDS Center at San Francisco General Hospital. "That's not a realistic way of taking care of these women, because their lives are much more complicated than that."

Road to recovery

For Steptoe, confronting her past trauma was one of the first steps she needed to take toward treating her HIV. She's lucky, she said, that she lived so long without medical care, even as she watched other women die of AIDS.

After moving to San Francisco in 2001, Steptoe went to UCSF for treatment and met Machtinger. He got her started on antiretroviral drugs and pushed her toward counseling programs. Her self-esteem has skyrocketed, she said.

She's now living with her granddaughter and taking care of them both. Her HIV is under control, and she said she's never felt healthier.

"I want to tell other women, we don't have to be beaten up on or have low self-esteem and no value or respect about our bodies," Steptoe said. "I'm on the right path now."

Erin Allday is a San Francisco Chronicle staff writer. eallday@sfchronicle.com

Source

Investigating the Serotonin-Liver Relationship

March 23rd, 2012

Serotonin, the hormone known to make people happy, may also be deeply involved in liver fibrosis.

By Nicole Cutler, L.Ac.

The human body is a complexity, involving countless amazing feats at every moment. Nowhere is this seemingly miraculous series of events more pronounced than in the liver. An organ subjected to repeated abuse, the liver maintains a remarkable ability to regenerate itself upon incurring cellular damage. A new study published in a peer-reviewed journal has found that a hormone known predominantly for its link to emotional well-being also appears to play a role in liver cell regeneration.

Especially in the presence of the Hepatitis B or C virus, alcoholism, a fatty liver or an autoimmune disease, sometimes the balance required to repair liver cells gets disrupted. This disruption impairs the liver’s regenerative abilities so that it can no longer keep up with relentless liver cell injury – and scars form. The propensity to scar more than repair the cellular damage describes the course of chronic liver disease – and British researchers believe that a well-known hormone could be the key to regaining balance.

Click here to continue reading full article …

March 23, 2012, 8:00 a.m. EDT Nordion to Launch Improved Physician Tools for TheraSphere® Liver Cancer Treatment at SIR Annual Scientific Meeting 2012

PRESS RELEASE

March 23, 2012, 8:00 a.m. EDT

OTTAWA, March 23, 2012 /PRNewswire via COMTEX/ -- Company will also present expert speakers and introduce new iPad app

Nordion Inc. ,a leading provider of products and services for the prevention, diagnosis and treatment of disease, will be attending the Society for Interventional Radiologists (SIR) Annual Scientific Meeting 2012, taking place March 24-29 in San Francisco. The company will introduce several new or updated physician education tools and resources for TheraSphere®, Nordion's Y-90 microsphere treatment for liver cancer.

"With more than 5,000 physicians, scientists and healthcare professionals in attendance, SIR represents one of the most important annual medical meetings Nordion attends," says Peter Covitz, Nordion Senior Vice President, Innovation. "SIR provides an opportunity to connect directly with our key users, share the latest information about TheraSphere, listen to feedback, and respond to questions firsthand."

Nordion representatives will be at Booth #1234 to talk about TheraSphere. The company will host two "Eat and Be Educated" learning sessions at the booth:

Sunday, March 25, 12:15pm How TheraSphere Y-90 Glass Microspheres Fits in Our Treatment Algorithm Matthew Johnson, MD Professor of Radiology and Surgery Indiana University School of Medicine Indianapolis, IN

Tuesday March 27, 12:15pm TheraSphere Multi-Vessel Delivery Siddharth Padia, MD Assistant Professor, Interventional Radiologist University of Washington - Harbourview Medical Center Seattle, WA

Each session will be followed by a Nordion presentation on how to start a TheraSphere program.

Other Nordion TheraSphere activities at SIR include:

Launch of the:

New custom dose feature in Europe and Canada*

Updated Treatment Window Illustrator tool to assist physicians with dose selection

New animated video demonstrating how TheraSphere works

Preview of the upcoming TheraSphere iPad app

Participation in SIR's Residents in Training program

* Nordion has filed a request with the Food and Drug Administration for approval of the custom dose feature in the United States.

About TheraSphere TheraSphere is a liver cancer therapy that consists of millions of small glass beads (20 to 30 micrometers in diameter) containing radioactive yttrium-90 (Y-90). The product is injected by physicians into the artery of the patient's liver through a catheter, which allows the treatment to be delivered directly to the tumour via blood flow.

In the US, TheraSphere is used to treat patients with unresectable hepatocellular carcinoma (HCC), the most common form of primary liver cancer, and can be used as a bridge to surgery or transplantation in these patients. It is also indicated for the treatment of HCC patients with portal vein thrombosis (PVT). TheraSphere is approved by the U.S. Food and Drug Administration (FDA) under a Humanitarian Device Exemption (HDE). HDE approvals are based on demonstrated safety and probable clinical benefit. However, effectiveness of the indication for use has not been established.

TheraSphere® is used in the European Union and in Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters.

Common side effects include mild to moderate fatigue, pain and nausea for about a week. Physicians describe these symptoms as similar to those of the flu. Some patients experience some loss of appetite and temporary changes in several blood tests. For details on rare or more severe side effects, please refer to the TheraSphere package insert/instructions for use at www.nordion.com/therasphere .

About Nordion Inc. Nordion Inc. is a global health science company that provides market-leading products used for the prevention, diagnosis and treatment of disease. We are a leading provider of medical isotopes, targeted therapies and sterilization technologies that benefit the lives of millions of people in more than 60 countries around the world. Our products are used daily by pharmaceutical and biotechnology companies, medical-device manufacturers, hospitals, clinics and research laboratories. Nordion has more than 500 highly skilled employees in three locations. Find out more at www.nordion.com  and follow us at http://twitter.com/NordionInc  .

SOURCE Nordion Inc.

Source