Does IL28B Genotyping Still have a Role in the Era of Direct-acting Antiviral Therapy for Chronic Hepatitis C Infection?

From Journal of Viral Hepatitis

J. A. Holmes; P. V. Desmond; A. J. Thompson

Posted: 09/28/2012; J Viral Hepat. 2012;19(10):677-684. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

IL28B genotype has been shown to be the strongest pretreatment predictor of sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C infection (CHC) treated with pegylated interferon (peg-IFN) and ribavirin (RBV). Patients carrying the good response genotype have a two- to threefold higher chance of SVR than those with a poor response genotype, manifest as dramatically improved early viral kinetics. However, the treatment paradigm for CHC is changing with the introduction of potent direct-acting antivirals (DAAs). IL28B genotype remains relevant to both telaprevir and boceprevir treatment regimens, although the strength of association with virological response is attenuated. The association between IL28B genotype and outcomes of treatment regimens that involve peg-IFN plus combination DAA therapy, or IFN-free regimens, is currently being evaluated. IL28B genotype may remain relevant to individualizing the choice of treatment regimen in the future.

Introduction

Chronic infection with the hepatitis C virus (HCV) is a global epidemic affecting 130 to 170 million individuals, who are at risk of progressive liver fibrosis, decompensation and hepatocellular carcinoma. These complications have been shown to be reduced by viral eradication. Pegylated-interferon-alpha (peg-IFN) combined with ribavirin (RBV) has been the standard-of-care therapy for chronic hepatitis C (CHC) since 2003. However, the rate of response is suboptimal for genotype 1 HCV (HCV-1), with only 40–50% of patients being cured by dual therapy. Furthermore, the ability to identify which individuals would respond to treatment was limited. In the last 3 years, the field has made two major advances. In late 2009, genome-wide association studies (GWAS) identified genetic variants in the region of the IL28B gene that are strongly associated with the outcome of peg-IFN and RBV (PR) therapy.^[1–3] In the IDEAL study pharmacogenetics cohort, carriage of the favourable IL28B genotype was associated with sustained virological response (SVR) rates of 70–80% in Caucasian patients treated with 48 weeks of PR, compared to 30–40% in patients carrying one of the unfavourable genotypes. Difference in population frequency of the favourable IL28B genotype explained much of the recognized ethnic disparity in PR response rates. IL28B genotyping immediately proved useful for pretreatment counselling for HCV-1 patients. However, PR is no longer standard-of-care for HCV-1 in many parts of the world. In 2011, the first direct-acting antivirals (DAAs) for HCV were approved for the treatment of HCV-1, increasing overall SVR rates almost twofold. 2011 also saw proof-of-concept that HCV could be cured using IFN-free regimens. DAA therapy clearly attenuates the association between IL28B genotype and HCV treatment response, but emerging data suggest that IL28B genotype will remain relevant to emerging treatment paradigms, including IFN-free therapy. In this article, we will discuss the clinical utility of IL28B genotyping for pretreatment counselling in the rapidly evolving era of DAA therapies for HCV.

IL28B Genotype and Response to Dual Therapy With peg-Interferon-A and Ribavirin

The first-generation DAAs are not yet universally available, and it is pertinent to briefly review the literature describing the association between IL28B polymorphism and response to peg-IFN and RBV therapy. IL28B genotype is the most important pretreatment predictor of response to peg-IFN and RBV therapy for HCV-1, where patients who carry the good response genotype (e.g. C/C at rs12979860) have reported SVR rates ≥70%, a two- to threefold increase over patients who carry one of the poor response genotypes (e.g. C/T, T/T at rs12979860).^[4,5] The frequency of the good response IL28B genotype varies between individuals of different ethnic backgrounds, being >80% in certain Asian populations, 35–55% in Caucasians and <20% in patients of African ancestry. This variation explains much of the disparity in treatment response rates observed according to ethnicity. It is also relevant to discussion of the health economics of novel DAA therapies (see below). The mechanism explaining the association between IL28B genotype and IFN responsiveness is not known, but it manifests as profound differences in on-treatment viral kinetics. The good response IL28B genotype is associated with increased phase-1 and phase-2 viral kinetics,^[5,6] resulting in increased rates of rapid virological response (RVR) and complete early virological response (cEVR) on-treatment (Table 1). In fact, most RVR patients carry the good response IL28B genotype.^[5] It is important to note that all patients who achieve an RVR do well, and a high rate of SVR is observed even in the minority of patients who carry a poor response IL28B genotype. It is also important to note that the good response IL28B genotype is not sufficient to indicate short-duration PR therapy using response-guided protocols for HCV-1. Recent data have shown that short-duration therapy (24 weeks) is only sufficient for patients who carry the good response IL28B genotype and have a low baseline viral load (<400–800 000 IU/ml) and achieve an RVR.^[7] Finally, the importance of IL28B genotype as a pretreatment predictor of IFN responsiveness should not discount other predictors of response, especially liver fibrosis stage. In the IDEAL study cohort, SVR rates in patients with advanced liver fibrosis were considerably lower (METAVIR F3-4, SVR in C/C = 41% vs C/T = 22% vs T/T = 11%).^[5]

IL28B Genotyping in the Setting of Telaprevir and Boceprevir Therapy

In the phase-3 registration studies of treatment-naïve HCV-1 patients, the addition of the NS3 protease inhibitors telaprevir (TVR) or boceprevir (BOC) to a PR backbone increased overall SVR rates from 40–45% to 68–79%.^{[8, 9]} In the setting of such high SVR rates, the association between IL28B genotype and treatment response is attenuated (Table 2). However, it remains clinically relevant.

A retrospective analysis of the relationship between IL28B polymorphism (rs12979860) and treatment outcomes from the SPRINT-2 study of BOC-PR therapy for treatment-naïve patients has recently been published.^[10] The analysis included 62% (653/1048) of the SPRINT-2 cohort who consented to genetic testing. Very high SVR rates were observed in all patients with the C/C genotype; in fact, SVR rates were equivalent in the BOC treatment arms and the PR control arm (Table 2). However, the C/C patients were much more likely to be eligible for short-duration therapy than the non-C/C patients (89% vs 52% non-C/C patients achieved undetectable HCV RNA levels at week 8). It was also notable that 97% of treatment-naïve C/C patients achieved ≥1 log₁₀ IU/mL reduction in HCV RNA at the end of the 4 week lead-in phase of PR treatment.^[10,11] A ≥1 log₁₀ reduction in HCV RNA identifies good IFN responders, with SVR rates >80% and low risk of selection of resistance-associated variants. BOC therapy was associated with much more benefit in non-C/C patients, with rates of SVR of 55–71% compared to 27–28% with PR therapy alone in SPRINT-2 (Table 2). The lead-in phase of PR was more useful for stratifying IFN responsiveness in the non-C/C naïve population, in which 27% C/T and 46% T/T patients were identified to have poor IFN responsiveness, predicting for low SVR rate and higher risk of selecting resistant variants. Patients with poor IFN responsiveness might be considered for deferral of DAA exposure to minimize risk of selection of resistant variants, awaiting future quadruple therapy or combination DAA regimens. This should be an individualized decision, according to the urgency for antiviral therapy. IL28B genotyping can therefore identify patients in whom the lead-in has greatest clinical utility for stratifying IFN responsiveness.

Logistic regression modelling found that IL28B genotype was independently associated with the outcome of BOC-based therapy, OR = 2.6 (1.3–5.1) for C/C vs T/T and OR = 2.1 (1.2–3.7) for C/C vs C/T.^[10] The other pretreatment predictors of SVR were low baseline HCV RNA level (< = 800, 000 IU/mL), the absence of cirrhosis, HCV-1 sub-type (1b vs 1a) and race (non-black vs black). IL28B genotype was the strongest predictor of good IFN response (≥1 log₁₀ decline at week 4), OR = 26.5 (7.6–92.6) for C/C vs T/T and 16.4 (5.0–55.6) for C/C vs C/T.^[10] When week 4 response was included in the SVR model, IL28B genotype was no longer independently associated with SVR. This is consistent with the observation from the PR literature that IL28B genotype informs IFN responsiveness, but once IFN responsiveness is defined in real-time by a trial of treatment, IL28B genotype is no longer clinically informative.^[12]

IL28B genotyping has also been shown to be informative in the context of TVR therapy for treatment-naïve patients. Retrospective analysis of the association between IL28B polymorphism and treatment outcome was performed in a subset of the ADVANCE study population (n = 454/1088 [42%]).^[13] The strength of association between IL28B genotype and treatment outcome was attenuated in the TVR treatment arms compared to the PR control arm. Rates of SVR were higher in the TVR treatment arms compared to the PR control arm among both C/C and non-C/C patients (it should be noted that the response rate among C/C patients in the PR control arm was lower than that observed in SPRINT-2, Table 2). SVR rates increased relatively more in non-C/C patients than C/C patients (Table 2). Similar to SPRINT-2, C/C patients were more likely to be eligible for short-duration therapy by achieving an extended rapid virological response (eRVR), defined as HCV RNA undetectable at weeks 4 and 12) with 12 weeks of TVR (C/C 78% vs C/T 57% vs T/T 45%).^[13] SVR rates were very high in all patients who achieved an eRVR regardless of IL28B genotype (97% in CC patients and 88% in CT/TT patients). In patients who did not attain an eRVR, patients carrying the CC IL28B genotype had higher SVR rates (67% vs 38% for CT/TT patients). No data have yet been presented linking IL28B polymorphism to risk of resistance during TVR therapy, but given the key role for IFN responsiveness in controlling the emergence of resistance-associated variants (RAVs), this can be assumed.

In patients who have previously failed PR therapy, IL28B genotype is less informative for the outcome of TVR or BOC-based therapy. This was evaluated in retrospective analyses of the RESPOND-2 study of BOC therapy for prior relapsers and partial responders to PR therapy,^[10] and the REALIZE study of TVR therapy for prior relapsers, partial responders and null responders (Table 2).^[14] There was no significant association between IL28B genotype and treatment response noted in either study. This reflects again that IL28B genotype is no longer informative for SVR once IFN responsiveness is known, here defined by the prior course of PR therapy. IL28B genotyping may have a clinical role in real world patients where the prior treatment history is not well defined.

Can IL28B Genotype Identify HCV-1 Patients for Whom Dual Therapy With peg-IFN and RBV Should Remain First-line Therapy in the DAA Era?

The introduction of TVR and BOC represents a significant advance for the treatment of HCV-1. However, both drugs are very expensive. Modelling studies suggest that it may be possible to develop treatment algorithms in which PR is more cost-effective first-line therapy for a subgroup of patients. Patients who carry the C/C IL28B genotype achieve high rates of SVR, and a number of groups have suggested that in this population, PR is more cost-effective than universal triple therapy.^[15–17] These patients also avoid the added morbidity of triple therapy, although this must be weighed against the need for an extra 24 weeks of total treatment time (most C/C patients will require 48 weeks of PR, but would be eligible for 24 weeks of triple therapy). There are a number of caveats to these modelling studies. They may be strongly influenced by underlying assumptions, as well as the set price for drug, and therefore may not be universally applicable to all patients and regions. One particular issue pertains to efficacy assumptions for patients with advanced liver fibrosis. In the IDEAL study, the rate of SVR was only 41% in C/C patients with F3-4 fibrosis,^[5] and although there are little data concerning outcomes of triple therapy in this sub-population, it seems reasonable that triple therapy will be more effective, and cost-effective, for these patients.

IL28B Genotyping in Other Clinical Scenarios

Telaprevir and boceprevir are approved for the treatment of HCV-1 mono-infection only at present. The standard-of-care treatment for chronic infection with other HCV genotypes remains PR dual therapy. IL28B genotype is associated with the outcome of PR treatment for HCV-4, with a similar effect size to that seen in HCV-1.^[18–20] IL28B genotype is less relevant to the outcome of PR treatment for HCV-2 and HCV-3.^[21–26] HCV-2/3 are more IFN sensitive, and the data are conflicting. IL28B genotype may be most relevant for HCV-2/3 patients who are slow responders to PR (e.g. non-RVR patients).^[21] IL28B genotype is associated with the outcome of PR therapy for HCV-1 in the setting of HIV co-infection, where HIV does not seem to attenuate the association.^[27] IL28B genotype has been associated with the outcome of PR treatment for HCV-1 after liver transplantation, where both donor and recipient IL28B genotype influence outcome.^[28–31] IL28B genotype is strongly associated with the outcome of acute HCV infection, where patients with poor response IL28B genotypes, particularly if anicteric, are unlikely to spontaneously clear infection and should be considered for early antiviral therapy.^[32,33]

IL28B Genotyping and Next-generation Therapies Involving peg-Interferon

Emerging data suggest that IL28B genotype will remain relevant to the outcomes of DAA therapy when used in combination with a PR backbone. This has been the case for the emerging protease inhibitors (PIs), NS5A inhibitors (NS5I) cyclophilin inhibitors and non-nucleos(t)ide inhibitors (NNI) of the NS5B polymerase.^[34–39] In general, rates of on-treatment response as well as SVR have been higher in patients with the good response IL28B genotype, and the good response genotype has predicted for short-duration therapy using response-guided regimens. Very recent interim data from the ATOMIC study suggest that the nucleotide inhibitor (NI) sofosbuvir (GS-7977) may overcome the IL28B effect. 90% of patients treated for 12 weeks with sofosbuvir plus PR achieved an SVR12 (n = 52).^[40] Quadruple therapy regimens are also being evaluated. These involve the combination of two DAAs with PR. A small cohort of prior null responders was treated using the combination of daclatasvir (NS5I) plus asunaprevir (PI) plus PR.^[41] 9/10 patients carried a poor response IL28B genotype. 10/10 patients achieved an SVR12; and 9/10 had a SVR24. Larger phase-3 studies are required in larger cohorts to confirm these encouraging results. Therefore, it seems likely that it will be possible to overcome the effect of IL28B polymorphism with the combination of PR plus either a high potency, high genetic barrier to resistance drug (sofosbuvir), or the combination of 2 DAAs. Even so, it may be that IL28B genotype might be used to individualize treatment strategies, such that patients who carry the good response IL28B genotype might be eligible for shorter, simpler or cheaper regimens, and conversely poor responder patients might require longer therapy with multiple DAAs. Such individualized treatment algorithms are yet to be explored in detail.

Finally, a brief note about IFN-lambda. IFN-lambda (IL29) is a type-3 IFN and member of the same family of IFNs as IL28B. The type-3 IFN receptor has a limited distribution of expression, and peg-IFN-lambda is being developed as a less toxic alternative to peg-IFNα. In a small phase-II dose escalation study, investigating the efficacy and safety of peg-IFN-lambda plus RBV, compared to peg-IFNα plus RBV, virological responses were similar, and similar associations between IL28B genotype and treatment response were observed comparing the two IFN preparations.^[42]

IL28B Genotyping and IFN-free Therapy

Interferon-free therapy for HCV-1 is likely to be approved in the next 3–5 years. Recent data suggest that the good response IL28B genotype may represent an 'easy-to-cure' characteristic for certain IFN-free regimens also. The INFORM-1 study was the first study to demonstrate that IFN-free therapy could have a potent antiviral effect. Patients were treated with a combination of mericitabine (NI) and the danoprevir (PI) for 14 days, before follow-on PR therapy to 48 weeks. Analysis of the on-treatment viral kinetics in 15 patients during the 2 weeks of oral therapy revealed a significant difference in phase-II viral kinetics according to IL28B genotype,^[43] suggesting that IL28B genotype influences the rate of clearance of infected hepatocytes during IFN-free therapy. This might be consistent with the association between IL28B genotype and spontaneous clearance of HCV.^[44] SOUND-C2 is the largest study of IFN-free therapy to date (n = 362).^[45] SOUND-C2 evaluated the combination of BI 201335 (PI), BI 207127 (NNI) ± RBV (Fig. 1a). Interim results demonstrated a clear difference in SVR12 according to IL28B genotype in HCV-1a patients (Fig. 1b,c). The low SVR rates observed in HCV-1a non-C/C patients resulted from virological breakthrough in most patients, suggesting that IL28B genotype influenced the emergence of RAVs. Future studies of this regimen plan to enrol only HCV-1a patients who carry the good response IL28B genotype. This IL28B effect may be overcome as more potent agents and combination regimens emerge. Analysis of the ELECTRON study observed SVR4 in 22/25 (88%) treatment-naïve HCV-1 patients treated with sofosbuvir plus RBV for 12 weeks.^[46] 22 of the patients were infected with HCV-1a, and only 11/25 carried the good response IL28B genotype. Response rates with 'optimized' DAA combinations may be higher still. A recent study of the combination of sofosbuvir plus the daclatasvir reported SVR4 of 100% in 44 HCV-1 naive patients, with or without ribavirin.^[47] Such optimized regimens are likely to be very expensive, however, and may not be necessary for all patients. IL28B genotype may continue to be useful to identify those patients for whom such regimens are most appropriate as first-line therapy.

Figure 1. Interim results from the SOUND-C2 study 42. (a) Patients were randomized to one of five arms, involving variable durations of treatment with the protease inhibitor BI 201335 once daily, the NS5B non-nucleoside inhibitor BI 207127 BID or TID, plus or minus ribavirin. Interim analysis of SVR12 results was recently presented (with SVR4 results for the 40-week treatment arm). Overall results according to treatment arm: A – SVR12 = 59%, B – SVR12 = 61%, C – SVR4 = 56%, D – SVR12 = 68% and E – SVR 12 = 39% (treatment arm E was halted early because of concerns about RBV-free treatment); (b) SVR12 results in treatment arm D, according to HCV-1 subtype and IL28B genotype (rs12979860); (c) SVR results in treatment arms A–D, comparing non-C/C patients infected with HCV-1a (grey columns), with a composite group including C/C patients infected with HCV-1a and all HCV-1b patients (white columns).

Conclusion

IL28B genotype is the strongest pretreatment predictor of response to dual PR therapy for patients chronically infected with HCV-1. The approval of the first generation of NS3 protease inhibitors represented a significant advance for the field. The association between IL28B polymorphism and treatment outcome is attenuated in the setting of triple therapy, but IL28B genotyping continues to be useful for pretreatment counselling, with the good response IL28B genotype identifying the likelihood of an individual being eligible for short-duration therapy. IL28B genotype may also be relevant to strategies for maximizing cost-effectiveness. IL28B genotype is also associated with the response to IFN-free regimens, and C/C patients remain easier to cure, particularly in the setting of HCV-1a. Future regimens involving potent NI plus PR, quadruple therapy or combinations of best-in-class DAAs are likely to achieve very high SVR rates, and IL28B polymorphism will no longer predict treatment outcome. However, IL28B genotyping may remain useful if it can be used to individualize treatment strategies, identifying patients who can be successfully treated with shorter, simpler or cheaper regimens.

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Source

Provider and Patient Correlates of Provider Decisions to Recommend HCV Treatment to HIV Co-Infected Patients

From Journal of the International Association of Physicians in AIDS Care

Glenn Wagner, PhD; Karen Chan Osilla, PhD; Jeffrey Garnett, MPP; Bonnie Ghosh-Dastidar, PhD; Laveeza Bhatti, PhD, MD; Mallory Witt, MD; Matthew Bidwell Goetz, MD

Posted: 09/28/2012; J Int Assoc Physicians AIDS Care. 2012;11(4):245-251. © 2012 Sage Publications, Inc

Abstract and Introduction

Abstract

Despite low uptake of HCV treatment among HIV co-infected patients, few studies have examined the factors that contribute to provider decisions to recommend treatment. Surveys of 173 co-infected patients and their primary care providers, as well as patient chart data, were collected at three HIV clinics in Los Angeles; 73% of the patients had any history of being recommended HCV treatment. Multivariate predictors of being offered treatment included being Caucasian, greater HCV knowledge, receiving depression treatment if depressed, and one's provider having a lower weekly patient load and more years working at the study site. These findings suggest that provider decisions to recommend HCV treatment are influenced by patient factors including race and psychosocial treatment readiness, as well as characteristics of their own practice and treatment philosophy. With changes to HCV treatment soon to emerge, further evaluation of factors influencing treatment decisions is needed to improve HCV treatment uptake.

Introduction

Nearly 30% of HIV-positive Americans are co-infected with the hepatitis C virus (HCV). Hepatitis C virus is a leading cause of death among HIV co-infected patients,^[1–3] with annual HCV-related mortality expected to peak at 13 000 in 2030 in this population.^[4] However, despite a majority of co-infected patients having signs of liver disease progression,^[5,6] only a minority (~30%) are deemed eligible for treatment and less than 10% actually receive treatment.^[7–10] Low treatment uptake is often attributed to the limited efficacy (20%-50% response rate among co-infected patients) and high toxicity of pegylated interferon (PEG-IFN) and ribavirin (RBV),^[11–16] the current standard of care for HCV treatment, and yet treatment can essentially cure the disease.

Whether a patient starts treatment depends first on the provider's decision to recommend treatment. Despite the disparity between the need for aggressive HCV treatment and low treatment uptake, few studies have examined the factors that contribute to provider decisions to offer treatment. Nonetheless, we expect provider decisions to offer treatment are likely influenced by the following: severity and stage of liver disease; stability of the patient's HIV disease and presence of other medical comorbidities; perception of the patient's readiness to tolerate and adhere to treatment; and the provider's beliefs and attitudes related to the urgency and expected outcomes of treatment.

CD4 counts temporarily decrease during the course of HCV treatment;^[17] therefore, to limit the risk of developing opportunistic infections, the treatment is preferably started when the patient has a high CD4 count, low HIV viral load, and on a HIV antiretroviral therapy (ART).^[18] Treatment is typically recommended for patients with moderate liver disease,^[18,19] while patients with minimal disease progression are monitored and treatment are deferred.^[20] However, some view the latter as optimal for treatment,^[19] given the more rapid disease progression among co-infected patients^[21] and the greater likelihood of treatment success with milder disease.^[22,23] These conditions hold for the predominant genotype 1 patients for whom treatment is considerably less successful, while patients with genotype 2 or 3 are generally considered good treatment candidates because they respond to treatment much more favorably.^[18,19]

Patients must also be ready to adhere to and tolerate treatment. Drug abuse and mental illness are among the most common reasons for patients being ineligible for HCV treatment,^{[8–10,24–26]} as clinicians are concerned that treatment side effects (eg, depression, fatigue, flu-like symptoms) may lead to psychiatric deterioration, relapse into substance abuse, and treatment nonadherence and discontinuation. However, there is some evidence that treatment can be equally effective when patients have active psychiatric illness and are using drugs.^[27–31]

Provider training and characteristics of their clinical practice may influence HCV treatment decisions, including experience and perceived skills and comfort in managing HCV care and treatment with HIV co-infected patients, and attitudes related to HCV treatment efficacy and patient readiness.^[32,33]

We surveyed primary care providers at 3 HIV clinics in Los Angeles, along with the HCV co-infected patients who attended these clinics over 4 months to examine patient and provider characteristics associated with provider decisions to offer or defer HCV treatment.

Methods

Setting

Cross-sectional surveys were administered to primary care providers and HCV co-infected patients at 3 HIV clinics in Los Angeles: the Greater Los Angeles Veterans Administration (VA) Medical Center, Harbor-UCLA Medical Center, and AIDS Healthcare Foundation (AHF). The sites differ on a number of characteristics including the number of HIV patients (400–1700) and HCV co-infected patients (100–650), involvement of a liver specialist (at only 1 site), and HCV treatment rates (10%-40% of co-infected patients have received treatment). The clients at all 3 clinics are mostly racial/ethnic minorities and of lower socioeconomic status.

All 3 clinics provide comprehensive primary and subspecialty care, and thus patients receive their HCV care at the HIV clinic. At Harbor-UCLA, HIV and HCV primary care are provided predominantly by 4 nurse practitioners (NPs) who are supervised by 2 attending physicians, and treatment decisions are made jointly between the NPs and physicians. At the VA, HIV primary care is provided by 4 physicians, but HCV care and treatment for the co-infected patients are managed by one of the hospitals' gastroenterologists (with the assistance of a physician's assistant from the clinic) who comes to the clinic to conduct biweekly HCV care clinic sessions; the primary care physicians are consulted regarding HCV treatment decisions when warranted. The AHF clinic serves as the central HCV care site for the full system of AHF clinics in Los Angeles County; HCV care is provided mostly by 2 providers (1 physician and 1 NP), although the HCV care for some patients at the clinic are managed by their primary care provider. Support staff at the sites includes pharmacists, nurses, case managers, and social workers; 1 clinic has a mental health professional onsite, the others refer out for psychiatric consultation and treatment.

Sample

All clinic patients who were HCV co-infected, aged 18 or older, and speak English were considered eligible for the study. During the 4-month study enrollment period, the study coordinator at each site performed a chart review of all patients attending the clinic for a routine visit to identify those who were eligible. Patients were informed of the study while they were waiting to be seen by their provider; those who were interested in participating provided signed informed consent for completing a self-report questionnaire prior to leaving the clinic and allowing the study to abstract data from their clinic chart. All primary care providers were asked to participate and complete a self-report survey. Patients ($40) and providers ($50) were compensated for their participation, except at the VA where providers were not compensated due to institutional policy. The study protocol was approved by the Institutional Review Boards at RAND Corporation and the individual clinics.

Measures

For patients who had been offered HCV treatment, data were abstracted from the clinic visit closest and prior to the date at which HCV treatment was offered to the patient; for patients who had not been offered treatment, the most recent data prior to the date of survey were abstracted as these represent the latest indicators upon which a decision had been made to not recommend treatment. However, some variables, including all provider measures, could only be assessed at study enrollment with the study survey as indicated below.

Patient Variables

The HCV treatment status was abstracted from the clinic charts by first determining whether the patient had ever been treated. Among those who had not been treated, it was determined whether the provider had ever offered or recommended treatment. Dates were abstracted for time HCV treatment was offered and started, if applicable.

Demographic and background characteristics that were assessed by the study survey included age, gender, race/ethnicity, and education. The date the patient was diagnosed with HIV and HCV and the date the patient started receiving care at the study site were abstracted.

Stability of HIV was assessed with CD4 count, HIV viral load, and whether or not the patient was on ART. With regard to the stability of HCV and liver disease, measures included HCV viral load, genotype, and other laboratory markers related to liver functioning (aspartate aminotransferase [AST]/alanine aminotransferase [ALT], hemoglobin, absolute neutrophil count [ANC]). All of these variables were chart abstracted.

Psychosocial functioning was assessed with chart abstracted data related to whether the patient had a current diagnosis of depression or any other psychiatric disorder, and whether they were receiving any form of psychiatric treatment (eg, psychotropic medication, and counseling). We also abstracted data regarding alcohol and illicit drug use and history of injection drug use.

Adherence was assessed in the study survey by asking respondents to report whether or not they had missed any scheduled clinic appointments over the past 6 months, and those on ART were asked how many doses they had missed over the past 7 days (from study entry). Both measured were then converted into dichotomous variables based on whether or not they had missed any clinic appointments or missed any ART doses.

Knowledge of HCV was assessed at study entry with a scale adapted from that used by Doab et al.^[34] The 4-item scale evaluates the patient's understanding of HCV (eg, whether a cure is possible, HCV always leads to sickness, and HIV worsens HCV, and genotypes 2 and 3 respond best to treatment); a yes/no response option was used and a score was calculated summing the correct responses.

Provider Variables

Demographic characteristics included age, gender, and race/ethnicity. Medical practice and training characteristics that were assessed included training discipline (eg, physician, NP, physician's assistant), number of years at the clinic, number of HIV/HCV co-infected patients cared for, number of patients treated with PEG-IFN/RBV, and average patient load per week.

Perceived challenges regarding HCV care were assessed with a measure adapted from that used by Meredith et al;^[35] 11 items assess structural and patient factors that limit or challenge a provider's ability to provide optimal HCV care (eg, absence of a liver biopsy, mental health, or substance abuse counselors not readily available, patient reluctant to seek mental health or substance abuse treatment, patient's comorbid medical problems). Participants chose from 3 response options (ie, does not limit, limits somewhat, and limits a great deal). Mean item score was computed and higher scores indicate greater perceived challenges to providing optimal care. Internal reliability was high (α = .91).

Provider philosophy regarding patient psychosocial treatment readiness was assessed by asking the provider about their approach to treatment if a patient reported (1) current drug use or (2) moderate depression, ''but was otherwise a good HCV treatment candidate,'' in separate questions. Response options consisted of 5 scenarios that ranged from deferring treatment until the condition (drug use, depression) was treated and in remission, to counseling the patient about the risks of the condition for HCV treatment but letting the patient decide whether or not to start or defer treatment. Due to skewed response distributions, the responses were dichotomized into providers who believed that HCV treatment should only be offered after the patient was in remission versus more lenient views of readiness.

Provider's general threshold for patient treatment readiness was measured with a scale developed for the study, which assessed the likelihood that a provider would prescribe HCV treatment to a patient with various conditions that could affect the patient's readiness or appropriateness for treatment (eg, decompensated liver disease, genotype 2 or 3, active depression, smokes marijuana regularly, etc). Providers responded on a 5-point Likert-type scale ranging from very likely to very unlikely, with regard to 14 specific conditions; internal reliability was high (α = .86). The mean item score was calculated and higher scores represented a higher threshold for determining patient readiness for treatment.

Data Analysis

Descriptive statistics were used to examine the response distributions of variables and a number of variables were converted from continuous to dichotomous variables based on clinical significance (eg, CD4 count ≤200 cells/mm³; HIV viral load ≤400 copies/mL; genotype 1 or 4 versus 2 or 3) or the skewed distribution of responses (eg, none vs any missed ART doses). Bivariate statistics (independent 2-tailed t tests, chi-square tests) were used to examine the correlates of whether or not the patient was offered HCV treatment. Variables that were significant at P <.05 level in the bivariate analysis were then entered into a logistic regression model as independent variables, with the indicator of whether treatment was offered being the dependent variable. To account for potential correlations among outcomes of patients in the same clinic that share a provider, we computed robust standard errors for the regression models to account for intracluster correlations within provider.

Results

Sample Description

A total of 173 patients were surveyed: 97 from AHF, 41 from the VA, and 35 from Harbor-UCLA. Most (87%) participants were male, mean age was 49.0 (SD = 9.1), 60% had at least some college education, 69% were racial/ethnic minorities (including 41% who were black and 21% who were Hispanic), 38% identified as heterosexual, and 58% had a history of injection drug use. Most had been diagnosed with HIV for several years (mean = 13.5 years) and had been receiving care from the study site for an average of 7.8 years. Mean time since HCV diagnosis was 7.1 years, and 78% had an HCV genotype of 1 or 4.

Fourteen primary HCV care providers completed the survey, accounting for the HCV care providers of 155 (90%) of the patient participants. Among the 14 providers surveyed, half were male, 57% were Caucasian, and 69% were physicians. The mean number of years of practice at the clinic site was 11.1 (SD = 6.1; range: 2–19); each provider sees an average of 34 HIV patients (HCV and non-HCV) per week (SD = 21; range: 5–90), and the mean number of co-infected patients that each provider had treated with interferon was 21 (SD = 19; range: 4–60).

Factors Associated With Recommending HCV Treatment

Of the 173 patients, 127 (73%) had been offered or recommended HCV treatment; 79 (62%) accepted the recommendation and started treatment, and the factors associated with this patient decision are presented elsewhere.^[36] For those who had been offered treatment, this event took place an average of 6.2 years (SD = 5.8 years; range: 1 week to 23.0 years) after HCV diagnosis and 2.3 years (SD = 2.7 years; range: 1 week to 10.9 years) prior to the study survey. The proportion of surveyed patients at each site who had been offered treatment was 85% at Harbor-UCLA, 71% at AHF, and 66% at the VA; these site differences were not statistically significant (p = .115).Table 1lists the characteristics of the subgroups that had been offered (N = 127) and not offered (N = 46) HCV treatment. Patients offered HCV treatment were more likely to have CD4 counts above 200 cells/mm³ and lower HIV viral loads; similarly, there were marginal trends (p <.10) for this group to have higher mean CD4 count and an undetectable HIV viral load. Other patient variables associated with being offered treatment included greater HCV knowledge, receiving depression treatment if depressed (compared to untreated depression), and not being black or Hispanic.

The providers of patients offered treatment were more likely to be female, to have worked longer at the clinic site, see fewer patients on a weekly basis, and to have a lower threshold for indicators of patient readiness for treatment (seeTable 1). Provider-related correlates that had marginal significance included fewer perceived challenges to providing optimal HCV care and the treatment philosophy that HCV treatment did not require that a drug using patient had entered a drug treatment program and been in remission.

In logistic regression analysis, significant independent predictors of being offered treatment included the patient not being black or Hispanic, having greater HCV knowledge, and receiving depression treatment if depressed, as well as the patient's provider having a lower weekly patient load and more years in practice at the clinic; the patient having a CD4 count >200 cells/mm³ was marginally significant as a predictor (seeTable 2).

Discussion

Findings from this study reveal that a majority of HIV/HCV co-infected patients are recommended PEG-IFN/RBV treatment by primary care providers over the course of receiving care, although like other studies,^[7–10,37] only a minority of patients had actually received treatment. The data reveal that factors influencing provider decisions to offer or defer treatment are multifaceted. Provider HCV treatment decision making is influenced by patient factors including the patient's stability of HIV disease and psychosocial readiness for treatment. However, the provider's decision process is not only influenced by patient characteristics but also aspects of the provider's clinical practice, attitudes toward HCV treatment and philosophy about patient treatment readiness.

Having a CD4 count above 200 and low HIV viral load were bivariate correlates of having been offered treatment, as treatment response is positively correlated with CD4 count,^[38] and PEG-IFN/RBV can temporarily deplete CD4 counts,^[17] rendering clients vulnerable to opportunistic infections if they have severe immunosuppression. However, some patients with CD4 counts below even 100 had been offered treatment, which is consistent with some Hepatitis Research Network clinical trials, and this highlights how even patients whose immune systems are severely compromised can still be considered appropriate for treatment. Also, the vast majority of all participants were on ART when the treatment was offered, which can help limit the risks associated with treatment of patients with low CD4 counts. Provider decisions to offer treatment were not related to our measures of HCV disease, including HCV genotype and HCV RNA, which are correlates of treatment response;^[11–13] however, we did not have measures of liver fibrosis.

Psychosocial indicators of patient treatment readiness, such as mental health, substance use, and adherence to clinical appointments and ART have been shown to be associated with HCV treatment eligibility in several other studies.^[9,10] However, in this study, depression treatment status for current depression and patient knowledge of the goals and potential costs and benefits of treatment were the only psychosocial variables associated with whether the treatment was recommended. Past history of depression, or current depression that was being managed with treatment, was not the limiting factor to being recommended treatment, which is consistent with data suggesting that such factors are not necessarily impediments to HCV treatment response.^[27–29] Greater HCV knowledge may be an indicator of patient self-advocacy or motivation for treatment,^[32] at least in the perception of providers, and may explain in part its relationship to the offering of treatment; however, this relationship could also be bidirectional, with patients who are offered treatment consequently developing greater knowledge about the disease and treatment from their provider or through actively seeking out information.

The other patient characteristic associated with treatment being offered was race or ethnicity. African American and Hispanic patients, who together comprise the majority of the study sample, were less likely to be offered HCV treatment compared to the Caucasian patients, even after controlling for other significant correlates. This finding may reflect health disparities that are commonly seen among minority ethnic groups in the United States.^[39] However, data show lower response rates to PEG-IFN/RBV among African American and Hispanic patients,^[40–42] and this could tip the cost–benefit ratio in the favor of the potential burden on patients in the minds of providers.

Provider decisions of whether to recommend HCV treatment to an individual patient are not only predicted by characteristics of the patient but also by provider-related variables. Having a smaller weekly patient load was associated with a greater likelihood of recommending treatment, which may be a proxy for how availability of time for the provider to manage what is often complex treatment can influence provider treatment decisions. Years in practice at the study site was also associated with provider decisions to offer treatment, suggesting that greater experience in providing care may translate into greater comfort offering and managing HCV treatment. In bivariate analysis, treatment offers were more likely when the provider had a lower threshold for gauging patient readiness, which may also be an indicator of how urgent the provider considers the HCV treatment in general.^[33]

The primary limitation of the study findings is the largely retrospective nature of the study design, and associated reliance on available chart abstracted data or current assessments that may not be reflective of the conditions present when the treatment was offered. While a prospective design that measured variables at the time the treatment decision was actually made would be optimal, such a design was not feasible in terms of time and resources. The findings cannot be considered generalizable to all co-infected patients, although nearly all coinfected patients who attended the clinic during the study enrollment period did participate. Also, we were unable to reliably abstract data regarding medical comorbidities from patient's charts and therefore cannot account for the role of this important factor in provider decision making. Furthermore, with newer, more efficacious (but perhaps even more burdensome) treatments soon to be available,^[43] it is unknown how this will affect provider decisions about the balance of the costs and benefits of treatment.

With HCV treatment rates continuing to be steadily low among HIV co-infected patients, the results of this study highlight both patient and provider variables that influence provider decisions to recommend treatment. Program administrators and intervention developers with an intent to increase treatment uptake should focus not only on factors that improve patient readiness for treatment but also on provider attitudes and comfort level regarding treatment, as well as patient load and time availability. With changes to HCV treatment soon to emerge, and its uncertain effects on both the benefits and burden associated with treatment, further evaluation of factors influencing treatment decision making and treatment uptake will be needed to promote optimal HCV care management among HIV coinfected patients.

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Source

Don't rule out IFN/ribavirin for HIV patients with hep C cirrhosis: study

Publish date: Sep 27, 2012

Clinical

Last Updated: 2012-09-27 18:45:28 -0400 (Reuters Health)

By Anne Harding

NEW YORK (Reuters Health) - In HIV patients with hepatitis C, compensated cirrhosis should not be considered a contraindication to therapy with pegylated interferon (peg-IFN) and ribavirin, researchers say.

As is the case in patients without HIV, peg-IFN plus ribavirin is more effective against hep C in HIV patients who are free of cirrhosis, the researchers reported online September 5th in Clinical Infectious Diseases.

"In spite of that, this antiviral combination still leads to an appreciable rate of sustained virological response in cirrhotic patients carrying HCV genotype 3," Dr. Jose A. Mira and Dr. Juan A. Pineda of Hospital Universitario de Valme in Seville, Spain, who helped conduct the new study, told Reuters Health.

While compensated liver cirrhosis is known to predict worse response to IFN plus ribavirin in patients who are only infected with HCV, the researchers note, just one small study has looked at the issue in individuals who are co-infected with HIV. That study, which included 41 patients, found similar rates of sustained viral response (SVR) for patients with and without cirrhosis.

To investigate further, Dr. Mira, Dr. Pineda and their colleagues looked at 629 HIV/HCV co-infected patients receiving treatment with peg-IFN and ribavirin, all of whom had undergone a liver biopsy or liver stiffness measurement within a year of beginning treatment. Twenty-eight percent had cirrhosis.

Intention-to-treat analysis showed SVR in 25% of patients with cirrhosis and 39% of cirrhosis-free patients (p=0.001). Among the patients with cirrhosis, SVR occurred in 14% of those with HCV genotype 1; 47% of patients with HCV genotype 2-3; and 30% of patients with HCV genotype 4.

Part of the difference in response could have been due to the fact that 17% of the cirrhotic patients discontinued treatment due to adverse events, compared to 8% of those without cirrhosis, the researchers note.

"We think that the efficacy of pegylated interferon plus ribavirin in HIV/HCV co-infected patients with HCV genotype 4 depends primarily on other known predictors of response to HCV therapy in these patients, specifically the IL28B genotype," Dr. Mira and Dr. Pineda said via email.

"In fact, in another study carried out in our research group (Mira JA et al. AIDS 2012; 26:1721-1724), we found that only IL28B genotype CC was associated with sustained virological response in this population," they continued. "There are data supporting that interferon-mediated immune response against HCV, which is associated with IL28B genotype, has a different impact depending on HCV genotype. To confirm this hypothesis, a study with a higher number of HCV-4-infected patients would be required."

Despite the fact that patients co-infected with HIV and HCV who have compensated cirrhosis are a "hard-to-cure population," the researchers add, HCV therapy should be a priority in these patients, "given that once decompensated cirrhosis emerges, death due to liver failure occurs in the short-term."

SOURCE: http://bit.ly/PIZa5p

Clin Infect Dis 2012.

Source

Companies may be holding back HCV cure

Hepatitis-C (HCV) is a virus that attacks the liver – it can be deadly and its effects (fatigue, nausea, weight loss, body aches) can be disabling. The disease can also behave like a silent killer, destroying a person’s liver over years without any symptoms. The Centers for Disease Control (CDC) recently issued a warning and recommends that everyone between the ages of 45 and 65 be tested -- potentially millions more could have the virus and not even know it. This story is about a cure for the disease -- a cure patients can’t get access to.

By Angela Covo | 21 de septiembre de 2012

San Antonio.- Hepatitis-C (HCV) is a virus that attacks the liver – it can be deadly and its effects (fatigue, nausea, weight loss, body aches) can be disabling. The disease can also behave like a silent killer, destroying a person’s liver over years without any symptoms. The Centers for Disease Control (CDC) recently issued a warning and recommends that everyone between the ages of 45 and 65 be tested -- potentially millions more could have the virus and not even know it. This story is about a cure for the disease -- a cure patients can’t get access to.

By Angela Covo, angela.covo@gmail.com

Last April, Bristol-Myers Squib (BMS) announced they achieved a 100 percent cure rate for HCV.

Using their HCV drug Daclatasvir together with an experimental drug from Gilead Sciences (GS) known as GS 7977 in phase 2 trials, the companies achieved a major milestone -- the 100 percent cure rate for HCV: type 1.They had similar results with the same drugs for HCV: type 2 and HCV: type 3, achieving a 91 percent cure rate.

The results of the all-oral combination are a huge advance, not only thanks to the remarkable results, but because they had mild side effects (think mild to moderate fatigue) that were well tolerated.

News of the cure moved the stock market and thrilled the medical world, which had been struggling with chemo-style therapies that were debilitating and not always effective.

In San Antonio, Margaret Dudley, who just missed entry to the successful study by a week, was overjoyed to learn a cure was found.

Almost exactly a year ago, Dudley went to see her doctor. She had been tired and just not feeling well for a couple of years and finally decided she needed a checkup. She learned she had HCV:type 3 and the treatment options were harsh with uncertain results. She has dropped more than 30 pounds since then – but she works hard not to let it hold her back.

And it’s a good thing Dudley is a fighter, because she decided to champion the millions of patients who won’t be getting the cure.

It turns out that BMS and GS have no plans to collaborate and move forward with phase 3 trials required to get the cure to market and the millions who desperately need the medication.

La Prensa contacted both companies by phone and by email. We asked both companies if they had plans to go forward with the phase 3 trials, but they would only comment they were trying to find the best options from all ongoing studies.

Cara Miller, spokesperson for Gilead Sciences, did not address the question and responded: “We are looking at the results from all of the ongoing studies to better understand what might be the best option or options for advancing as quickly as possible the best all-oral regimen.”

Bristol Myers-Squib at least acknowledged the existence of the phase II trials, but could not explain why the companies will not collaborate for the sake of the patients.

“We are committed to driving advances both through internal development and external collaborations to get the best treatment to patients. While this external collaboration was limited to Phase II, we have other external collaborations as well as many clinical trials involving our internally developed compounds, including a robust development program for our lead compound Daclatasvir, which continues to drive advances in the research and development of all oral combinations in HCV …,” Cristi Barnett, spokesperson for BMS, wrote in an email.

If the two companies do not collaborate, a new successful cocktail of drugs that works could take years – time many patients don’t have.

So Dudley, who likely picked up the virus at Permanent Cosmetics by John Shumate, explains she has “spent every waking moment since working on getting the word out.”

She founded the HCV Coalition for the Cure (hepc-cured.com) to lead the campaign to bring both companies to the table so they can move forward with their successful collaboration and get the cure for HCV to the market. Through the Coalition website, she manages a petition which has more than 7100 signatures.

“I hope people will be as outraged by this as we are and will take the time to visit the website and sign the petition. To think the cure everybody has been praying for is here, but not available because of corporate greed is shocking – why are they still chasing the cure when they’ve already found it?” Dudley said.

She also wants people to understand that HCV is not only spread by needles. It can happen when you share a razor, get a tattoo, permanent cosmetics or even a manicure when the utensils are not properly sanitized. Anybody can get HCV.

Just a few weeks ago, BMS halted another trial for an all-oral treatment for HCV using their Daclatasvir and a different drug because one patient died of heart failure and several others were hospitalized.

We contacted the Food and Drug Administration to ask if it was ethical to subject patients to potentially dangerous experimental treatments when an actual cure is available.

Stephenie Yao, a spokesperson for the FDA, responded, “We're not able to comment on this issue. Federal law prohibits our releasing information about any investigational new drug application.”

Dr. Robert Lanford of Texas Biomedical Research right here in San Antonio has been looking for the answer to HCV for 28 years.

“I’ve been working on the virus for 28 years – and we know we’re going to have a cure. There will be a whole series of cocktails because it may not be one size fits all,” he explained.

Still, Lanford agrees many patients can’t wait that long.

“It would be a good thing to allow 7977 and Daclatasvir to proceed to phase III at least temporarily … Gilead has a lot of good drugs to put into that cocktail but it’s still a question of time,” he said.

To learn more and to sign the petition, visit hepc-cured.com.

PHOTO: Founder of HCV Coalition for the Cure, Margaret Dudley accompanies her spouse, Gary Dudley, president and cofounder of SWBC, to the Alamo Colleges Open House earlier this week. Mrs. Dudley is working on getting out the news about a cure for HCV. Visit hepc-cured.com for more info. (Photo by Speedy Gonzalez)

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Despite Setbacks, Optimism on Drugs for Hepatitis C

Science 21 September 2012:
Vol. 337 no. 6101 pp. 1450-1451
DOI: 10.1126/science.337.6101.1450

News Focus

Infectious Disease

Jon Cohen

Summary

Bristol-Myers Squibb recently pulled the plug on a drug against hepatitis C virus, one of the furthest along in clinical trials of a new class of agents against HCV, because of toxicity. Researchers are now trying to understand why the drug failed and the impact it might have on other drugs in the pipeline—some of which work through similar mechanisms. Most are cautiously optimistic, however, that other drugs in development will pan out and that the failure will not seriously dent hopes of curing the disease with a short, relatively safe course of treatment that would work worldwide.

Read the Full Text (subscription required)

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New health education website launched

Thursday, 20 September 2012 21:41 AJPress

A NEW health education website, HepBsmart.com, sponsored by Gilead Sciences, Inc., intended for audiences in the United States, is launching Friday, September 7. HepBsmart.com contains practical information about chronic hepatitis B (CHB), a potentially life-threatening liver disease that affects an estimated two million people in the United States and is the leading cause of liver cancer.

Chronic hepatitis B is caused by a virus and can slowly damage the liver, without causing obvious symptoms. Chronic hepatitis B can be diagnosed with a simple blood test, prevented with a vaccine, and managed with appropriate care – but alarmingly, most people living with the disease don’t know they are infected.

Without treatment, 1 in 4 people with CHB may die of disease-related complications. The impact of chronic hepatitis B in the United States is more severe among Asian American communities.

HepBsmart.com features:

• Information on how to prevent CHB, testing for the disease, and management of CHB.

• An innovative animated video depicting a CHB patient’s journey from diagnosis to care (available in 14 languages with subtitles).

• Educational brochures in 14 languages, including Chinese, Korean, Vietnamese, and Tagalog among others.

HepBSmart.com is an educational website created by Gilead Sciences, a maker of medicines for chronic hepatitis B. The website is part of Gilead’s ongoing effort to raise community awareness of chronic hepatitis B.

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Idenix Pharma: Guilty By Association

By Nathan Sadeghi-Nejad 09/21/12 - 07:48 AM EDT

Stock quotes in this article: IDIX, BMY

NEW YORK (TheStreet) -- Thursday, Idenix Pharmaceuticals (IDIX) presented investors with a detailed update on IDX-184 and the earlier-stage IDX-19368, two hepatitis C drug candidates that were placed on clinical hold by the FDA last month.

Idenix' new investor slide deck, also filed as an SEC Form 8-K, offers lots of detail about the compounds' status and highlights management's admirably open-minded communication style. Unfortunately, I'm not convinced the company's woes will be easily fixed.

IDX-184 has had no safety issues to date. Nonetheless, structural similarities between Idenix's IDX-184 and Bristol-Myers Squibb's (BMY) BMS-094 were sufficient to warrant concern. Clinical development of the latter drug, which Bristol-Myers acquired in the $2.5 billion takeover of Inhibitex, has been discontinued because of severe cardiovascular toxicity.

The FDA's clinical hold -- effectively a "stop work" order triggered by unexpected safety issues -- suggests that regulators are also concerned about the safety of IDX-184. In order to get the clinical hold lifted and continue development, Idenix must now convince the FDA that IDX-184 doesn't put patients' lives at unnecessary risk. (At least one patient in the Bristol-Myers study died.)

Continue reading full article here …

Centre for Public Health report featured on BBC and ITV

21 September 2012

The outstanding research from LJMU’s Centre for Public Health has once again been recognised by the national media.

The report ‘Burden of Liver Disease and Inequalities in the North West of England’ published by the Centre and the Health Protection Agency North West in collaboration with the National Treatment Agency North West, North West Cancer Intelligence Service and NHS North West, presents data on liver disease and has received coverage on BBC and ITV, among others.

Liver disease currently accounts for 2% of all deaths in England, and its main causes are alcohol, hepatitis B and C, and fatty liver disease by age, gender, deprivation and geography.

The key findings from the report are that:

• Numbers of men dying from liver disease each year in the North West are up 20% since 2005 (27 per 100,000 population in 2005 to 30.9 per 100,000 population in 2010), and deaths occur at a relatively young age (peak ages are 55 to 64 years). Numbers of deaths among women have remained fairly constant over time.
• Deaths from liver disease are 42% higher in the North West compared to England (23.5 per 100,000 in North West, 16.6 per 100,000 in England, in 2010) and there are substantial variations within the region (42.7 per 100,000 population in Blackpool and 8.2 per 100,000 population in Eden in 2006 to 2010).
• Hospital admissions for liver disease as the primary diagnosis increased 30% between 2005/6 and 2010/11 (from 6,413 to 8,334).
• Alcohol-related liver disease1 accounts for 47% of liver disease deaths in men and 43% in women and affects more people living in deprived areas.
• Hospital admissions due to fatty liver disease2 as a primary or secondary diagnosis have increased 182% (from 913 in 2005/6 to 2,578 in 2010/11).
• Hepatocellular cancer3 accounts for 15% of male and 5% of female deaths from liver disease and chances of survival at five years for patients diagnosed with hepatocellular cancer are worse in the North West than in other areas of England (8.3% in the North West, 12.3% for England).
• Laboratory reports of hepatitis C4 have increased 123% in the North West over the last decade (from 898 in 2000 to 2000 in 2010) and hospital admissions for hepatitis C as a primary or secondary diagnosis increased 65% since 2005 (from 2,929 in 2005 to 4,841 in 2010). 65% of injecting drug users tested positive for the hepatitis C virus in 2010.

Professor Martin Lombard, National Clinical Director for Liver Disease, commented: “Liver disease is emerging as one of the major health problems for our population. People can be at risk of developing liver disease from an early age and may not even know they have a liver problem until the disease is at an advanced stage. The main causes are alcohol, obesity and hepatitis viruses and there is a lot people can do to avoid liver disease or prevent its progression by looking after themselves, paying particular attention to their diet and reducing their habitual alcohol consumption. This report highlights the fact that in the North West liver disease has reached a very significant level, getting to the stage where most residents will know someone, or know someone who knows someone else, who has died of liver disease or has a health issue from liver disease. The report is a call to action to everyone interested in health and well being, to tackle this issue."

Professor Mark Bellis, Director of the Centre for Public Health, commented: “The increasing levels of obesity and alcohol consumption we have seen over recent decades have resulted in rising levels of liver disease across the North West, while much of Europe has seen levels fall. Liver disease is the tip of a growing iceberg of ill health resulting from poor diet and excessive drinking and a stark reminder that so far we have failed to tackle either.”

To see some of the coverage generated by the report, go to:

http://www.bbc.co.uk/news/uk-england-19632951

http://www.itv.com/news/granada/2012-09-18/new-report-reveals-rising-burden-of-liver-disease/

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The odds are too high to ignore

PUBLISHED: 19 Sep 2012 00:06:21 | UPDATED: 20 Sep 2012 00:45:58PUBLISHED: 19 Sep 2012

If 100 people are infected with hepatitis C, about 25 will clear the virus spontaneously and completely within six months of infection. They will still have antibodies in their blood and if exposed again can become re-infected.

The other 75 will develop a chronic infection and be at risk of cirrhosis of the liver. About 20 will experience no noticeable illness but will still be infectious and can transmit the virus to others.

About 15 years later, 40 to 60 of those with chronic infection will experience symptoms and develop some liver damage.

By 20 years, up to 10 of those with liver damage will develop cirrhosis. Of them, up to half will have liver failure or develop liver cancer.

The length of time from initial infection is a major determinant of the risk of cirrhosis and cancer.

Other determinants include alcohol intake, being male, being overweight and the age of infection. Beyond 40, the disease progresses faster. Hepatitis B and HIV are also factors.

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Race For Next Hepatitis C Drug Gets Tighter

A Bristol-Myers Squibb scientist conducts lab research. The company halted its phase-two study of a hepatitis C drug after a patient death.

By AMY REEVES, INVESTOR'S BUSINESS DAILY

Posted 09/18/2012 05:52 PM ET

The race for the next blockbuster hepatitis C drug is still at full speed, but the field is thinning out.

Last month, Bristol-Myers Squibb (BMY) officially pulled the plug on its candidate, BMS-986094, after it had to halt a phase-two study after the death of one of its subjects from heart failure. The Food and Drug Administration was so concerned about this development that it also put a hold on two similar drugs by Idenix (IDIX), punishing that biotech's already low-priced stock.

Bristol-Myers said it will take a $1.8 billion charge to end the study, which resulted not only in the one death but in the hospitalization of eight other people. "While the cause of these unexpected events, which involve heart and kidney toxicity, has not been definitively established, the company has determined that it is in the best interest of patients to halt development of BMS-986094," the company said.

Yet, the Centers for Disease Control at about the same time affirmed that the potential market for such a drug is huge. On Aug. 16, the CDC released new guidelines urging everyone born between 1945 and 1965 — baby boomers — should be tested for HCV, the hepatitis C virus. Previously it had only recommended testing for people who've injected illegal drugs or who received blood or organ donations before these things were properly screened. But the new report noted the "limited effectiveness" of this approach, and concluded that everyone from that generation notorious for its drug use and sexual activity is at sufficient risk for a test.

"With an HCV antibody prevalence of 3.25%, persons born during 1945—1965 account for approximately three-fourths of all chronic HCV infections among adults in the United States," the report said.

The CDC estimated that 2.7 million to 3.9 million Americans are living with HCV, though many don't realize it because the virus can germinate without causing symptoms for years. If left untreated, though, it can end up causing fatal liver damage.

Current treatment relies on pegylated interferon, which leaves much to be desired, so in the past year massive amounts of money have gone into creating better alternatives. Bristol's ill-fated drug came with its $2.5 billion buyout of Inhibitex in February, amid a rush by drugmakers to acquire hot HCV candidates. Not long before, Roche (RHHBY) shelled out $230 million for Anadys, and, in the most jaw-dropping development, Gilead Sciences (GILD) paid nearly $11 billion for Pharmasset.

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Fructose Intake Linked to Liver Damage

By Michael Smith, North American Correspondent, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

In obese patients with diabetes, a high intake of fructose – a sugar widely used in soft drinks and other foods – is associated with impairment in cellular energy balance that may play a role in liver disease, researchers said.

A small pilot study also suggested that elevated uric acid levels in response to a fructose challenge might be a marker for energy depletion, according to Manal Abdelmalek, MD, of Duke University Medical Center, and colleagues.

The findings suggest that energy depletion in the liver might be a factor in the development and progression of nonalcoholic fatty liver disease (NAFLD), Abdelmalek and colleagues reported in the Sept. issue of Hepatology.

Increasing rates of NAFLD in the U.S. parallel those of type 2 diabetes and obesity, the researchers noted, while at the same time fructose consumption has more than doubled in the past 30 years.

The main player in that latter increase, Abdelmalek and colleagues wrote, is the use of high-fructose corn syrup -- a mixture of glucose and fructose -- to sweeten such foods as bread, cereal, and soft drinks.

"Given the concurrent rise in fructose consumption and metabolic diseases," Abdelmalek said in a statement, "we need to fully understand the impact of a high-fructose diet on liver function and liver disease."

Research has shown that in overweight or obese adults, fructose-sweetened beverages (but not their glucose-sweetened counterparts) increase lipogenesis, promote dyslipidemia, impair insulin sensitivity, and increase visceral fat.

There's also evidence linking fructose-sweetened beverages with the development of diabetes, so it's "plausible that habitual and/or excessive fructose consumption" might increase the risk of NAFLD and also exacerbate liver injury and promote fibrosis progression, the researchers wrote.

To investigate, they looked at the 244 participants in the Action for Health in Diabetes Fatty Liver Ancillary Study, where they have estimated dietary fructose consumption and measured both hepatic adenosine triphosphate (ATP) -- a compound involved in the energy transfer between cells -- and uric acid levels.

Abdelmalek and colleagues hypothesized that people with higher fructose intakes would have lower ATP, and that those with higher uric acid would be at higher risk for ATP depletion in the liver, following a fructose challenge.

To test those notions, they performed magnetic resonance spectroscopy and conducted a fructose challenge (with an intravenous bolus of the sugar) in a subset of 25 participants.

For the analysis, habitual fructose intake was classified as low or high -- below or above 15 g per day. The cutoff is about the same as Americans would have consumed -- mainly from fruits and vegetables -- before 1900, the researchers noted.

In addition, uric acid levels were deemed to be high if they were above 5.5 mg/dL of serum.

In the study subset, Abdelmalek and colleagues found that:

• 64% had NAFLD, defined as more than 5% fat in the liver on magnetic resonance spectroscopy.
• Average fructose consumption was 22.3 g per day in the high-intake group and 11.13 in the low-intake group, a significant difference (P<0.001).
• Total energy intake averaged 1,716 calories a day in the high-fructose group and 1,497 in the low-fructose group (P=0.046).
• Serum uric acid averaged 6.39 mg/dL in the high-uric acid group versus 4.35 in the low group (P<0.001).

The effect of the fructose challenge, they reported, was to lower hepatic ATP sharply before a rebound after 50 minutes.

Those with a habitually high fructose intake, they reported, began with lower hepatic ATP on average than those in the low-fructose group. They reached a lower nadir during the challenge, and their rebound was not as complete.

The pattern was similar for those with high uric acid levels, the researchers reported.

"High fructose consumption and elevated levels of uric acid are associated with more severe depletion of liver ATP," Abdelmalek said, adding that the findings suggest that increased dietary fructose intake impairs energy balance in the liver.

The researchers cautioned that the study was small, was not powered to determine significance, was cross-sectional without a control group, and had no randomized intervention.

Further research is needed, they added, to understand the role of uric acid and fructose in the development and progression of NAFLD.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Disorders and the Johns Hopkins University School of Medicine General Clinical Research Center. The journal said Abdelmalek did not make any disclosures.

Primary source: Hepatology
Source reference:
Abdelmalek MK, et al "Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes" Hepatology 2012; 56: 952-960.

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Docs Don't Trust Pharma-Funded Studies

By Nancy Walsh, Staff Writer, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Physicians tended to be skeptical of clinical trials funded by the pharmaceutical industry, even if they considered the study design to be methodologically rigorous, an analysis based on hypothetical studies found.

In a survey of board-certified internists, participants expressed more willingness to prescribe a drug evaluated in a highly rigorous hypothetical study (OR 3.07, 95% CI 2.18 to 4.32, P<0.001) than if the trial design was considered to have low methodologic rigor, according to Aaron S. Kesselheim, MD, JD, of Harvard Medical School in Boston, and colleagues.

Yet they were less likely to view a trial as having a rigorous design if industry funding was disclosed -- regardless of the methodologic quality of the study -- than if no funding source was provided (OR 0.63, 95% CI 0.46 to 0.87, P=0.006), the researchers reported in the Sept. 20 New England Journal of Medicine.

Prominent medical journals have made major efforts in recent years to provide conflict of interest information for published studies, but considerable skepticism remains on the part of clinicians regarding potential bias.

To explore the effects of funding disclosures on physicians' perceptions of study credibility, the researchers asked 263 physicians to examine a series of abstracts describing drug trials for three hypothetical newly approved drugs, and to rate their impressions of the studies and their willingness to accept the results.

For each of the three drugs, the researchers constructed an abstract that reflected a highly rigorous trial -- being randomized, double-blinded, having a large sample size and long follow-up, and providing safety data -- as well as abstracts that would be considered as reflecting medium- or low-level rigor.

All the abstracts reported that the results were statistically significant.

Each abstract then was amended to report no funding, industry funding, or support by the National Institutes of Health (NIH).

The median age of survey participants was 48, and more than two-thirds were men.

Participants reported having read a median of four journal abstracts within the previous month that related to prescription drugs.

When presented with simulated studies having low, medium, or high degrees of rigorous design, clinicians were likely to correctly identify high-quality trials (OR 3.95, 95% CI 2.81 to 5.55, P<0.001).

They also reported being more confident in the results of studies they considered highly rigorous (OR 2.73, 95% CI 1.95 to 3.82, P<0.001), and that they would be more willing to prescribe drugs evaluated in these trials.

But they reported having less confidence overall in studies sponsored by industry (OR 0.71, 95% CI 0.51 to 0.98, P=0.04), and being less likely to prescribe drugs from those studies (OR 0.68, 95% CI 0.49 to 0.94, P=0.02).

Participants also said they were less willing to consider industry-sponsored studies as being "important" than those sponsored by NIH (OR 0.59, 95% CI 0.42 to 0.82, P=0.002).

Physicians' unwillingness to prescribe drugs studied in industry-sponsored trials was greater regardless of whether the study design was high versus medium in rigor (P=0.87) or medium versus low rigor (P=0.83).

Conversely, they were more likely to prescribe a drug evaluated in a trial sponsored by NIH regardless of whether the study design was high versus medium rigor (P=0.81) or medium versus low rigor (P=0.56).

And regardless of sponsorship disclosure or the degree of methodologic rigor, physicians who felt strongly that drug company funding had an influence on trial results were less likely to prescribe a drug than were physicians who disagreed that funding played a role in study outcomes (OR 0.58, 95% CI 0.37 to 0.91, P=0.02).

The findings that the surveyed physicians held negative views of industry-sponsored clinical trials had "important implications," according to the researchers.

"Despite the occasional scientific and ethical lapses in trials funded by pharmaceutical companies, it is also true that the pharmaceutical industry has supported many major drug trials that have been of particular clinical importance," they observed.

The researchers commented that they found it "reassuring" that participants in their survey clearly were interested in the methodologic quality of the hypothetical studies.

However, they noted that if clinicians are overly skeptical about all industry-sponsored studies, major advances in drug treatment could be undervalued.

"Pharmaceutical companies seeking to enhance the appropriate use of important new products or to expand the appropriate uses of existing products must address the attitudes that our survey revealed, so that the credibility of the results of industry-supported trials is more likely to be based on methodologic rigor than on funding sources," Kesselheim and colleagues stated.

Among the strategies his group recommended were avoidance of "selective reporting" of trial results, ensuring the transparency of data, and allowing independent oversight of study endpoints.

In addition, because the physicians surveyed in this analysis rated NIH sponsorship highly, joint funding with industry might encourage trust in results.

"The methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility," the researchers argued.

The study was supported by the Edmond J. Safra Center for Ethics at Harvard; the Agency for Healthcare Research and Quality; the Robert Wood Johnson Foundation; the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School; and the National Cancer Institute.

One author reported receiving grants from AstraZeneca and Novartis for data monitoring and trial analysis, and two others reported consulting for Merck and Genzyme/Sanofi.

Primary source: New England Journal of Medicine
Source reference:
Kesselheim A, et al "A randomized study of how physicians interpret research funding disclosures" N Engl J Med 2012; 367: 1119-1127.

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Stamp-Sized Device Could Cut Liver Test Costs

By Michael Smith, North American Correspondent, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A paper-based device about the size of a postage stamp could improve testing for drug-induced liver toxicity in the developing world, researchers reported.

In a series of experiments, the device agreed more than 90% of the time with the gold-standard tests for liver enzymes, according to Nira Pollock, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues.

At a projected cost of less than 10 cents a test, the device could make it significantly easier to monitor patients being treated for such diseases as TB and HIV in the developing world, where standard testing is difficult to obtain and costly, Pollock and colleagues reported in the Sept. 19 issue of Science Translational Medicine.

"Our device is designed to use a droplet of blood from a finger prick to deliver results in 15 minutes," Pollock said in a statement. "It could have significant implications around the world, particularly in developing nations where blood tests can be prohibitively expensive and the results can sometimes take weeks to return."

The device uses layers of patterned paper and a plasma separation membrane. Blood applied to the plasma separation membrane wicks into the layers of paper and travels through microfluidic channels to separate zones for testing aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

The read-out is a series of dots that change color to report levels of the enzymes in three "bins" – less than 3 times the upper limit of normal (ULN), 3 to 5 times ULN, and more than 5 times ULN – that correspond to cut-offs used for clinical management of patients with TB and HIV, Pollock and colleagues reported.

The device was developed in collaboration with Diagnostics For All, a Cambridge, Mass., nonprofit organization.

The researchers tested the device on paired whole-blood and serum specimens, drawn simultaneously from 223 patients within the previous 5 hours for routine clinical testing and for which results of standard automated transaminase testing were available.

They applied 30 microliters of blood or serum to the devices and – after 15 minutes – three readers blinded to the gold-standard outcomes analyzed the results.

ALT results were more accurate for the serum samples than for whole blood, the researchers noted, possibly because of the age of the specimens at the time of analysis. Previous experiments had shown that values drifted higher as the whole blood aged.

But overall, Pollock and colleagues reported, the paper device got it right at least 90% of the time and was especially accurate in placing specimens in the lowest bins – those that would usually mean no action was needed.

For example, the paper device correctly placed 88 of 89 serum samples tested for ALT in the less than 3 times ULN bin and 85 of 88 tested for AST – accuracies of 99% and 97%, respectively.

No specimens that the standard test placed above 5 times ULN were misread by the paper device to be below 3 times ULN, Pollock and colleagues reported – an important finding given that guidelines for TB treatment suggest that patients with levels more than 5 times ULN stop their medications even in the absence of symptoms.

Pollock and colleagues cautioned that the device has still to be tested in the field with TB and HIV patients. A planned field trial in Ho Chi Minh City, Vietnam, will evaluate the performance of the test in 600 HIV patients from that city's Hospital of Tropical Diseases.

The study had support from the Department of Defense/Center for Integration of Medicine and Innovative Technology, the National Institutes of Health, and the Bill & Melinda Gates Foundation. A patent application has been filed based on the results; four authors are listed as inventors.

Primary source: Science Translational Medicine
Source reference:
Pollock NR, et al "A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing" Sci Transl Med 2012; DOI: 10.1126/scitranslmed.3003981.

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