Integrated Internist – Addiction Medicine – Hepatology Model for Hepatitis C Management for Individuals on Methadone Maintenance

From Journal of Viral Hepatitis

D. Martinez; R. Dimova; K. M. Marks; A. B. Beeder; M. Zeremski; M. J. Kreek; A. H. Talal

Posted: 01/24/2012; J Viral Hepat. 2012;19(1):47-54. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co-localized care model in which an internist-addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti-HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6–22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty-four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices.

Introduction

Five million individuals in the United States are infected with hepatitis C virus (HCV), a virus that can result in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Conventional therapy, consisting of pegylated interferon (PEG-IFN) and ribavirin (RBV), results in viral eradication in roughly one-half of infected individuals.^[1,2] Currently, injection drug use is the strongest risk factor for HCV acquisition with HCV seroprevalence >70% among injection drug users (DUs) older than 40 years. However, DUs have been systematically excluded from treatment for HCV owing to stigmatization, physicians' concerns regarding adherence and patients' misinformation concerning the importance of a diagnosis of HCV.^[3,4] Between 2010 and 2030, the prevalence of cirrhosis is estimated to increase from 25% to 45% among chronic hepatitis C patients.^[5] Simultaneously, the number of treated patients is projected to decline,^[6] unless new strategies are developed to enable DUs to obtain antiviral treatment.

Despite the potential benefits of treatment, surprisingly few HCV-infected DUs are offered anti-HCV therapy, even though expert panels have endorsed HCV treatment in this population.^[7,8] Active engagement in therapy for addiction has been shown to increase treatment access for various infectious diseases, such as HIV and tuberculosis, among illicit substance users.^[9,10] It has also been demonstrated that the longer a patient is engaged in substance abuse treatment the greater the stability and retention in treatment for medical conditions.^[11]

Traditional HCV management via referral of DUs to outpatient specialty clinics has resulted in the appearance in the clinic of less than one-third of referred patients.^[12] Among DUs, therapeutic effectiveness is an issue of treatment access, acceptance and adherence rather than drug efficacy.^[13] Consequently, an approach that integrates the expertise of a variety of disciplines, including specialists in addiction medicine, hepatology, infectious diseases, primary care and psychiatry, has been advocated for the treatment of HCV among DUs.^[14] Adherence is likely to be further enhanced if a program offers familiarity, continuity among providers and ready access to health care professionals, as a strong relationship with medical personnel has been shown to be an important determinant of patients receiving preventative care as well as HCV and HIV treatment services.^[15–17]

To address these concerns, we devised the 'internist-addiction medicine-hepatology colocalization model', an integrated, co-located program in which an internist-addiction medicine specialist (ADM) evaluated methadone-maintained patients for HCV infection in the hepatology clinic under the direction of a hepatologist (AHT). We applied our model to patients from our institution's two methadone maintenance clinics located in close proximity to our viral hepatitis clinic. A primary premise of our model was that methadone-maintained patients would be more likely to accept an HCV evaluation if continuity of care was maintained between the methadone maintenance treatment program (MMTP) and the viral hepatitis clinic by the same physician caring for patients in both venues.

Methods

Treatment Setting and Patient Selection

A total of 401 patients in our institution's two MMTP clinics between July 2006 and June 2008 with available HCV serology were eligible for inclusion. Inclusion criteria were broad, and we purposefully did not exclude active drug or alcohol use except in the case of severe incapacitation as determined by either MMTP staff psychiatrists or the internist-addiction medicine specialist as we desired to pursue HCV management in as many MMTP patients as possible. Patients were excluded if HCV serostatus was unavailable or if their active enrolment in the MMTP during the period under study could not be verified. Patients who had poorly compensated psychiatric disease as determined by MMTP staff psychiatrists were also excluded. No patients were excluded for other medical co-morbidities, such as neurological, endocrine or autoimmune conditions.

The two MMTPs are located within a one-block radius of the viral hepatitis clinic and are staffed by internists, psychiatrists, nurses and social workers. The internist-addiction medicine specialist from the MMTP, who provided comprehensive medical services including chronic disease management, was the primary care physician for the majority of patients. All MMTP patients met DSM IV^[18] criteria for a diagnosis of opiate dependence and most had an additional diagnosis of dependence on alcohol, benzodiazepines or cocaine. Data were collected retrospectively through chart review. The study was conducted in accordance with a protocol approved by the Institutional Review Board and consistent with the Helsinki Declaration of 1975, as revised in 1983.

Hepatitis C virus antibody testing was performed on all individuals on admission to the MMTP and then annually in seronegative persons. Upon receipt of a positive HCV antibody test result, the patient was informed of their seropositive status, if not previously aware, provided HCV education and offered referral to the hepatitis clinic (Fig. 1). If the patient accepted referral, MMTP staff scheduled the appointment and recorded the date and time in the computerized methadone-dispensing system. During the week preceding the appointment, patients were reminded twice of their upcoming appointment. All patients who missed their initial appointments were questioned as to the reason for failure to appear. For reasons such as forgetfulness or competing priorities at the time of the initial visit, MMTP staff scheduled a second or third appointment as indicated. If a patient missed more than three appointments, they were considered noncompliant. Hepatitis C virus RNA testing was performed in the hepatitis clinic during the first 6 months of our program, and subsequently testing was performed in the MMTP to expedite the referral process. HIV antibody testing was encouraged at admission to the MMTP and repeated every six to twelve months depending upon whether or not the patient continued to engage in high-risk activities.

Figure 1. Internist-addiction medicine-hepatology colocalization model for hepatitis C evaluation and treatment among patients in the methadone maintenance treatment program. The number of patients at each step of the HCV management process is indicated. HCV, hepatitis C virus; MMTP, methadone maintenance treatment program.

In the hepatitis clinic, the patient was seen by the internist-addiction medicine specialist under the supervision of a hepatologist. All patients underwent a standard medical examination and comprehensive assessment of HCV status that included HCV RNA measurement, HCV genotyping and liver biopsy, if desired and indicated. Consistent with the 2002 NIH Consensus Conference^[19] and American Association for the Study of Liver Disease guidelines,^[20] patients were strongly encouraged to have histologic assessment of liver disease severity through biopsy as a surrogate marker of adherence. Histology was assessed by staff pathologists using the Scheuer 0–4 point scale.^[21] In five patients, we performed FibroSURE™ (LabCorp., Research Triangle Park, NC, USA), a noninvasive test of hepatic fibrosis.

After the biopsy, patients discussed potential HCV treatment in the hepatitis clinic. Besides patient's willingness, we considered fibrosis stage and potential contraindications to PEG-IFN/RBV prior to initiating therapy. All psychiatrically unstable patients underwent psychiatric assessment prior to PEG-IFN/RBV initiation and were monitored monthly while on therapy by MMTP staff psychiatrists. Staff psychiatrists were available on a daily basis in the MMTP for patient consultation. In addition, a psychosomatic medicine fellow was present in the hepatitis clinic on the designated clinic day for consultation if requested by either the hepatologist or the internist-addiction medicine specialist.

According to standard practice, daily attendance in the MMTP is required 6 days per week. Subsequently, phased reductions in attendance can be initiated if the patient maintains abstinence from the use of illicit substances, complies with the predetermined attendance schedule and actively engages in treatment including attendance at counselling sessions with their assigned social worker. Throughout the stabilization process and treatment course, the patient must comply with random urine toxicology screening at frequent intervals.

Antiviral Therapy

Pegylated interferon α-2a 180 μg/week was injected subcutaneously. Prior to initiation of treatment, all patients participated in a teaching session with nursing staff from the viral hepatitis clinic during which the patient was instructed in interferon administration. The first dose was administered during the teaching session, and all subsequent doses were self-administered. In no case did the physicians managing the patient deem it necessary that they receive directly observed therapy. Weight-adjusted RBV was taken orally twice daily at a dose of 800–1200 mg. Hematopoietic stimulating factors were utilized as indicated for anaemia and neutropenia. All patients on PEG-IFN/RBV were seen weekly in the MMTP by the internist-addiction medicine specialist and at 6-week intervals in the liver clinic by both the hepatologist and the addiction specialist on the designated clinic day. Patients were monitored for clinical evidence of opiate withdrawal on a weekly basis by the internist-addiction medicine specialist. If a patient missed the follow-up appointment in the hepatitis clinic, they were seen in the MMTP and rescheduled to be seen in the hepatitis clinic at the first availability. Haematologic parameters and aminotransferase levels were measured weekly for the first month and at 6-week intervals thereafter. Patients had the option to have their blood drawn at either the hepatitis clinic or the MMTP. The internist-addiction medicine specialist and the hepatologist maintained a list of all HCV-seropositive patients and reviewed the status of each patient on a weekly basis either by phone or in person.

Statistical Analysis

Statistical analysis was performed using SAS (SAS Institute Inc., Cary, NC, USA) and R (R Language, version 2.10.0 http://www.r-project.org) The associations between the variables of interest were determined through chi-square tests, Fisher's exact tests, logistic regression modelling and Wald tests. Model selection was based on the Akaike information criterion (AIC). Logistic regression was used to model the probability that a patient who was referred to the liver clinic was adherent and to assess the significant factors that influenced adherence with the referral. First, simple logistic regression was used to determine the factors (gender, ethnicity, age and duration in the MMTP) for inclusion in the model. Criterion for inclusion was P ≤ 0.25. Secondly, the AIC criterion was used to select the best multiple logistic model. In addition, we modelled the probability that a patient in whom treatment was indicated actually initiated PEG-IFN/RBV. The significance level for these tests was set at 0.05, two-tailed.

Results

Patient Characteristics

Of a total of 401 patients, 51% were Caucasian, 34% were Hispanic, 13% were African American and 66% were male (Table 1). HIV antibody testing results were available for 322 subjects, 48 of whom were positive. Of 48 HIV-positive patients, 2 were HCV seronegative, 13 were HCV seropositive but HCV RNA negative and 33 were co-infected with HCV (both HCV RNA and antibody positive).

HCV Disease Characteristics and Evaluation

Serology Hepatitis C virus antibody was obtained at a median age of 43 (33–50) years, on average 2 years after admission to the MMTP. Of 257 HCV-seropositive patients, 86% were older than 40 years, 48% were Caucasian, 35% Hispanic and 16% African American. We found higher HCV seroprevalence with increasing age. Subjects aged 40 years or older were more likely to be HCV antibody positive compared to younger people (odds ratio [OR] = 3.11; 95% CI: 2.00, 4.83, P < 0.0001). However, the association between anti-HCV positivity and age differs significantly among different ethnic groups (P = 0.049). While the likelihood of being anti-HCV positive was higher among Caucasians (OR = 3.5; 95% CI: 1.89, 6.39) and African Americans (OR = 20.7; 95% CI: 2.06, 206.64) older than 40 years, age was not associated with HCV serostatus among Hispanics (OR = 1.51; 95% CI: 0.72, 3.17). Seropositivity did not differ significantly by gender (P = 0.23). Our population was quite stable with a median duration in the MMTP of 65 months among seropositive individuals. We also found that patients who were in the MMTP for more than 36 months were 1.61 times more likely to be HCV seropositive compared to those enrolled in the MMTP for a shorter period (95% CI: 1.06, 2.46, P = 0.026).

HCV RNA Hepatitis C virus RNA was obtained from 222 (86%) HCV-seropositive patients. Of these, 65 (29%) patients were HCV RNA negative, indicating spontaneous viral eradication. Chronic HCV infection was detected in 157 (71%) patients as indicated by detectable HCV RNA. Of these, 33 patients were HIV/HCV co-infected. In 35 (14%) of seropositive patients, HCV viral quantitation was unattainable: 8 declined testing citing lack of interest, 8 had no insurance, 3 received HCV treatment elsewhere and 16 were inaccessible during the study owing to discharge/transfer from the MMTP (n = 9), death (n = 4) or incarceration (n = 3). Hepatitis C virus genotypes were obtained on 118 (75%) patients with chronic HCV infection. Hepatitis C virus genotype 1 was detected in 91 (77%) patients, followed by genotypes 2 and 3 (11% and 10%, respectively) (Table 2).

Liver Clinic Evaluation Of the 157 chronically HCV-infected patients, 125 were eligible to be seen in the clinic, 29 of whom were HIV co-infected. Seventy-six individuals adhered with the referral of whom 17 (25%) were HIV/HCV co-infected. The following patients were considered ineligible for referral: 13 received HCV care elsewhere; 12 were not evaluated owing to discharge (n = 5), transfer (n = 4), incarceration (n = 1) or death (n = 2) during the study period; and 7 were uninsured. Twenty-three patients refused hepatitis clinic referral citing lack of interest, and 26 initially accepted referral but failed to appear.

We found that patients who had been enrolled in the MMTP for more than 36 months were more likely to have been seen in liver clinic than those engaged in treatment for <36 months (OR = 3.32, 95% CI: 1.51, 7.28, P = 0.003). However, this relationship depended upon subject gender (P = 0.017). The odds of male patients engaged in MMTP for >36 months accepting and adhering to referral were significantly higher than for men enrolled in MMTP for <36 months (OR = 7.7; 95% CI 2.6–22.9). Among patients who were on methadone treatment for <36 months, men were significantly less likely to be seen in the liver clinic than women (OR = 0.167, 95% CI: 0.04, 0.69). No other demographic or disease-related factors predicted referral adherence. Of the 76 patients with chronic HCV infection evaluated in the viral hepatitis clinic, assessment of fibrosis was achieved in 63 (83%): 54 underwent liver biopsy to assess fibrosis, 4 were diagnosed with cirrhosis based upon laboratory data and/or imaging studies, and 5 preferred noninvasive blood testing to assess the degree of fibrosis. Among 58 patients with histologic assessment based upon biopsy or laboratory/imaging evidence of cirrhosis, 49 (84%) had moderate to advanced liver disease (stage ≥2) indicating the need for urgent treatment. Among patients with liver biopsy, advanced fibrosis (stage >2) differed significantly by ethnicity (P = 0.039); 58% of Caucasians and Hispanics combined had stage >2 vs 20% of African American subjects. Caucasian or Hispanic individuals were 5.5 times more likely to have fibrosis stage >2 when compared to African Americans (95% CI: 1.05, 33.33). Necroinflammatory activity was also significantly associated with fibrosis (P = 0.013 for lobular and P = 0.001 for portal inflammation). Age and gender were not associated with fibrosis.

HCV Treatment Characteristics

Of the 76 patients who underwent the evaluation process, 24 initiated treatment, including 9 individuals co-infected with HIV (Table 3). Thirty-five patients were ineligible for treatment including 2 (3%) with decompensated psychiatric disease, 6 (11%) with decompensated cirrhosis, 10 (13%) who refused a biopsy, 4 (5%) with no insurance and 2 (3%) who were treated elsewhere. Of these two patients, upon evaluation in the liver clinic, it was determined that one had successfully been treated at an outside institution and the other was treatment ineligible owing to severe thrombocytopenia. Eleven (14%) subjects with mild fibrosis postponed treatment based upon physician recommendation. Twenty-four of 41 treatment eligible patients began treatment. Of the remaining treatment eligible patients, 3 (4%) declined PEG-IFN/RBV citing fear of therapy-related side effects, 4 (5%) had unstable living conditions, 3 (4%) had relocated to different geographic areas complicating pursuit of anti-HCV treatment, 3 declined (4%) owing to co-occurring illnesses and 4 (5%) were lost to follow-up. Patients with stage 3–4 fibrosis were significantly more likely to be treated than those with stage 0–2 (OR = 11.2, 95% CI: 2.89, 43.35, P = 0.0005). Of 24 treatment initiators, 19 completed a full course of therapy with PEG-IFN/RBV. Three patients interrupted treatment owing to reasons unrelated to therapeutic success, including hepatic decompensation (n = 1), severe thrombocytopenia (n = 1) and nonadherence (n = 1). Thirteen patients (54%) achieved sustained virological response (SVR), eight of who were genotype 1 and four were co-infected with HIV. Two HIV/HCV co-infected patients currently remain on treatment.

Discussion

In this investigation, we demonstrate the effectiveness of an integrated, co-localized care model for HCV utilizing a multidisciplinary approach (Fig. 1). We applied our model to patients from a large MMTP in Manhattan. Overall, HCV seroprevalence was 64% and 61% of those with chronic HCV who were eligible for referral were evaluated in the hepatitis clinic. Of those who initiated treatment, 54% successfully eradicated the virus consistent with the previous studies of HCV treatment in opiate-dependent patients.^[22–26]

Despite a high prevalence of HCV infection among DUs, less than one-third of eligible individuals receive HCV therapy owing to variety of reasons at the institutional, provider and patient levels.^[3] Institutional reasons often include difficulties obtaining or navigating the complexities of the referral system. In addition, many health care providers are concerned about adherence with HCV treatment by DUs, including concerns that they may be disinterested in treatment, that interferon-based therapy may potentiate psychiatric decompensation and that they might be reinfected of continued high-risk practices. Studies of HCV reinfection among successfully treated DUs, however, have shown the converse.^[27,28] Using our model, we obtained an HCV evaluation in more than one-half of chronically infected individuals, markedly higher than previous clinic-based cohorts. In addition, we were able to stage the degree of fibrosis in 83% of those evaluated in the liver clinic. Factors that likely contributed to the high degree of acceptance of HCV management and adherence to an evaluation included evaluation by the same physician in both clinics, their geographical proximity and an institution-wide electronic medical record that fosters communication facilitating data access and continuity of care. The fact that these patients had a regular, stable source of medical care that originated in the MMTP and continued to the hepatitis clinic was likely crucial to the success of our program.^[15,17]

Substance abuse treatment can serve as an entry point into the health care system and is possibly an essential step in preparing DUs for HCV evaluation and treatment. Well-structured MMTPs, with attributes such as access to mental health professionals and general medical staff, likely have advantages for HCV evaluation and treatment over those without such services. Consistent with the findings of prior studies,^[11,29] we found that men who were engaged in the MMTP for 36 months or more were significantly more likely to appear in the hepatitis clinic than those with shorter duration of opiate substitution therapy.

Our study is limited in its retrospective, non-comparative design and its conduct at a single institution. Our goal, however, was to demonstrate the feasibility and effectiveness of an integrated, co-localized model of care. The health care services offered at our MMTP provided the requisite infrastructure to facilitate HCV evaluation and treatment among MMTP patients. Unfortunately, however, many MMTPs may not be able to offer as wide a spectrum of health care services onsite, which might impact on the ability to offer HCV management except through traditional referral based mechanisms. Our model may be utilized by community-based primary care providers or addiction medicine specialists with immediate access to experts in HCV management who can assist in navigating the complexities of treatment of the infection.

Despite our integrated, colocalized approach, a substantial number of patients did not undergo an HCV evaluation in the hepatitis clinic, with an approximate equal number refusing referral as those initially accepting referral but not appearing for their initial evaluation. Men enrolled in the MMTP for <36 months appeared to be at greatest risk for not accepting or complying with referral to the hepatitis clinic. When questioned, patients indicated that they refused HCV evaluation owing to an apparent lack of interest, reticence or a lack of education or misinformation concerning HCV. Our findings are consistent with previous data that demonstrated significant knowledge gaps among DUs.^[30] Implementation of patient-oriented interventions, such as formal, structured HCV educational programs, individual case management to address patient level barriers or staff/peer accompaniment to appointments, might improve adherence with HCV evaluation and treatment and are interventions deserving of further study.

In an effort to inform patients of the severity of their infection and consistent with standard clinical practice in 2006,^[20] we strongly encouraged patients to undergo a liver biopsy. On biopsy, we found that the vast majority of patients had at least moderate hepatic fibrosis, indicating the need for urgent treatment. In this model, 41% of patients who had accurate hepatic fibrosis assessment began PEG-IFN/RBV, 79% of whom completed a full course of therapy with an overall SVR rate of 54%. Notably, only one patient had treatment interrupted for issues relating to nonadherence and no patients discontinued treatment because of psychiatric decompensation.

In summary, we demonstrated that localization of addiction medicine specialists and hepatologists in a viral hepatitis clinic is both an effective and efficient model to deliver HCV evaluation and treatment to MMTP patients. This approach could be most appropriate in settings that offer pharmacologically based treatment of addiction which have ready access to expertise in the management of liver disease. As many DUs have advanced stages of hepatic fibrosis, HCV treatment is particularly urgent. Additionally, successful treatment combined with safe injection practices could decrease virus transmission even among individuals who continue to inject. Unless disenfranchised populations with the highest infection prevalence, such as DUs, have access to and accept treatment for HCV, the burden of disease will remain high.

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Source

France: Is more frequent monitoring for liver cancer among co-infected people needed?

9 January 2012

In high-income countries such as Canada, Australia and in Western Europe, the widespread availability of potent combination therapy for HIV (commonly called ART or HAART) has greatly reduced deaths from AIDS-related infections. Furthermore, the benefit of ART is so profound that researchers in the UK recently estimated that HIV-positive people who have minimal co-existing health conditions and who are diagnosed and receive treatment early in the course of HIV disease are very likely to have near-normal life spans.

Many possible factors can affect access to and engagement in care and treatment—and thus survival; addiction is one such factor. Some HIV-positive people may not be able to seek and receive the help and support needed to break free from addiction to substances—including alcohol, street drugs and tobacco—and their associated risks. Such risks can include serious bacterial infections, overdose, cardiovascular disease, liver and kidney damage, accidents, suicide and violence.

Even among some HIV-positive people who have been able to successfully overcome their addiction, past engagement in substance use or unprotected sex may have also exposed them to co-infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). These viruses attack the liver, injuring this vital organ. Chronic hepatitis caused by these viruses degrades the liver, causing it to lose healthy tissue and have scar tissue build up. In the absence of treatment, over time the liver becomes increasingly dysfunctional and serious complications including liver failure, liver cancer and death can occur.

Treatment

In high-income countries, treatment for HBV co-infection is usually one of the following combinations:

• 3TC (lamivudine) + tenofovir (Viread)
• tenofovir + FTC (sold as a fixed-dose combination called Truvada)

In the case of HCV mono-infection (HCV alone), a combination of the following three drugs is used:

• ribavirin
• interferon-alpha
• boceprevir (Victrelis) or telaprevir (Incivik)

Note that neither boceprevir nor telaprevir are approved in Canada for the treatment of HIV-HCV co-infection.

Viral hepatitis and liver cancer

French researchers have found that while ART can greatly reduce deaths due to AIDS-related infections, complications from liver disease are increasingly taking their toll. One complication of infection with HBV or HCV is liver cancer, and researchers in France continue to study this cancer both in people with either HBV or HCV or HIV co-infection. Their most recent study results suggest that liver cancer occurs earlier and is more extensive in some co-infected people who are at high risk for liver cancer. If the French findings are confirmed, increased medical monitoring of co-infected people at high risk for liver cancer may be necessary.

Study details

The French team reviewed data collected from 2,256 participants who were being monitored as part of research on viral hepatitis. They selected 32 people from this group for further analysis. All 32 participants had cirrhosis—extensive liver damage arising from chronic infection with HBV or HCV, whereby healthy tissue is replaced by scar tissue. Additionally, all participants had liver cancer. The diagnosis of cirrhosis was made using one or more of the following methods:

• analyzing a tiny sample of the liver
• specialized blood tests (Fibrotest)
• specialized ultrasound scans of the liver (Fibroscan)

The distribution of viral infections among the 32 participants was as follows:

• HIV-HCV co-infection – 16 participants
• HCV mono-infection – 16 participants

As people with cirrhosis are at heightened risk for the development of liver cancer, all participants underwent ultrasound scans of the liver every six months, along with medical monitoring.

On average, participants were monitored for 30 months.

All participants had tumours in their liver that arose from abnormal liver cells (primary liver cancer); none of the tumours had migrated to the liver from another part of the body.

Results

The researchers found that co-infected people were generally younger (48 years) than mono-infected people (60 years)—a statistically significant difference. Additionally, there was a trend that approached statistical significance: Co-infected people (56%) drank more alcohol than HCV mono-infected people (20%).

In reviewing the medical records, the research team found that all mono-infected participants had previously received treatment for HCV while 67% of co-infected people received this treatment. This difference was also statistically significant. The reasons for this difference were not clear to the research team.

The researchers also found that 87% of co-infected people were taking ART; of these, 69% had low levels of HIV in their blood (less than 40 copies/ml).

Cure vs. palliative therapy

Treatment for liver cancer can vary depending on several factors, including the following:

• the health of the liver
• the size and number of tumours
• whether or not the tumours have spread (metastasized) beyond the liver

In cases where doctors decide that a person does not have a good chance of recovery from cancer, palliative care—measures to minimize discomfort and complications in the short term—may be provided. In the case of the current report, when French oncologists judged that recovery was likely they choose from several options, including surgery, attacking the tumour with an electrical current (radiofrequency ablation), or surgery followed by a liver transplant.

Oncologists gave the 32 study participants either palliative or curative therapy, distributed as follows:

• HIV-HCV co-infection – 25% received therapy with the intention to cure cancer
• HCV mono-infection – 69% received therapy with the intention to cure cancer

This difference was statistically significant.

As cancer patients were assessed and treated outside of the study by oncologists, the research team is not certain why there was a difference in who received curative therapy. However, the researchers found that when liver cancer was diagnosed within the study, it was generally more severe (more and larger tumours) in co-infected people. Also, some co-infected participants had higher-than-normal levels of a protein called AFP (alpha-fetoprotein). Past studies have suggested that high levels of AFP are sometimes associated with liver cancer and that elevated AFP at liver cancer diagnosis may indicate a poor outcome. Thus it was possible that because liver cancer was more “advanced” when diagnosed in co-infected people, oncologists may have decided that the prospects of recovery in this group were poor.

Over an average of 30 months of monitoring, deaths due to complications from liver cancer were distributed as follows:

• HIV-HCV co-infection – 10 out of 16 people died
• HCV alone (mono-infection) – one out of 16 people died

Monitoring

International liver cancer management guidelines suggest that people with cirrhosis (who are at high risk for liver cancer) should undergo ultrasound scans of their liver and have AFP tests to help their doctors detect tumours. According to the researchers, these guidelines were followed in the French study. Therefore, the French team suggests that the worse pattern of liver cancer among co-infected people did not arise due to lack of monitoring.

The precise cause for the more rapid appearance of liver cancer among co-infected people in this study is not clear but it may be due to a weakened immune system caused by HIV infection. While most participants with HIV in the study were taking combination therapy, ART can only partially restore the immune system; residual immune dysfunction continues.

The French study had a major weakness: A relatively small number of participants (32). A larger study is necessary to confirm its findings.

If another team confirms the French results, more frequent monitoring of HIV-HCV co-infected people at high risk for liver cancer may be deemed necessary. For instance, the French team suggests that ultrasound scans and other tests could be done every three months. This shorter time span might allow technicians and doctors to detect liver cancer when it is at an early stage. This could make a difference to the prospects of surviving liver cancer for co-infected people.

—Sean R. Hosein

REFERENCES:

1. May M, Gompels M, Delpech V, et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ. 2011 Oct 11;343:d6016.
2. Larsen MV, Omland LH, Gerstoft J, et al. Impact of injecting drug use on mortality in Danish HIV-infected patients: a nation-wide population-based cohort study. Addiction. 2010 Mar;105(3):529-35.
3. Hser YI, Kagihara J, Huang D, et al. Mortality among substance-using mothers in California: a 10-year prospective study. Addiction. 2012 Jan;107(1):215-22.
4. Ferreros I, Lumbreras B, Hurtado I, et al. The shifting pattern of cause-specific mortality in a cohort of human immunodeficiency virus-infected and non-infected injecting drug users. Addiction. 2008 Apr;103(4):651-9.
5. Smit C, van den Berg C, Geskus R, et al. Risk of hepatitis-related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: a 20-year prospective study. Journal of Acquired Immune Deficiency Syndromes. 2008 Feb 1;47(2):221-5.
6. Bonacini M. Alcohol use among patients with HIV infection. Annals of Hepatology. 2011 Oct-Dec;10(4):502-7.
7. Downey JS, Attaf M, Moyle G, et al. T-cell signalling in antiretroviral-treated, aviraemic HIV-1-positive individuals is present in a raised state of basal activation that contributes to T-cell hyporesponsiveness. AIDS. 2011 Oct 23;25(16):1981-6.
8. Appay V, Almeida JR, Sauce D, et al. Accelerated immune senescence and HIV-1 infection. Experimental Gerontology. 2007 May;42(5):432-7.
9. Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS. 2009 Jan 2;23(1):35-40.
10. Boasso A, Royle CM, Doumazos S, et al. Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis. Blood. 2011 Nov 10;118(19):5152-62.
11. Grebely J, Dore GJ. What is killing people with hepatitis C virus infection? Seminars in Liver Disease. 2011 Nov;31(4):331-9.
12. El-Serag HB. Hepatocellular carcinoma. New England Journal of Medicine. 2011 Sep 22;365(12):1118-27.
13. Tyson GL, Duan Z, Kramer JR, et al. Level of α-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clinical Gastroenterology and Hepatology. 2011 Nov;9(11):989-94.
14. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology. 2010 Jul;52(1):132-41.
15. Bourcier V, Winnock M, Ait Ahmed M, et al. Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir). Clinics and Research in Hepatology and Gastroenterology. 2012; in press.

Source

Effect of IL28B Genotype on Early Viral Kinetics during Interferon-Free Treatment of Patients with Chronic Hepatitis C

Gastroenterology. 2012 Jan 13. [Epub ahead of print]

Chu TW, Kulkarni R, Gane EJ, Roberts SK, Stedman C, Angus PW, Ritchie B, Lu XY, Ipe D, Lopatin U, Germer S, Iglesias VA, Elston R, Smith PF, Shulman NS.

Source

Roche, Nutley, NJ, USA.

Abstract

BACKGROUND & AIMS:

Although IL28B genotype affects the response of patients with chronic hepatitis C (CHC) to peginterferon and ribavirin, little is known its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and hepatitis C virus (HCV) protease inhibitor danoprevir.

METHODS:

We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment-naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts, then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hrs or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a bi-phasic model to describe first- and second-phase slopes of viral decay during therapy.

RESULTS:

At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log(10) IU/mL) than those without (4.59 log(10) IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up.

CONCLUSIONS:

IL28B genotype appears to affect early VKs in patients with CHC receiving interferon-free treatment.

Source

Treatment failure with new hepatitis C drugs

Expert Opin Pharmacother. 2012 Jan 14. [Epub ahead of print]

Soriano V, Vispo E, Poveda E, Labarga P, Barreiro P.

Source

Hospital Carlos III, Department of Infectious Diseases , Calle Sinesio Delgado 10, Madrid 28029 , Spain +34 91 4532500 ; +34 91 7336614 ; vsoriano@dragonet.es.

Abstract

Introduction: The combination of pegylated interferon-α plus ribavirin (pegIFNα-RBV) has been the only therapeutic option for patients with chronic hepatitis C virus (HCV) infection during the last decade. Unfortunately, it provides cure to less than a half of individuals infected with HCV genotype 1, which is by far the most prevalent worldwide. The recent introduction of new direct-acting antivirals (DAA) has revolutionized the hepatitis C field. The addition of any of the two recently approved HCV protease inhibitors, boceprevir or telaprevir, to pegIFNα-RBV results in the cure for two-thirds of HCV genotype 1, interferon-naive patients. Areas covered: This paper reviews new antivirals for hepatitis C and HCV treatment failures, along with HCV drug resistance and rescue therapies. Expert opinion: The application of early stopping rules may reduce the enrichment of drug-resistant viruses in patients failing first-generation HCV protease inhibitors, potentially allowing more chances of response to rescue interventions with other compounds within the same class in the near future. On the other hand, the advent of DAA belonging to distinct drug families may provide further opportunities for clearing definitively HCV in patients currently failing first-generation HCV protease inhibitors. Thus, hepatitis C has entered a new era that hopefully will end with its eradication. In the meantime, a wise use of DAA is warranted, including adequate selection of candidates for therapy, close monitoring of drug adherence, proper management of side effects and early application of stopping rules.

Source

Hepatitis Health Action Alert: Stop the Attacks on Prevention and Public Health Fund

Posted on January 23, 2012 on The Hepatitis B Foundation blog

Action Alert! The Hepatitis Community Responds to Health Care Reform. Tell Congress Not To Cut The Prevention and Public Health Fund

The Prevention and Public Health Fund is under attack in Congress once again. Some leaders in the House of Representatives would like to make drastic cuts to the Fund as part of negotiations on a long-term deal on the payroll tax cut and Medicare payments rates to medical providers.

The Prevention and Public Health Fund, part of the Affordable Care Act, provides money each year for vital prevention and public health services. The fund will grow each year until it eventually provides $2 billion/year.

This fund is extremely important to the nation’s fight against the viral hepatitis epidemic. Later this year, the Department of Health and Human Services is expected to allocate $10 million from the Fund for viral hepatitis screening, testing, and education programs. This initiative will greatly help efforts to identify the millions of Americans who have chronic hepatitis B or C and link them to care and treatment.

Please take a few minutes to call Congress in support of this lifesaving program!

What YOU can DO:

Please call your U.S. House Representative and two U.S. Senators immediately. We are hearing directly from Congressional staff that phone calls are the most effective form of communication.

Call the Capitol Switchboard toll-free at 1-888-876-6242 and ask to be connected to your United States Representative. When you reach your Representative’s office, tell whoever answers the phone that you are a constituent and that you would like to speak to the staff person who handles health care issues. Whether you speak to the staff person live or leave a voicemail, tell him/her:

“My name is _______________ and I live in (city/state). I am calling in strong support of the Prevention and Public Health Fund, which is an important part of the Affordable Care Act. This Fund is a great opportunity to provide badly needed funding for viral hepatitis prevention, testing, and screening programs and must be preserved. I urge Representative_____________ to oppose any efforts to cut the Fund as part of the payroll tax/Medicare physician reimbursement negotiations.”

After you speak to your Representative’s office, call the Capitol Switchboard again and deliver the same message to the health care staff person in your two U.S. Senators’ office.

Thank you for taking the time to make a difference! Please spread the word.

Get involved with Hepatitis Health Action!

• Sign up for the Hepatitis Health Action email list by visiting http://groups.google.com/group/HepHealth or, email rclary@projectinform.org and we will make sure you are added.

• Join Hepatitis Health Action’s Facebook group: http://tinyurl.com/hephealthfacebook where you can participate in discussions with other advocates and share your ideas and strategies.

Hepatitis Health Action is a campaign led by viral hepatitis advocates working to make sure that health care reform addresses hepatitis B and C.

Entry point for hepatitis C infection identified

Public release date: 24-Jan-2012

Contact: Jeanne Galatzer-Levy
jgala@uic.edu
312-996-1583
University of Illinois at Chicago

A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of Illinois at Chicago College of Medicine.

The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online in advance of publication in Nature Medicine.

An estimated 4.1 million Americans are infected with hepatitis C virus, or HCV, which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests.

Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1, known to help maintain cholesterol balance might also be transporting the virus into the cell.

The receptor is common in the gut of many species -- but is found on liver cells only in humans and chimpanzees, says Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV.

Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.

Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said because the receptor is involved in cholesterol metabolism it was already well-studied. A drug that "specifically and uniquely targets NPC1L1" already exists and is approved for use to lower cholesterol levels, he said.

The FDA-approved drug ezetimibe (sold under the trade-name Zetia) is readily available and perfectly targeted to the receptor, Sainz said, so the researchers had an ideal method for testing NPC1L1's involvement in HCV infection.

They used the drug to block the receptor before, during and after inoculation with the virus, in cell culture and in a small-animal model, to evaluate the receptor's role in infection and the drug's potential as an anti-hepatitis agent.

The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike any currently available drugs, ezetimibe was able to inhibit infection by all six types of HCV.

The study, Uprichard said, opens up a number of possibilities for therapeutics.

Hepatitis C is the leading cause for liver transplantation in the U.S., but infected patients have problems after transplant because the virus attacks the new liver, Uprichard said.

While current drugs are highly toxic and often cannot be tolerated by transplant patients taking immunosuppressant drugs, ezetimibe is quite safe and has been used long-term without harm by people to control their cholesterol, Uprichard said. Because it prevents entry of the virus into cells, ezetimibe may help protect the new liver from infection.

For patients with chronic hepatitis C, ezetimibe may be able to be used in combination with current drugs.

"We forsee future HCV therapy as a drug-cocktail approach, like that used against AIDS," Uprichard said. "Based on cell culture and mouse model data, we expect ezetimibe, an entry inhibitor, may have tremendous synergy with current anti-HCV drugs resulting in an improvement in the effectiveness of treatment."

###

The study was supported by NIH Public Health Service grants, the American Cancer Society Research Scholar grant, the UIC Center for Clinical and Translational Science NIH grant, the UIC Council to Support Gastrointestinal and Liver Disease, and a grant from the Ministry of Health, Labor and Welfare of Japan.

Naina Barretto, Danyelle Martin, Snawar Hussain, Katherine Marsh and Xuemei Yu, of UIC; Nobuhiko Hiraga, Michio Imamura and Kazuaki Chayama, of Hiroshima University in Japan; and Waddah Alrefai of UIC and the Jesse Brown VA Medical Center in Chicago also contributed to the study.

[Editor's Note: Images available at newsphoto.lib.uic.edu/v/uprichard/]

For more information about the University of Illinois Medical Center, visit www.uillinoismedcenter.org

Source

Hope for Hepatitis C

Posted by John Staples • January 18th, 2012

Imagine, for a moment, that you recently received a brand new Time-O-Matic Time Machine as a gift. How far back would you have to set the dial to see that meaningful progress has been made in the treatment of hepatitis C?

First, let’s say you set the dial to January 2011 and –- Puff-kachunk! — you’re there. Standard treatment for chronic hepatitis C genotype 1 infection consisted of 48 weeks of pegylated interferon-alpha and ribavirin, an approach more likely to produce adverse effects than clearance of the virus.

Your next trip (Zing-kersplat!) takes you to May 2011. The oral serine protease inhibitors boceprevir and telaprevir have just become available for treatment of chronic HCV genotype 1 infection. When added to pegylated interferon and ribavirin, these direct-acting antivirals dramatically improve the rate of sustained virologic response (SVR). But many patients still do not respond to treatment, and medication intolerance remains an issue. You step into your Time-O-Matic and return to January 2012 feeling somewhat discouraged.

Fortunately, this week’s NEJM might raise your spirits. In it, Dr. Anna S. Lok (University of Michigan, Ann Arbor, MI) and colleagues report on an open-label, phase 2a study that used a combination of two direct-acting antivirals to treat chronic HCV genotype 1 infection. Twenty-one ‘null responders’ (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were randomized to 24 weeks of treatment in one of two treatment arms:

• Group A received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor);
• Group B received BMS-790052 and BMS-650032 plus peginterferon alfa-2a and ribavirin.

Four of eleven (36%) patients in Group A and ten of ten (100%) of patients in Group B achieved an undetectable HCV RNA twelve weeks after completion of study treatment (SVR12, the primary end point). There were no deaths, serious adverse events, or discontinuations. The most common mild-to-moderate adverse effects were diarrhea, fatigue, headache, and nausea.

These results are exciting. The high rate of SVR12 achieved in Group B suggests that more effective treatment regimens may soon be available for null responders. But for editorialist Dr Raymond T. Chung (Massachusetts General Hospital, Boston, MA), it’s the Group A proof-of-concept results that really put HCV therapy “on the threshold of a treatment revolution.” The 36% of Group A patients achieving SVR12 demonstrate that combination direct-acting antivirals with non-overlapping resistance profiles can achieve HCV clearance without the use of interferon. If interferon and its adverse effects can be avoided, there is hope that treatment might be offered and accepted by a much greater number of patients.

“Current HCV treatment regimens are far from perfect,“ says primary care physician and NEJM deputy editor Dr. Mary Beth Hamel, “so it’s satisfying to see encouraging results from this kind of early-phase trial. It will be exciting to see what the future brings.”

Curious? Go ahead. Step into the Time-O-Matic and set the dial to see how far HCV therapy has progressed by January 2017. The rest of us, however, will just have to wait.

Source

New National Hepatitis C Helpline Promises "One Call – Lots of Help"

Fort Lauderdale, FL, January 24, 2012 --(PR.com)-- A new national helpline, 877-HELP-4-HEP, run by and for people affected by hepatitis C will formally launch February 1, 2012. This new consumer resource is the result of a year-long collaboration among five national nonprofits with a combined 90 years’ experience in phone-based peer counseling.

Being diagnosed with hepatitis C creates many emotional and social challenges. It is especially complicated by the lack of comprehensive medical, mental health, and community support services. People with hepatitis C report spending countless hours trying to find a reliable support and information. Resources are few and often transient based on available funding.

Judi, one of the 877-HELP-4-HEP counselors states, “People with hepatitis C just can’t seem to get the help they need. Sometimes, I’m the fourth or fifth person they have spoken to. As a peer counselor, I can share common experiences and talk about different coping strategies and resources. When I was diagnosed I had many of the concerns and questions that they are having and since then have spoken to people with similar experiences. I can really set their minds at ease with answers to their questions that contribute to a sense of well-being and hope.”

Unique to 877-HELP-4-HEP (877-435-7443) are specially trained peer counselors using a structured approach to help callers navigate through screening, diagnosis, medical evaluation, and treatment. Follow-up contact by the counselors keep callers engaged at each step of their journey and help them make and follow through with their hepatitis C related decisions.

Additional HELP-4-HEP assets include an up-to-date national database of 25,000 referral resources and a secure shared caller database for counseling continuity. Andi Thomas, the helpline’s managing partner, stated, “What sets us apart is our standardized health messaging and the follow-up call feature. HELP-4-HEP is designed to maintain contact with callers to improve health outcomes as well as document and measure the impact of our services.”

HELP-4-HEP is administered by The Support Partnership whose mission is to improve the well-being of people affected by viral hepatitis through collaborations that increase service quality, access, and impact. Founding partners are HealthPro (formerly Hep-C ALERT), FL; Hepatitis C Association, NJ; Hepatitis Education Project, WA; Hep C Connection, CO; and Project Inform, CA.
877-HELP-4-HEP (877-435-7443) operates Monday through Friday 9:00am to 7pm EST. To learn more, visit www.help4hep.org or email info@help4hep.org.
###

Contact Information

The Support Partnership
Andi Thomas
954-692-0450
Contact
www.help4hep.org
Denny Simon
908-812-2488

Source

Germany’s IQWiG sees added benefits for Incivo (Telaprevir)

Article | 24 January 2012

In an early benefit assessment pursuant to Germany’s Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG), has examined whether Incivo (telaprevir) offers an added benefit compared with the present standard therapy.

According to the findings of the assessment, telaprevir offers advantages in various groups of patients with chronic hepatitis C infection of genotype 1. The available studies provide proof, indications or "hints” of an added benefit. However, not only the probability but also the extent of added benefit varies, said the IQWiG.

The European Commission has approved Johnson & Johnson (NYSE: JNJ) subsidiary Janssen’s Incivo, a direct acting antiviral (DAA) protease inhibitor, for the treatment of genotype-1 chronic hepatitis C virus (HCV), in combination with peginterferon alfa and ribavirin, in adults (The Pharma Letter September 21, 2011). The drug was developed in collaboration with the USA’s Vertex and Japan’s Mitsubishi Tanabe and is approved and marketed under the trade name Incivek in the USA and Canada (TPLs May 24 and August 23).

In accordance with the approval status, different patient groups are treated for different periods, which was allowed for in the assessment. The dual combination of peginterferon alfa and ribavirin is the present standard therapy, and this was compared with the triple combination of these two standard drugs and telaprevir.

Studies largely only provide data on morbidity and adverse effects

Overall three relevant studies were identified. The outcomes considered were "mortality,” "secondary complications of treatment (morbidity)” measured in the studies by means of the surrogate outcome "SVR,” as well as "health-related quality of life” and "adverse effects.”

The quality-of-life results for treatment-naive (ie, previously untreated) patients without cirrhosis were not statistically significant. No evaluable data on this outcome were available for other patient groups. Due to the too short study duration, the event rates for mortality were too low in all patient groups to be able to draw robust conclusions.

Extent of added benefit cannot be classified on the basis of the surrogate outcome for morbidity

The extent of added benefit cannot be classified on the basis of the surrogate outcome "SVR,” the agency noted. This parameter is not a patient-relevant outcome in itself and there are no studies in which SVR is validated as a surrogate outcome in accordance with the usual criteria employed by IQWiG. Nevertheless, the Institute accepts SVR in the context of this assessment as a surrogate for the reduced incidence of liver cancer. This is because it is currently accepted that patients with no detectable hepatitis C virus in the blood are at lower risk of liver cancer. However, it is not known how many cases of liver cancer can in fact be prevented by telaprevir and it is therefore unclear whether the added benefit can be classified as "minor” "considerable” or "major.” According to the corresponding legal ordinance, the added benefit is thus "unquantifiable.”.Under consideration of the beneficial and harmful effects of telaprevir, overall IQWiG reaches different conclusions for different patient groups.

Advantages for treatment-naive patients without cirrhosis who have a high viral load

Different results for morbidity were shown for treatment-naive patients without cirrhosis, depending on the viral load in the blood at the start of treatment. Proof of an added benefit of telaprevir was only determined for patients with a high viral load. However, the extent of the added benefit is unquantifiable as it refers to the surrogate outcome "SVR.”

For treatment-naive patients without cirrhosis, the data also provide proof and an indication of greater harm due to the adverse effects anaemia and rash, respectively, the extent being classified as "considerable” in the former and "minor” in the latter case. In the consideration of the beneficial and harmful effects of telaprevir, this did not lead to a restriction in the overall conclusion for patients with a high viral load, as these side effects were nearly exclusively classified as "not serious,” said the IQWiG.

In contrast, for treatment-naive patients without cirrhosis who have a low viral load at baseline, the data provide an indication of lesser benefit of telaprevir versus the comparator therapy. This is due to the fact that an added benefit regarding SVR is not proven, so that only the harmful effects are taken into account. An added benefit of telaprevir is not proven for treatment-naive patients with cirrhosis, as the manufacturer dossier did not contain any evaluable data.

Indication of an advantage also in patients with unsuccessful pre-treatment

Depending on the cirrhosis status, different results were shown for patients in whom treatment had so far been unsuccessful (non-responders). Regarding morbidity, the data provide an indication of an added benefit of telaprevir in patients without cirrhosis. The data only provide a "hint” of an added benefit in non-responders with cirrhosis. In this context, "indication” and "hint” refer to the surrogate outcome "SVR.” Therefore the extent of added benefit is unquantifiable. As in the case of treatment-naive patients without cirrhosis, indications of greater harm due to the side effects "anaemia” and "rash” did not lead to a restriction in the overall conclusion.

No additional benefit for relapsed patients

In patients without cirrhosis who relapsed after standard therapy, the treatment regimen deviated from the approval status. Consequently, the added benefit cannot be assessed on the basis of the available data so that an added benefit is not proven, noted the IQWiG.

In patients with cirrhosis who relapsed, the data provide an indication of an added benefit regarding SVR. However, at the same time they also provide an indication of greater harm (extent: considerable) regarding serious adverse events. Under consideration of the beneficial and harmful effects of telaprevir, the IQWiG concluded that overall an added benefit is not proven for this patient group.

Source

BioLineRx Signs Exclusive License Agreement for BL-8020, an Oral Treatment for Hepatitis C

PRESS RELEASE

Jan. 24, 2012, 7:00 a.m. EST

JERUSALEM, Jan 24, 2012 (BUSINESS WIRE) – BioLineRx (tase:BLRX), a biopharmaceutical development company, announced today it has signed a worldwide, exclusive license agreement with Genoscience, a French company focused on viral disease therapeutics, to develop and commercialize BL-8020, an orally available treatment for Hepatitis C.

BL-8020 has been developed for anti-viral therapy by Professor Philippe Halfon, Co-Founder and President of Genoscience. Prof. Halfon is a founder of several biotechnology companies and is world renowned for his work on HIV (AIDS virus), HPV (human papilloma virus causing cervical cancer) and Hepatitis.

BL-8020 acts via a unique mechanism of action, by inhibiting Hepatitis C virus (HCV)-induced autophagy, which differs from the mechanism of currently used anti-HCV agents. BL-8020's safety and efficacy were demonstrated in pre-clinical studies. These studies have shown that BL-8020, when combined with other anti-Hepatitis C virus (HCV) agents, has a synergistic effect. BL-8020's synergistic effect on other therapies is likely to increase their potency and reduce the numerous adverse effects often associated with these drugs, by enabling utilization of lower dosages. In addition BL-8020 may reduce therapy duration, which is currently up to 48 weeks. The use of two drugs acting by different mechanisms is also likely to be beneficial for patients who have developed resistance to current treatments and is an effective strategy used against other viruses such as HIV.

Dr. Kinneret Savitsky, CEO of BioLineRx, said, "We are excited about entering the field of Hepatitis C therapeutics, which is a very important field in the pharmaceutical market today. The current global Hepatitis market is estimated at approximately $6.5 billion and is growing steadily. Current therapies are characterized by numerous severe side effects, long treatment duration and development of resistance. In these respects, BL-8020 has a demonstrated safety and efficacy profile, may shorten therapy duration and may combat resistance by acting as an add-on platform which can potentially be combined with other oral Hepatitis C therapies to increase their efficacy."

"We were impressed by the drug development expertise of the BioLineRx team and are very pleased to collaborate with them for the further development of our product for the treatment of Hepatitis C," said Prof. Philippe Halfon, Co-Founder and President of Genoscience. "There is clearly a huge unmet medical need in finding a safe and effective treatment for the disease, and based on pre-clinical results, its unique mechanism of action and synergistic effect, we believe that our product, especially when combined with other available Hepatitis C drugs, has the potential to bring remedy to millions worldwide."

About Hepatitis C

Hepatitis C infection is a blood borne infection of the liver caused by the Hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to the World Health Organization (WHO), more than 170 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The global Hepatitis market was estimated at $6.5 billion in 2010 and is forecasted to grow to $11.5 billion in 2016.

About BioLineRx

BioLineRx Ltd. is a publicly-traded biopharmaceutical development company. It is dedicated to building a portfolio of products for unmet medical needs or with advantages over currently available therapies. BioLineRx's current portfolio consists of five clinical stage candidates: BL-1020 for schizophrenia has commenced a Phase II/III study; BL-1040, for prevention of pathological cardiac remodeling following a myocardial infarction, is currently undergoing a pivotal CE-Mark registration trial and has been out-licensed to Ikaria Inc. for a total deal value of $282.5 million, in addition to sales royalties; BL-5010 for non-surgical removal of skin lesions has completed a Phase I/II study; BL-1021 for neuropathic pain is in Phase I development and BL-7040 for treating Inflammatory Bowel Disease (IBD) has completed Phase I. In addition, BioLineRx has 12 products in various pre-clinical development stages for a variety of indications, including central nervous system diseases, oncology, infectious diseases, cardiovascular and autoimmune diseases.

BioLineRx's business model is based on acquiring molecules mainly from biotechnological incubators and academic institutions. The Company performs feasibility assessment studies and development through pre-clinical and clinical stages, with partial funding from the Israeli Government's Office of the Chief Scientist (OCS). The final stage includes partnering with medium and large pharmaceutical companies for advanced clinical development (Phase III) and commercialization. For more information on BioLineRx, please visit www.biolinerx.com .

The estimates and judgments with respect to BL-8020 included in this release are considered forward-looking statements, which involve certain risks and uncertainties, and are based on information available to the Company at the time of this release. Such estimates may not be realized or may be only partially realized, due to the significant uncertainty characterizing research and development activities in general, particularly those of drug development, including changes in regulation or uncertainty relating to the application of regulation, unexpected delays in obtaining regulatory approval, unexpected delays in patient recruitment for clinical trials, unexpected delays in other clinical trial preparatory activities, inefficiencies, inability to manufacture, toxicity, a high level of risk/reward in comparison. Any forward-looking statements represent the Company's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

SOURCE: BioLineRx Ltd.

Source

Rapid HIV Test Results Better With Blood

By Michael Smith, North American Correspondent, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

A rapid HIV test gives slightly less exact results when used with oral samples compared with blood samples, researchers reported.

In pooled results from a systematic review and meta-analysis, the sensitivity of the Oraquick rapid test was 98.03% when oral samples were used, compared with 99.68% using blood, according to Nitika Pant Pai, MD, of McGill University Health Centre in Montreal, and colleagues.

On the other hand, the specificity of the test was similar regardless of the type of samples at 99.74% for oral samples and 99.91% for blood, Pant Pai and colleagues reported online in The Lancet Infectious Diseases.

The Oraquick test, originally approved as a point-of-care HIV test for use with blood, received approval from the FDA in 2004 for use with oral mucosal transudate, the researchers noted. The test has become especially popular in developing countries.

Given the increased emphasis on HIV testing, data on the performance of the Oraquick test using the different sampling approaches will be important to help clinicians and patients interpret results, they argued.

Pant Pai and colleagues analyzed data from 45 studies, including 24 that could be used to understand the comparative accuracy of the test using oral or blood samples, and 21 that could be used to analyze positive predictive values. Because they depend on prevalence, positive and negative predictive values can only be derived from cross-sectional or other population-based studies.

Seven of the 24 accuracy studies contained head-to-head comparisons, while six only gave results for oral samples and 11 only looked at whole blood samples.

Pooling the analyses showed that the sensitivity of the test was about 2% lower when oral samples were used, but specificity was about the same, the researchers reported. In other words, using oral samples was likely to yield more false-positive results.

The researchers calculated positive predictive values using the 21 studies that permitted the analysis. They found that the test's value was similar regardless of sample type in high-prevalence regions, but differed if prevalence was low.

In high-prevalence groups, defined as more than 1% of the population infected with HIV, the positive predictive value of the test was 98.5% using blood samples and 98.65% using oral samples.

But in low-prevalence populations, the value for blood samples was 97.65% compared with 88.55% for oral samples.

Put another way, if the prevalence is low, a positive result using oral samples is less likely to be correct than if blood were used.

The researchers cautioned that although the test's sensitivity seems to be lower with oral versus blood specimens, the estimates "were at the extreme upper end of the range and there is a great deal of overlap" in confidence intervals.

It's possible that the "clinical significance of this difference might also be overshadowed by intrinsic variability in host status and time of testing relative to exposure," they added.

Much of the data comes from high-income settings and the rest from well controlled studies in developing settings, they noted, so the results may not reflect routine testing services in poorer areas.

Finally, the results only apply to the Oraquick test, they wrote.

The Oraquick test is attractive because it is convenient and non-invasive, commented Chi Chiu Leung, MBBS, of the Hong Kong Department of Health, and Shui Shan Lee, MD, of the Chinese University of Hong Kong.

Those characteristics might help increase the rate of HIV testing, they argued in an accompanying comment article, but they appear to come "at the cost of a substantial false-positive rate."

That false-positive rate has to be taken into consideration by clinicians as the rapid test becomes more widely used, they concluded, especially in areas where the prevalence of HIV is low.

Confirmatory testing will remain important, given that the diagnosis of HIV has such profound implications, they wrote.

The study was supported by the Canadian Institutes for Health Research. The authors said they had no conflicts of interest.

The comment authors said they had no conflicts of interest.

Primary source: The Lancet Infectious Diseases
Source reference:

Pant Pai N, et al "Head-to-head comparison of accuracy of a rapid point-of-care HIV test with oral versus whole-blood specimens: a systematic review and meta-analysis" Lancet Infect Dis 2012.

Additional source: The Lancet Infectious Diseases
Source reference:

Leung C, Lee S "Rapid HIV tests: from meta-analysis to field application" Lancet Infect Dis 2012.

Source

Teens Lacking in Protection Against Hepatitis A

By Todd Neale, Senior Staff Writer, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Most adolescents have not been vaccinated against hepatitis A virus, leaving them vulnerable to serious disease as they move into adulthood, a cross-sectional study showed.
In 2009, only 42% of U.S. teens ages 13 to 17 had received at least one dose of the vaccine and only 29.5% had received two doses, according to Christina Dorell, MD, MPH, of the CDC's National Center for Immunization and Respiratory Diseases in Atlanta, and colleagues.
Rates were highest in states that had been covered by recommendations for routine hepatitis A vaccination the longest, the researchers reported in the February issue of Pediatrics.

Finally, in 2006, ACIP recommended routine vaccination for all U.S. children starting at age 1, bringing the remaining 33 states and the District of Columbia into the fold.

Gradual implementation of the recommendations has been associated with a dramatic drop in rates of hepatitis A infection in the U.S. The virus likely will persist, however, because of introductions through contaminated food, international travel, and international adoption, placing unvaccinated individuals at risk.

To assess vaccine coverage in U.S. adolescents, Dorell and colleagues turned to the 2009 National Immunization Survey-Teen, which collected information through landline telephone surveys of parents and guardians and mailed surveys of vaccination providers.

Most of the 20,066 teens, ages 13 to 17, included in the current analysis had not received any doses of vaccine by 2009.

One-dose coverage was 74.3% among the states covered by a routine vaccination recommendation since 1999; 54% among those covered by a recommendation for consideration of the vaccine since 1999; and 27.8% for the remaining states not covered by a recommendation until 2006.

The most consistent predictor of having been vaccinated was receipt of a recommendation from a healthcare professional. That was associated with a 30% to 160% relative increase and 21% to 34% absolute increase in coverage rates among the three groups of states.

"Recommendations from healthcare providers increase parental acceptance of vaccination, and parents change their minds about delaying and refusing vaccines because of information or assurances from healthcare providers," according to Dorrell and colleagues.

Only one-quarter of the teens in the study received such a recommendation, however.

"Provider concerns about vaccine reimbursement and insurance coverage and some physicians' perception that hepatitis A is not a significant health problem have been identified as barriers to recommending [the vaccine]," the authors wrote.

"As a result, it may be useful to continue educating vaccination providers about the severity of hepatitis A infection among adolescents and adults and the safety and high efficacy of [the vaccine], which can be given to anyone needing or wishing protection."

Aside from provider input, other factors that were tied to vaccination rates were presence of a state requirement, racial and ethnic background, type of living area (urban, suburban, or rural), household income, and geographic region.

The researchers acknowledged some limitations of the study, including the possibility that it may not be representative of households without landline telephones. Also, they relied on parental report to determine whether a healthcare provider gave a recommendation about the vaccine. There was the possibility of nonresponse bias and the potential for incomplete information from the provider regarding vaccination.

The authors reported that they had no conflicts of interest.

Primary source: Pediatrics
Source reference:
Dorell C, et al "Hepatitis A vaccination coverage among adolescents in the United States" Pediatrics 2012; 129: 213-221.

Source

FDA Warnings Not Heeded Equally

By Kristina Fiore, Staff Writer, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

The attention paid to FDA notices about drug risks appears to be highly variable, with some notices having a wide impact and others garnering a delayed response or none at all, researchers found.

In a review of the literature, serious adverse event warnings appeared to be most heeded of all FDA communications, but response still varied depending on the drug, Caleb Alexander, MD, of the University of Chicago, and colleagues reported in Medical Care.

For instance, use of rosiglitazone (Avandia) fell tremendously after an FDA warning about cardiovascular events associated with use of the drug

On the other hand, cautioning against the use of long-acting beta-agonists (LABAs) without inhaled controller medications didn't impact the use of those drugs in asthma, the researchers found.

"We will need a better understanding of how to make [FDA risk communications] work, and where they can go wrong," Alexander said in a statement. "And we will need more and better studies of the successes and failures of this process."

To assess the full impact of FDA risk communications on the use of drugs and other outcomes, the researchers looked at 49 studies, published between 1990 and 2010, that evaluated the success of these notices.

They divided the notices into four categories:

• Warnings about serious adverse events
• Recommendations against use in specific subpopulations
• Prevention of drug-drug interactions
• Calls for increased lab or clinical monitoring

Warnings about potential serious adverse events with specific drugs were associated with large drops in use of those agents, but the impact varied by drug, as seen with rosiglitazone versus LABAs, the researchers found.

Notices about use of drugs for certain populations tended to spill over into others, they reported. For instance, a warning about antidepressant use in children and adolescents led to declines in their use among adults as well.

"As with other public policies, FDA communications have the potential for unintended consequences," they wrote.

They also found that warnings about drug-drug interactions appeared to take a long time to be put into practice. Several studies found the largest declines in cisapride (Propulsid) co-prescribing happened only after a third FDA warning, and the greatest drop in terfenadine (Seldane) co-prescribing didn't occur until 18 months after the initial notice.

Finally, there was no evidence that practitioners heeded recommendations about increased monitoring, though some may have done so transiently, Alexander and colleagues found.

Rates of glucose testing for patients on antipsychotics, for example, went unchanged after the FDA advised keeping watch for hyperlipidemia and diabetes, while rates of liver enzyme monitoring after a black box warning for troglitazone (Rezulin) increased slightly after FDA warnings, but waned again over time.

Studies that assessed provider attitudes about FDA communications generally found high levels of clinician awareness of warnings and label changes.

The researchers concluded that based on settings where incident and prevalent use were examined, notices are adopted more quickly for new patients rather than those continuing on their medication.

They also said the findings suggest that "warnings will be most effective in cases where they are specific, where acceptable alternatives are available, and where the messaging is reinforced over time."

They called for more research on factors associated with fast and sustained responses to risk communications, and continued work on characterizing the effects of advisories and warnings on a variety of behaviors "to enhance the science of risk communication regarding prescription drugs."

The study was limited by the heterogeneity of the included analyses and because regulatory advisories have a level of complexity that may not be fully captured by the studies.

The researchers reported no conflicts of interest.

Primary source: Medical Care
Source reference:
Dusetzina SB, et al "Impact of FDA drug risk communications on healthcare utilization and health behaviors: A systematic review" Med Care 2011.

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