HIV treatment under the Affordable Care Act: What you need to know

More than 50,000 new cases of HIV occur in the U.S. annually. (Shutterstock photo)

Posted on October 2, 2012 By Hope Gillette

The Affordable Care Act (ACA) will impact the lives of millions of people in the United States, and while attention has been given to the broader implications of the law, the ACA will mean something specific for every medical issue. For Latinos and other groups suffering disproportionately from HIV, the health reform law makes significant changes to how the condition can be treated. HIV treatment and prevention will be greatly affected by the ACA.

According to a report from the Kaiser Family Foundation (KFF), the ACA “is expected to significantly expand access for people with HIV, many of whom are uninsured or otherwise unable to access affordable and stable health care coverage.”

With approximately 50,000 new HIV infections in the United States each year, according to the Centers for Disease Control (CDC), the viral infection remains a public health concern, especially among certain demographics.

Latinos accounted for 20 percent of all new HIV infections in 2009, the year from which the most recent data is available. During that year, the HIV infection rate for Latinos was three times that of non-Hispanic whites, states the CDC.

The access to affordable health care is the crux of how the ACA will benefit individuals with HIV; however, shortly after the ACA was passed, KFF notes the White House released the first national HIV/AIDS strategy. The initiative included three main goals:

• Reduce the number of new yearly infections
• Increase access to care to those HIV positive
• Reduce HIV-related health disparities

The ACA will assist those goals through the implementation of a number of provisions, many of which will be in place before 2014.

Some of those provisions which can be applied directly to HIV treatment include:

• A change to Medicare drug coverage which makes the AIDS Drug Assistance Program (ADAP) spending on HIV drugs considered true-out-of-pocket (TrOOP) costs for purposes of reaching the Medicare catastrophic drug coverage level
• The elimination of lifetime limitation on insurance coverage
• The elimination of denial for coverage based on a pre-existing condition
• Providing a discount on brand named drugs as well as generic drugs through the year 2020
• The creation of the Prevention and Public Health Fund; $30 million was allocated for HIV prevention activities
• Free preventative HIV screening tests
• Enhanced data collection regarding chronic illnesses

While many other provisions in the ACA will benefit HIV sufferers, KFF states it is the continuation of care which will mean the most for people with this condition.

“Recently, researchers have begun to popularize the concept of an HIV ‘treatment cascade’ which depicts the continuum of HIV care, from initial diagnosis of HIV through to maximal viral suppression,” stated the report.

KFF explains that a significant drop off occurs at each stage of HIV treatment, something the ACA should help to rectify. Of the 82 percent of people formally diagnosed with HIV, 66 percent have been linked to care, but only 37 percent have been retained in care. That’s approximately 300,000 people who do not seek continuation of HIV treatment.

“The Affordable Care Act has already led to improvements in access to and quality of care for people living with HIV and, when fully implemented in 2014, is expected to significantly expand access even further,” concluded the report. “There are also key opportunities for working to ensure that new systems of care will include high quality HIV standards for realizing the potential of the ACA to be a “game changer” in reducing the burden of the HIV epidemic in the United States.”

Source

Efficacy and Tolerability of Pegylated Interferon-α-2a in Chronic Hepatitis B: A Multicenter Clinical Experience

From Journal of Gastroenterology and Hepatology

Dilip Ratnam; Anouk Dev; Tin Nguyen; Vijaya Sundararajan; Hugh Harley; Wendy Cheng; Alice Lee; Ferry Rusli; Robert Chen; Sally Bell; Stephen Pianko; William Sievert

Posted: 10/01/2012; J Gastroenterol Hepatol. 2012;27(9):1447-1453. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Background and Aim: Pegylated interferon-α (PEG-IFN) provides potential advantages over nucleos(t)ide analogues in the treatment of chronic hepatitis B (CHB) given its finite course, durability and lack of drug resistance. Much of the evidence is derived from controlled studies and it is unclear whether these results can be replicated in an everyday, non-controlled setting. The aim of this study was to examine the efficacy and tolerability of PEG-IFN-α2A in CHB patients in a clinical setting.
Methods: Chronic hepatitis B patients treated with PEG-IFN-α2A (180 μg/week, 48 weeks) at five tertiary hospitals were retrospectively identified. Baseline demographic and clinical data, on-treatment virological and serological responses and adverse events (AE) were recorded. Treatment outcomes were defined as alanine aminotransferase (ALT) normalization, hepatitis B virus DNA < 351 IU/mL and hepatitis B e antigen (HBeAg) seroconversion.
Results: Sixty three HBeAg positive patients were identified (65% male, 80% born in Asia, 84% with viral loads > 6log IU/mL, 9.5% advanced fibrosis). Six months after therapy 46% achieved normalization of ALT, 16% had viral loads < 351 IU/mL and 32% achieved HBeAg seroconversion. 29 HBeAg negative patients were treated (75% male, 86% born in Asia, 48% had viral loads > 6log IU/mL, 24% advanced fibrosis). Six months post-treatment, 55% and 36% maintained a normalized ALT and HBV DNA < 351 IU/mL, respectively. Optimal viral suppression was maintained in 50–75% of patients over 2 years of follow up. 6.5% of all patients discontinued therapy due to AEs.
Conclusion: In everyday clinical practice PEG-IFN therapy in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials.

Introduction

Chronic infection with the hepatitis B virus (CHB) is a global health concern, affecting up to 400 million people worldwide. Between 20% to 40% of affected individuals will develop the most serious consequences of cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC), resulting in approximately 500 000 to 1.2 million deaths per year worldwide.^[1] Treatment can reduce mortality from end stage liver disease.^[2–6] Two classes of antiviral therapy are available—nucleoside or nucleotide analogues, and interferon-α (INF-α) (standard or pegylated forms). The choice of a particular therapy for a given individual can be complex, influenced by factors including age, serum alanine transasminase (ALT), histological findings, hepatitis B e-antigen (HBeAg) status, hepatitis B virus (HBV) viral load and genotype, previous therapy and tolerability of potential adverse effects. Globally, nucleos(t)ide analogues are the more commonly used option, often favored due to their combination of high antiviral potency, ease of use and high tolerability. However, this class has limitations such as the potential development of viral resistance, as well the need for long term therapy in many individuals.

Interferon-α acts against HBV by both immunomodulatory and direct antiviral mechanisms. Compared with the nucleoside analogues it is associated with higher rates of HBeAg to anti-HBe seroconversion, greater durability of response and lack of antiviral resistance.^[7] However, it is not as potent at achieving viral suppression, is less convenient to use and is associated with a number of side effects. Pegylated interferon-α (PEG-IFN) was introduced approximately a decade ago with a view to improving efficacy, convenience and tolerability through its improved pharmacodynamic profile compared with standard interferon. While the evidence suggests that PEG-IFN is both effective and safe in the treatment of CHB, this data has been derived almost exclusively from a handful of controlled trials. Whether these results can be replicated in a day to day, non-controlled setting is unclear, particularly given concerns that tolerability of the drug may adversely affect adherence. In this study we performed a retrospective evaluation of the outcomes of PEG-IFN-α therapy for both HBeAg positive (HBeAg[+]) and HBeAg negative (HBeAg[−]) CHB patients treated in Australian tertiary hospitals, with the aim of determining effectiveness and tolerability in an everyday clinical setting.

Methods

Five tertiary medical centres in Australia participated in this study. Institutional databases were used to identify individuals with CHB commenced on a 48 week course of Pegylated Interferon-α2a (Pegasys, Roche Products, Dee Why, Australia) at a dose of 180 μg weekly by subcutaneous injection between 2005 and 2009.

Baseline data included patient demographics, previous antiviral therapy and hepatic fibrosis scores (METAVIR scoring system).^[8] Serum ALT (U/L) was recorded at baseline, at 4-weekly intervals during therapy and at 12 and 24 weeks post-therapy. HBeAg, anti-HBe, and HBV DNA viral load (IU/mL) were recorded at 3-monthly intervals until 24 weeks post-treatment. HBV viral load was measured using either the Bayer Versant bDNA HBV 3.0 test (range 351–1.8 × 10⁷ IU/mL), Roche Cobas Taqman assay (55–1.1 × 10⁸ IU/mL) or Abbott M2000 test (15–1 × 10⁹ IU/mL). HBV genotyping was tested at only two institutions while hepatitis B surface antigen (HBsAg) and anti-HBs were not routinely measured after the completion of therapy.

Treatment outcomes were defined as normalization of serum ALT, HBV viral suppression, loss of HBeAg and development of anti-HBe and measured at the end of therapy and after 6 months of follow up. The upper limit of the normal (ULN) range for ALT at one hospital was 45 U/L for males and 35 U/L for females, and 55 U/L for all patients at the remaining hospitals. Optimal viral suppression was considered to be a viral load ≤ 351 IU/mL, which was the lower limit of detection of the Bayer Versant test used by most centres. Sustained virological suppression (SVS) was defined as the achievement of optimal viral suppression 6 months after completing therapy. Suppression of HBV DNA levels to below 2000 IU/mL was used as a secondary measure of efficacy in line with the threshold used in numerous guidelines to differentiate between active and inactive CHB.^[9–11] Early relapse was defined as a rebound in viral load to ≥ 351 IU/mL within 6 months of having achieved optimal suppression at the end of therapy. Patients achieving either level of viral suppression were followed for 2 years to assess the durability of the response. Tolerability and safety were assessed by the ability to complete 48 weeks of treatment, incidence of adverse events (AE) and deaths.

Statistical Analysis

Statistical comparisons were performed using Stata Statistical software Version 11 (StataCorp, College Station, TX, USA). Continuous variables with normal distribution were expressed as mean and standard deviation, and variables with skewed distribution as median and range. Baseline categorical variables were compared by Pearson's χ² test, and continuous variables were compared by the Mann–Whitney U-test. The relation between characteristics at baseline and during therapy and post-treatment response was examined by logistic regression analyses. All statistical tests were two-sided. Statistical significance was taken as P < 0.05.

HBeAg[+] Patients

A total of 63 HBeAg[+] patients were commenced on PEG-IFN, of which 58 (92%) completed the 48 week course. Four patients ceased treatment prematurely due to AEs and one was lost to follow up before completion of therapy. A further two were lost to follow up after treatment. Patient demographics and baseline investigations are outlined in Table 1. The majority were male (65%), born in North or South East Asia (80%) and the median age was 32.5 years. Of the eight (13%) patients previously exposed to antiviral therapy (six Lamividine[LAM] monotherapy two combination LAM and Adefovir), four had confirmed LAM resistance mutations (M204V/I + L180M). Of the 23 patients who were genotyped (Gt), three were Gt A, eight Gt B, 10 Gt C and two Gt D, reflecting the ethnic origins of the cohort. Serum ALT > 2×ULN occurred in 75% of patients, 84% had a viral load > 6 log IU/mL and 9.5% had advanced fibrosis on pretreatment liver biopsy.

Biochemical, serological and virological responses are shown in Table 2. By the end of 48 weeks of therapy 52% of patients had normalized serum ALT and this was sustained in the majority of patients over the 6 month follow up period. A total of 20 (32%) individuals lost HBeAg and seroconverted to anti-HBe over the study period. In three patients this response was delayed, occurring in the 6-month post-treatment follow-up period. Despite not being routinely measured, two (3.5%) patients (both genotype A) achieved loss of HBsAg.

The proportion of patients with optimal viral suppression at the end of treatment and sustained viral suppression at the end of 6 months follow up was 25% and 16%, respectively. Viral load dynamics during the 48 weeks of treatment were similar in the SVS and early relapser groups, with a progressive decline in mean viral load over the first 36 weeks that was most marked during the initial 12 weeks of therapy (Fig. 1a). This was in contrast to those who did not respond to treatment who after an initial modest decline in viral load demonstrated little change thereafter.

Figure 1. Virological responses to pegylated interferon-α (PEG-IFN). (a) Viral dynamics of hepatitis B e antigen (HBeAg) [+] patients. Those patients displaying sustained virological suppression (SVS) (solid light grey line) and early relapse (black line) displayed a similar progressive decline in mean viral load during therapy, with the latter group subsequently experiencing a rapid rebound soon after completing PEG-IFN. In contrast, those who were virological non-responders (dark grey broken line) showed little change in mean viral load after an early modest decline so that significant differences were apparent by 12 weeks compared to the other two groups. (b) Viral dynamics of HBeAg [−] patients. These patients who achieved SVS had a significantly lower median viral load at baseline compared with the non-responders (5.1 log vs 6.3, P = 0.02) but not the early relapsers (5.1 vs 6.0, P = 0.12). The viral load dynamics on treatment followed a similar trend to the HBeAg[+] cohort, though the time taken by the early relapsers and SVS patients to achieve optimal suppression was shorter. Despite experiencing a modest fall over the 48 weeks, the median viral load of the non-responders remained significantly higher than the responders and early relapsers at all timepoints during therapy. Non-responders; , Early relapsers; , Sustained viral suppression.

HBeAg[−] Patients

Twenty-seven of 29 patients completed the 48 week course, with two ceasing treatment prematurely due to AEs (one of whom was subsequently lost to follow up). Compared with the HBeAg[+] group, these patients were older (42 vs 33 years, P < 0.005), had a greater proportion of advanced fibrosis (24 vs 9.5%, P = 0.03), lower baseline ALT (median 68 vs 123 IU/L, P = 0.003) and fewer individuals with a viral load > 6 logIU/mL (48% vs 84%, P = 0.001) (Table 1). These differences are consistent with the natural history of CHB, where the HBeAg[−] phase usually represents a later and often more advanced stage of disease. Of the four patients who had previously received antiviral therapy, none had documented resistance mutations.

Treatment outcomes are shown in Table 3. Six months after treatment, 55% of patients had an ALT within normal range and 37% achieved sustained viral suppression. Patients who achieved SVS had a significantly lower median viral load at baseline compared with the non-responders (5.1 log vs 6.3, P = 0.02) but not the early relapsers (5.1 vs 6.0, P = 0.12) (Fig. 1b). The viral load dynamics on treatment followed a similar trend to the HBeAg[+] cohort, although the time taken by the early relapsers and SVS patients to achieve optimal suppression was shorter. Despite experiencing a modest fall over the 48 weeks, the median viral load of the non-responders remained significantly higher than the responders and early relapsers at all timepoints during therapy. Two patients (both genotype C) lost HBsAg without seroconverting to anti-HBs.

In order to determine factors that might allow for individualization of therapy, we analyzed a number of baseline factors that might predict virological response. These included age, gender, genotype, previous treatment, serum ALT (stratified into < 2×ULN, 2 − 5×ULN and > 5×ULN), advanced fibrosis and HBV DNA levels greater or less than 4 or 6 log IU/mL (Table 4). Of these, only viral load > 6 log IU/mL in HBeAg[−] patients had significant predictive value, with these patients far less likely to achieve SVS (OR 0.12, P = 0.017). We then analyzed the on-treatment variables of ALT and viral load at 12 and 24 weeks of treatment. Similar to baseline, the only significant predictor was a week 12 viral load > 6 log IU/mL in HBeAg[−] patients, which was also associated with a reduced chance of achieving SVS (OR 0.57, P = 0.009)(Table 5).

Long Term Durability of Viral Suppression

HBeAg[+] Long term follow up data was available on 8 of 11 (72%) HBeAg[+] patients who achieved both SVS and HBeAg seroconversion. The durability of this response decreased from 100% at 1 year to 75% at 2 years; one patient was commenced on Entecavir for an increasing viral load and one was lost to follow up. For patients with viral suppression < 2000 IU/mL, 60% maintained this response 2 years after treatment.

HBeAg[−] Long term follow-up data was available for 8 of 10 patients who achieved SVS and normalized ALT. After 2 years, four patients (50%) maintained this response while three had detectable viremia between 2 to 4 log IU/mL and one patient with a viral load < 351 IU/mL was commenced on Entecavir due to advanced fibrosis. Two-year follow up data were available for 10 of 15 patients who achieved a HBV DNA < 2000 IU/mL and demonstrated a durable response in 60%.

Tolerability

Four HBeAg[+] and two HBeAg[−] patients ceased therapy prematurely due to AEs. In four patients this was a consequence of non-specific symptoms such as fever, headaches and fatigue, while two had more serious disease including pneumonitis and thrombocytopenia leading to GI hemorrhage. Two other patients developed symptomatic hyperthyroidism that required treatment with carbimazole but were able to complete a full course of therapy. There were no deaths.

Discussion

To date, most of the evidence pertaining to PEG-IFN efficacy has been derived from large controlled trials.^[7,12–15] Outcomes from such studies are often better than what can be achieved in routine clinical practice as a consequence of the increased monitoring, support and improved compliance. Given the relatively low rates of viral suppression following PEG-IFN, even in these controlled circumstances, and the expectation of poor tolerability, the level of response that can be expected in a non-trial setting is unclear. Therefore, we studied a cohort of patients treated in the setting of routine clinical care in order to address these concerns. This multicentre study provides a number of valuable insights relating to the use of PEG-IFN for CHB in an everyday clinical setting.

In HBeAg[+] disease, we identified a PEG-IFN induced HBeAg seroconversion rate of 32% that compared well with the rates of 21% to 32% in controlled studies. ALT normalization occurred in 46%, which was also consistent with the published rates of 35–48%.^[7,12,14,15] The definition of optimal viral suppression has evolved with increasingly sensitive assays to measure viral load, the degree of suppression now achievable with oral antivirals and evidence suggesting viral load as an independent predictor of adverse outcomes.^[16] We evaluated viral load suppression below 351 IU/mL (lower limit of detection of our assay) and 2000 IU/mL, which is a widely accepted cutoff for inactive disease.^[9–11] Six months after completing treatment, 16% and 22% of HBeAg [+] patients remained below these respective thresholds. The combined response of viral load suppression plus HBeAg seroconversion was seen in 13% and 19% of patients, an even more desirable result as the combined outcome is more likely to decrease the risk of long term complications.^[17,18]

PEG-IFN has typically been used less frequently in HBeAg[−] disease, largely due to low response rates, the absence of an endpoint such as HBeAg seroconversion and the high rates of relapse previously seen following conventional interferon.^[10] The sustained viral suppression rate (< 351 IU/mL) of 36% that we observed in this group appears encouraging, though difficult to compare to other controlled studies, which used a lower cutoff of 400 copies/mL (approximately 50 IU/mL) and achieved suppression rates of 9–19%.^[19,20] In relation to the threshold of < 2000 IU/mL, our viral suppression rate of 50% compared favorably with a rate of 20% for a comparable cutoff in a recent controlled trial and a rate of 43% below 4000 IU/mL observed in a large phase 3 registration study.^[19,20]

Another advantage of IFN based therapy is the durability of the response. Three-year follow-up data from the large registration studies revealed PEG-IFN induced HBeAg seroconversion was sustained in over 80% of responders, with 60% also maintaining a viral load less than 2000 IU/mL. Similarly, in HBeAg negative patients the initial rates of viral suppression were also effectively well maintained over the 3 years.^[21,22] Though not part of the initial study design, we were able to follow the majority of viral responders for up to 2 years post-treatment. In both HBeAg positive and negative patients with initial viral suppression below 2000 IU/mL (and HBeAg seroconversion in the HBeAg[+] group) the response was maintained in approximately 60% over the 2 years. For those with initial suppression below 351 IU/mL the durability ranged from 50% in the HBeAg [−] group to 75% in the HBeAg[+] group. Given the small number of patients involved, further studies are required to definitively assess durability of response in a non-controlled setting. The potential benefit of such long term IFN induced viral suppression is shown in studies involving standard IFN-α in which HBsAg clearance rates in both HBeAg positive and negative patients displaying an initial response to IFN-α exceeded 60% over 15 years.^{[3,4,6,23–25]} Most importantly, these studies also show that successful IFN-α therapy reduces the risk of developing cirrhosis, hepatic decompensation and HCC.^[3,25–27]

Concerns relating to AEs and poor tolerability are often cited as a barrier to the use of PEG-IFN. However, observational studies demonstrate that when used in CHB, PEG-IFN is associated with significantly less AEs, treatment withdrawals and impact on health related quality of life compared with when used as monotherapy in chronic hepatitis C.^[28] Although our cohort included a significant proportion with advanced fibrosis, we found PEG-IFN to be well tolerated, with 94% of all patients able to complete 48 weeks of therapy. Nevertheless, given the potential AEs and lower antiviral potency compared with the nucleos(t)ide analogues, identifying and treating patients that are more likely to respond to PEG-IFN is important in defining its optimal use in CHB therapy. Multiple studies have demonstrated that female sex, high serum ALT, low HBV viral load and genotype A are among these factors.^[29–31] Apart from the negative predictive value of a high viral load in HBeAg negative patients, our study was unable to confirm the predictive value of the other baseline variables, which may be related to our sample size. The predictive value of "on treatment" markers such as the week 12 HBV viral load has also been studied.^[32] We found that the failure to suppress viral load to below 6log IU/mL by week 12 of therapy was an indicator of poor outcome in HBeAg[−] patients. Recently, the emergence of quantitative HBsAg and HBeAg measurements as both pre- and on-treatment predictors of outcome has been another encouraging development that is likely to improve results.^[33–37] Not only can these measurements contribute to better patient selection but in future may also form the basis of on-treatment stopping rules similar to that used in HCV therapy.

There are some limitations to our study due to retrospective data collection that restrict its comparability to data from prospective controlled studies. HBV genotype, a factor shown to influence PEG-IFN induced HBeAg seroconversion rates was only tested in 41% of the cohort. Nevertheless it is unlikely that our outcomes were skewed by genotype given that over 80% of our patients were from East Asia where genotypes B and C predominate. These two have a modest influence on outcome compared with genotypes A and D, which are the most and least favorable genotypes, respectively.^[31] The upper limit of normal range of 55 U/L for ALT was also higher than that used in the majority of controlled trials as well as current guidelines. We elected to use this limit in assessing biochemical response given it formed part of the range used by the majority of the centers in clinical decision making. This may, however, have led to an overestimation of ALT normalization rates in our study when compared with the existing literature. Similarly, differences in the viral load detection limits of assays used in our study (< 351 IU/mL) and previous trials (50 IU/mL) made direct comparisons difficult.

In conclusion, our study provides a "real world" perspective to data obtained from controlled studies. Evaluating over 90 patients, we found that both HBeAg positive and negative patients treated in a clinical setting can expect efficacy and safety outcomes equivalent to those seen in those large trials. In addition, our cohort was principally of Asian ethnicity, in which genotypes B and C, typically associated with poorer outcomes than genotype A, predominated. Combined with the existing literature these results should engender a greater sense of confidence regarding the use of PEG-IFN. It is also likely that the availability of well characterized pretreatment and on treatment predictors will allow greater individualization of therapy in future to maximize beneficial patient outcomes.

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Source

Human hepatitis threat present in domestic pigs

By Sarah Guy, medwireNews Reporter

02 October 2012

Zoonoses Public Health 2012; 59: 477–481

medwireNews: The prevalence of hepatitis E virus (HEV) in domestic pigs is between 10% and 30%, with a likelihood that infected pigs enter the pork production chain thereby threatening public health, indicate Portuguese study results.

Fecal samples from just over a fifth of pigs from five industrial pig farms included in the study tested positive for HEV RNA, with a higher detection rate in younger than older animals, report the researchers.

Furthermore, all HEV-positive samples that were sequenced by polymerase chain reaction (PCR) were genotype 3 - which "together with genotype 4, is found to be responsible for human autochthonous HEV infection in industrialized countries," says the team.

"Considering that zoonotic spread has been proposed, this study provides insight on HEV sequences circulating in the pig population in Portugal...[where] there is a strong tradition of pork consumption," comment Alessandra Berto (Wageningen University and Research Centre, Lelystad, the Netherlands) and co-workers.

The team collected 40 pig fecal samples between December 2010 and February 2011 from five farms containing every age group of pig: weaners, growers, fatteners, and sows.

Samples were tested via PCR and sequencing and phylogenetic analysis, which revealed the presence of HEV-positive feces at every farm in the study. Indeed, HEV-positive feces was detected in pigs from every age group, at 32% in weaners and fatteners, 20% in growers, and 4% in sows.

The overall prevalence of HEV-positive samples was 22%, report Berto and colleagues.

One HEV-positive sample from each farm was randomly selected to undergo realtime PCR, and all five sequences were characterized as genotype 3, write the researchers in Zoonoses and Public Health.

"There is now compelling evidence that in industrialized countries, human HEV infection mainly originates from swine," they explain, adding that with the results presented in their study, "it is clear that HEV is highly circulating."

They conclude that in Portugal: "HEV-infected animals are likely to enter the pork production chain and hence HEV contaminations in the food chain are likely to occur. This could be an increasing public health concern."

medwireNews (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

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The Effectiveness of Current Acute Variceal Bleed Treatments in Unselected Cirrhotic Patients: Refining Short-Term Prognosis and Risk Factors

Subject Category: Liver

Am J Gastroenterol advance online publication 25 September 2012; doi: 10.1038/ajg.2012.313

Lucio Amitrano MD¹, Maria Anna Guardascione MD¹, Francesco Manguso MD¹, Raffaele Bennato MD¹, Antonio Bove MD¹, Claudio DeNucci MD¹, Giovanni Lombardi MD¹, Rossana Martino MD¹, Antonella Menchise MD¹, Luigi Orsini MD¹, Salvatore Picascia MD¹ and Elisabetta Riccio MD¹

¹Gastroenterology Unit, AORN A. Cardarelli, Naples, Italy

Correspondence: Lucio Amitrano, Gastroenterology Unit, AORN A. Cardarelli, Via Morghen 92, Napoli 80129, Italy. E-mail: luamitra@tin.it

Received 29 January 2012; Accepted 10 August 2012
Advance online publication 25 September 2012

Abstract

OBJECTIVES:

The mortality from esophageal variceal hemorrhage in liver cirrhosis patients remains approximately 15–20%. Predictors of short-term outcomes, such as the hepatic venous pressure gradient, are often unavailable in the acute setting. Clinical variables seem to have a similar predictive performance, but some variables including active bleeding during endoscopy have not been reevaluated after the utilization of endoscopic banding as endoscopic procedure. In addition, patients with severe liver failure are often excluded from clinical trials. The aim of this study was to prospectively reevaluate the risk factors affecting a 5-day failure after acute variceal bleeding in unselected cirrhotic patients, managed with the current standard treatment using vasoactive drugs, band ligation, and antibiotics.

METHODS:

One hundred and eighty five patients with liver cirrhosis and variceal bleeding admitted from January 2010 to July 2011were evaluated.

RESULTS:

Hepatocellular carcinoma was present in 28.1% of cases and portal vein thrombosis (PVT) was present in 17.3% of cases. Band ligation was feasible in 92.4% of cases. Five-day failure occurred in 16.8% of cases; 12 patients (6.5%) experienced failure to control bleeding or early rebleeding, and 66.7% of patients died within 5 days. The overall 5-day mortality rate was 14.6%. By multivariate analysis, we determined that Child-Pugh class C, a white blood cell count over 10×10⁹/l, and the presence of PVT were the only independent predictors of the 5-day failure.

CONCLUSIONS:

The prognosis of a consistent group of liver cirrhosis patients with variceal bleeding remains poor. The current treatment is highly effective in controlling variceal bleeding, but mortality is related mainly to the severity of liver failure.

Source

Aethlon Medical Releases Hepatitis C Virus (HCV) Treatment Protocol and Inclusion/Exclusion Criteria Underlying Compassionate-Use Commercialization Program

SAN DIEGO, Oct. 2, 2012 /PRNewswire/ -- Aethlon Medical, Inc. (OTCBB: AEMD), the pioneer in developing selective therapeutic filtration devices to address infectious disease, cancer and other life-threatening conditions, today released the treatment protocol underlying a program that will provide hard-to-treat HCV-infected individuals with expanded access to Hemopurifier® therapy. The Company also disclosed inclusion and exclusion criteria for candidate patients as well as details on the physicians who will administer the program, which is expected to generate first product sales of the Aethlon Hemopurifier®.

(Photo: http://photos.prnewswire.com/prnh/20090325/LA88762LOGO-b)

The Aethlon Hemopurifier® is a first-in-class medical device with broad-spectrum capability to address infectious viral pathogens and immunosuppressive exosomes underlying cancer and other life-threatening conditions. In the expanded access program, Hemopurifier® therapy will be administered to selectively target the rapid clearance of HCV from the entire circulatory system to improve benefit, dose, duration and tolerability of standard-of-care drug therapy. The program is being initiated with support from the Institutional Review Board at the Medanta Medicity Institute (Medicity) to allow compassionate usage of the Aethlon Hemopurifier® for individuals who previously failed or subsequently relapsed standard-of-care drug regimens. The Medicity is a leading center for medical tourism in India.

In addition to offering Hemopurifier® therapy to the citizens of India, HCV-infected individuals from the United States, European Union and other regions of the world may pursue treatment through the expanded access program. It is estimated that approximately 170 million people worldwide are infected with HCV, which leads to chronic liver disease or cirrhosis, and is a leading cause of liver transplantation.

"We are grateful for the opportunity to provide hard-to-treat HCV-infected individuals with access to Hemopurifier® therapy," stated Aethlon Chairman and CEO, Jim Joyce. "Beyond advancing our therapeutic objectives, the resulting Hemopurifier® product sales will augment the government contract revenue stream we established this past year."

The Medicity Expanded Access Treatment Protocol

The Medicity expanded access program will offer HCV-infected individuals the option of either a 3-day or 7-day Hemopurifier® therapy regimen. Under each regimen, Hemopurifier® therapy will be administered continuously for a period up to six hours on each treatment day. While there will be a difference in cost, Hemopurifier® therapy underlying both regimens will be initiated in combination with standard-of-care drug therapy. The treatment objective will be to accelerate the rate and increase the likelihood that patients achieve undetectable HCV RNA. Details related to therapy pricing and candidate patient enrollment processes at the Medicity are anticipated in the coming weeks.

Candidate Patient Inclusion Criteria

• Males or females 18 years of age and older testing positive for any HCV genotype
• HCV-infected individuals that have relapsed after completing a previous course of standard-of-care drug therapy
• Null responders or individuals who previously were unable to achieve > 2 log viral load reduction at month three of standard of care drug therapy
• Candidate patients must be willing to submit to temporary vascular access catheterization
• Ability to tolerate blood volume losses of up to 150 ml per week
• Stable clinical condition, including stable hematocrit
• Individuals on ACE inhibitors must suspend ACE inhibitor administration for a minimum of six days prior to initiating therapy
• Karnofsky score ≥ 60
• Details of blood chemistry inclusion criteria will be provided to candidate patients who meet the above criteria
• Candidate patients will be required to sign a written informed consent prior to enrollment in the treatment access program

Candidate Patient Exclusion Criteria

• Clinically significant infection, other than HCV, defined as any acute viral, bacterial, or fungal infection, which requires specific therapy (Anti-infectious therapy must have been completed at least 14-days before entry into study)
• Co-infections with Hepatitis B virus and Human immunodeficiency virus (HIV)
• Received any investigational drug agent(s) within 28-days of entry into study
• Any known pre-existing medical condition that could interfere with the subject's participation in the protocol, including serious psychiatric disorders, CNS trauma or active seizure disorders requiring medication, poorly controlled diabetes mellitus, significant cardiovascular dysfunction within the past 6 months (e.g., angina, congestive heart failure, recent myocardial infarction, severe hypotension, or significant arrhythmia)
• Subjects with ECG showing clinically significant abnormalities
• Need for frequent blood transfusions.
• Recent History of bleeding or bleeding disorders requiring the restriction in use of anticoagulants during study treatments.
• Active immunologically mediated disease (e.g., inflammatory bowel disease [Crohn's disease, ulcerative colitis], rheumatoid arthritis, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, autoimmune or inherited hemolytic anemia, scleroderma, severe psoriasis)
• Any medical condition requiring, or likely to require during the course of the study, chronic systemic administration of steroids or other immune-regulatory medications
• Substance abuse, such as alcohol (~80 gm/day), IV drugs, and inhaled drugs (If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 months
• Any cancer requiring systemic chemotherapy
• Any other condition that, in the opinion of the principal investigators or treating physicians, would make the subject unsuitable for enrollment, or could interfere with the subject participating in and completing the expanded access protocol

Current HCV Studies

In addition to the forthcoming expanded access program, Aethlon has been conducting a study at the Medicity which is evaluating the capability of the Aethlon Hemopurifier® to accelerate HCV RNA depletion at the outset of standard of care peginterferon+ribavirin (PR) therapy. Specifically, HCV-infected individuals are enrolled to receive up to three, six-hour Hemopurifier® treatments during the first three days of PR drug therapy. Aethlon recently reported that two HCV-infected patients who received Hemopurifier® therapy in combination with PR drug therapy achieved undetectable viral load at day-7, which is rarely reported in drug therapy alone.

A primary clinical endpoint of the Medicity protocol has been to increase the incidence of rapid virologic response (RVR), defined as undetectable HCV RNA at day 30 of therapy. RVR represents the clinical endpoint that best predicts treatment cure, otherwise known as sustained virologic response (SVR), defined as undetectable HCV RNA 24-weeks after the completion of PR drug therapy. As a point of reference, the landmark IDEAL Study of 3,070 HCV genotype-1 patients documented that only 10.35% (n=318/3070) of PR treated patients achieved a RVR. However, patients that achieved a RVR had SVR rates of 86.2% (n=274/318) versus SVR rates of 32.5% (n=897/2752) in non-RVR patients. While the incidence of undetectable HCV RNA at day-7 is not reported in the IDEAL study, the study did reveal that just 4.3% (n=131/3070) of patients achieved undetectable HCV RNA at day-14, which equated to a 91% (n=118/131) SVR rate.

Aethlon reported that Hemopurifier® therapy has been well tolerated and without device-related adverse events in ten treated patients. Of these ten patients, seven patients were infected with HCV genotype-1; two patients were infected with HCV genotype-3; and one patient was infected with HCV genotype-5. At present, undetectable HCV RNA is reported in eight of the 10 treated patients. Of the two patients with detectable HCV RNA, one discontinued PR therapy as a result of a diabetes related condition. HCV RNA is undetectable in all patients (n=4) that have been monitored for 48 weeks since receiving Hemopurifier® therapy. Among the 10 treated patients, Aethlon reported that six genotype-1 patients received the three treatment Hemopurifier® protocol, which resulted in four (67%) patients achieving a RVR. The IDEAL study predicts it would normally require approximately 40 PR treated patients to achieve 4 RVR outcomes. Both patients who achieved undetectable HCV RNA at day-7 also achieved a RVR. Beyond the high likelihood of a SVR, genotype-1 patients that achieve a RVR also have the opportunity to reduce the duration of PR drug therapy from 48 weeks to 24 weeks.

About Medanta – The Medicity

Medanta – The Medicity is one of India's largest multi-super specialty institutes located in Gurgaon, a bustling town in the National Capital Region. Founded by eminent cardiac surgeon, Dr. Naresh Trehan, the institution has been envisioned with the aim of bringing to India the highest standards of medical care along with clinical research, education and training. Medanta is governed under the guiding principles of providing medical services to patients with care, compassion and commitment.

Spread across 43 acres, the institute includes a research center, medical and nursing school. It has 1250 beds and over 350 critical care beds with 45 operation theatres catering to over 20 specialties. Medanta houses six centers of excellence, which provide medical intelligentsia, cutting-edge technology and state-of-the-art infrastructure with a well-integrated and comprehensive information system. The Medicity brings together an outstanding pool of doctors, scientists and clinical researchers to foster collaborative, multidisciplinary investigation, inspiring new ideas and discoveries; and translating scientific advances more swiftly into new ways of diagnosing and treating patients and preventing diseases. A one-of-its-kind facility across the world, Medanta through its research integrates modern and traditional forms of medicine to provide accessible and affordable healthcare.

The Medicity Expanded Access Program Physicians

Dr. Vijay Kher - Chairman, Division of Nephrology, Kidney & Urology Institute
Dr. Vijay Kher is currently Chairman, Division of Nephrology, Medanta Kidney & Urology Institute. Dr. Kher has established Academic & Clinical departments of Nephrology at Shere-Kashmir, Institute of Medical Sciences in Srinagar, SGPGIMS Lucknow, Apollo Hospitals, New Delhi, Fortis group of hospitals NCR, Delhi & now at Medanta. His research interests are kidney transplantation (clinical immunosuppression, pre emptive kidney transplantation & steroid free immunosuppression, cost-containment), progression of renal disease, acute kidney injury and glomerulonephritis. An astute clinician, a teacher par excellence and a keen researcher, Dr. Kher combines these assets with a friendly and inclusive demeanor to inspire the Nephrology fraternity in India by his professional dedication, academic excellence and social responsibility. He has been awarded fellowships of National Academy of Medical Sciences, Royal College of Physicians Edinburg & Indian Society of Nephrology. Dr. Kher has published more than 150 papers in peer-reviewed journals, 24 book chapters and has edited 5 books.

Dr. Randhir Sud - Chairman, Medanta Institute of Digestive & Hepatobiliary Sciences
Dr. Sud is Chairman of The Medanta Institute of Digestive & Hepatobiliary Sciences, which is a dedicated facility for patients with gastrointestinal, liver, pancreatic and biliary diseases, There are multiple treatment options for a disease and to provide the best available treatment to patients, this Institute has devised protocols where medical, surgical and allied teams jointly decide patient treatments and management.

About Aethlon Medical, Inc.

The Aethlon Medical mission is to create innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT™ System is a revenue-stage technology platform that provides the basis for a new class of therapeutics that target the selective removal of disease enabling particles from the entire circulatory system. The Aethlon ADAPT™ product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer; HER2osome™ to target HER2+ breast cancer, and a medical device being developed under a contract with DARPA that would reduce the incidence of sepsis in combat-injured soldiers and civilians. For more information, please visit www.aethlonmedical.com.

Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that this expanded treatment program will augment the company's current government contract revenue stream, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies whether revenue or non-revenue generating of the Aethlon ADAPT™ system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer or hepatitis C therapies or as a standalone cancer or hepatitis C therapy, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings. The Company undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Contacts:

James A. Joyce
Chairman and CEO
858.459.7800 x301
jj@aethlonmedical.com

Jim Frakes
Chief Financial Officer
858.459.7800 x300
jfrakes@aethlonmedical.com

Marc Robins
877.276.2467
mr@aethlonmedical.com

SOURCE Aethlon Medical, Inc.

Source

Milk Thistle No Help in Tough Hep C Cases

By Kristina Fiore, Staff Writer, MedPage Today

Published: July 17, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Silymarin, a milk thistle extract, probably will not be of much help to patients with chronic hepatitis C virus (HCV) who have already failed interferon therapy, researchers found.

In a randomized, controlled trial, there were no differences in improvements in alanine aminotransferase (ALT) levels between two doses of silymarin -- often used as an alternative therapy -- and placebo in these hard-to-treat patients, Michael Fried, MD, of the University of North Carolina at Chapel Hill, and colleagues reported in the July 18 issue of the Journal of the American Medical Association.

Currently, standard therapy for HCV involves a basic regimen of peginterferon and ribavirin, now buffered by two newer protease inhibitors. Still, a large proportion of patients don't respond to these therapies, and many others can't be treated with them because of medical comorbidities, the researchers said.

Patients often turn to alternative therapies such as silymarin in hopes of some added benefit. According to some estimates, about a third of HCV and cirrhosis patients report using the milk thistle extract for their disease -- but studies have yielded inconsistent results regarding its benefit.

So Fried and colleagues conducted a double-blind, placebo-controlled trial at four medical centers in the U.S., totaling 154 patients with chronic HCV who'd already failed interferon therapy. Just over half (56%) had never used milk thistle before.

Patients were enrolled between May 2008 and May 2010, with last follow-up in May 2011. The median age was 54, almost three-quarters (71%) of patients were male, and the median body mass index (BMI) was 29. Most patients (91%) had HCV genotype 1 infection.

They were randomly assigned to placebo or one of two doses of silymarin (420 mg or 700 mg) three times a day for 24 weeks. The primary outcome was a serum ALT of 45 U/L or less, or under 65 U/L provided that was at least a 50% drop from baseline values.

By study end, two participants from each treatment group met the primary outcome measure -- as did two patients in the placebo group.

The mean decline in serum ALT didn't differ significantly across the groups, either:

• -4.3 U/L for placebo
• -14.4 U/L for 420 mg silymarin
• -11.3 U/L for 700 mg silymarin

Nor were there any significant differences in HCV RNA levels or in quality-of-life measures, the researchers reported.

Adverse events were similar across all groups, with the most frequent being gastrointestinal symptoms, occurring in 12% of both silymarin groups compared with 5% of those on placebo.

The percentage of patients with serious adverse events was numerically higher in the silymarin groups, but Fried and colleagues noted that the power to detect differences was limited by the small number of patients in each group.

They concluded that oral silymarin "used at higher than customary doses did not significantly alter biochemical or virological markers of disease activity in patients with chronic HCV infection who had prior treatment with IFN-based regimens."

Recently, researchers reported that intravenous silibinin, another milk thistle extract, helped patients with liver toxicity resulting from mushroom poisoning. A trial of the compound in this indication is ongoing.

The study was supported by the National Center for Complementary and Alternative Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases.

Rottapharm/Madaus donated the silymarin and placebo.

Abbott Molecular donated the HCV assays.

The researchers reported relationships with Genentech, Merck, Vertex, Gilead, Tibotec, Janssen, Bristol Myers Squibb, Abbott, Rottapharm/Madaus, Novartis, GlaxoSmithKline, Springbank, Medgenics, Boehringer Ingelheim, Ikaria, Anadys, and Gore.

Primary source: Journal of the American Medical Association
Source reference:
Fried MW, et al "Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy" JAMA 2012; 308(3): 274-282.

Source

Vertex Nuke Program ALS-2200

Vertex Announces Positive Results from Viral Kinetic Study of the Nucleotide Analogue ALS-2200 in People with Hepatitis C - (07/30/12)

Vertex Nucleotide Analysis - (08/01/12)

Excerpted from report by: Y. Katherine Xu, Ph.D.

William Blair Stock Analysts

ALS2158 Discontinued Because of Lack of Efficacy; ALS2200 Pushes Into Phase II studies

On Tuesday, September 25 before markets opened, Vertex and partner Alios BioPharma provided an update on the collaborators' nucleotide polymerase inhibitors (nuke) ALS2158 and ALS2200. The discontinuation of ALS2158 is only slightly negative to the stock, in our opinion, as the vast majority of Vertex valuation lies in the cystic fibrosis franchise. We summarize the details below. We note that Vertex gained exclusive worldwide rights to the two nuke candidates through an agreement with Alios in June 2011.

ALS2158 development discontinued because of insufficient antiviral activity. ALS-2158, an adenosine nuke analogue, was evaluated in a seven-day, monotherapy Phase I study in genotype 1 (GT1) hepatitis C (HCV) patients. Results from the study demonstrated that seven days of dosing with up to 900 mg of ALS-2158 was well-tolerated, but a lack of antiviral activity was observed.

Combo of ALS2200 plus ribavirin delivers similar antiviral activity (4.18 log) to previously reported ALS2200 monotherapy (4.54 log, exhibit 1). Previously, only a purine-based nuke BMS094 (INX189, discontinued) demonstrated antiviral synergy with ribavirin in a seven-day study because ribavirin is a purine-based nuke as well. As ALS2200 is pyrimidine-based, it is not expected to demonstrate antiviral synergy with ribavirin in a seve-nday study. Vertex reported that a once-daily (QD) dose of 200 mg of ALS- 2200+ribavirin (R) led to a median 4.18 log drop in viral load from baseline at 7 days in treatment-naïve GT1 HCV patients (n=8). Additionally, after seven days of treatment, five patients achieved viral loads below the limit of quantification (LOQ, ≤25 IU/mL), and two of these five patients achieved viral loads below the limit of detection (LOD, ≤10 IU/mL). On the safety side, ALS-2200 was well-tolerated with no patient discontinuations due to adverse events (AEs) or no serious adverse events (SAEs). Additional details of the study are expected at upcoming American Association for the Study of Liver Diseases (AASLD, November 9-13, Boston).

In July, Vertex reported that 200 mg QD ALS-2200 monotherapy led to 3.85 log drop in viral load at three days and 4.54 log drop at seven days. ALS-2200 (or VX- 135) is a uridine nuke analog, similar to Gilead's (GILD $67.16; Outperform) GS-7977, which at 400 mg QD (the dose that is used in all the later stage studies) demonstrated a 3.4 log drop at 3 days and 4.7 log drop at 7 days (exhibit 1).

Next steps: 12-week combination Phase II studies of ALS2200 to build safety database and explore efficacy. Initial combination partners include ribavirin and Incivek; however, we believe Vertex will likely need to partner ALS2200 with other companies' protease inhibitors or NS5a inhibitors to form competitive all-oral combinations. Vertex plans to conduct a series of small Phase II studies of ALS-2200+Incivek, and ALS-2200+R in GT1 HCV patients. The primary endpoint of the studies is SVR12 (sustained viral response, 12-weeks post end of treatment). In addition, the other main goal of the studies is to build up the safety database of ALS-2200 to several hundred patients and characterize 12-week safety, as the 12-week treatment duration is the goal the industry is pushing for. Since the opportunity to form a proprietary nuke+nuke combo is no longer available given the discontinuation of ALS-2158, we assume Vertex may also seek to initiate ALS-2200 combination studies with compounds from other classes as well as other companies in the near future.

Phase III studies are possible to start before year-end 2013, a timeline that could positions Vertex well in the HCV race for all-oral regimens. Vertex plans to initiate Phase III studies of oral regimens in parallel, likely before year end 2013. Should this timeline be achieved, Vertex would be among the front runners in the race of all-oral regimens. The composition of the regimen(s) to be taken into Phase III depends on data to be obtained over the next 12-15 months.

(Click on picture to enlarge)

September 25, 2012

Vertex Announces New Data on ALS-2200 in People With Hepatitis C, Supporting Advancement into Phase 2 All-Oral Studies in 2012; Ends Development of ALS-2158

- ALS-2158: Well-tolerated in a seven-day viral kinetic study; development discontinued due to lack of efficacy -

- ALS-2200: Data from additional cohort of seven-day viral kinetic study with ALS-2200 (200 mg, QD) in combination with ribavirin show median 4.18 log10 reduction in HCV RNA with 5 of 8 people below the limit of quantification; treatment was well-tolerated -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and its collaborator Alios BioPharma, Inc. today announced results from a viral kinetic study of the adenosine nucleotide analogue pro-drug ALS-2158 for the treatment of hepatitis C. Data showed that seven days of dosing with up to 900 mg of ALS-2158 was well-tolerated in people with genotype 1 chronic hepatitis C, but that there was insufficient antiviral activity to warrant proceeding with further clinical development. The companies also announced new data from an additional cohort of an ongoing viral kinetic study of the uridine nucleotide analogue pro-drug ALS-2200 in combination with ribavirin. There was a median 4.18 log10 reduction from baseline in HCV RNA after seven days of dosing with a once-daily 200 mg dose of ALS-2200 in combination with ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment (n=8). Five patients achieved HCV RNA levels below the limit of quantification ( < LOQ = < 25 IU/mL) and two of these five achieved HCV RNA levels below the limit of detection (Roche COBAS Taqman HCV test, Version 2) after seven days of treatment.

Similar to previously announced data from the monotherapy cohort, ALS-2200 was well-tolerated, no patients discontinued due to adverse events and there were no serious adverse events. Data from the ALS-2200 study will be presented in an oral presentation at The Liver Meeting®, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, November 9 to 13, 2012.

"Our goal is to develop all-oral regimens that are well-tolerated and provide a high rate of viral cure in a broad population of people with chronic hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We're making good progress and expect to begin all-oral Phase 2 combination studies by the end of this year."

Pending discussions with regulatory agencies, Vertex is planning one Phase 2 study to evaluate ALS-2200 (VX-135) in combination with ribavirin, and one to evaluate ALS-2200 (VX-135) in combination with INCIVEK® (telaprevir), the company's approved protease inhibitor for people with genotype 1 chronic hepatitis C. These studies will evaluate 12 total weeks of treatment with a primary endpoint of SVR12 (sustained viral response: undetectable hepatitis C virus 12 weeks after the end of treatment) in people with genotype 1 chronic hepatitis C.

About ALS-2200

ALS-2200 is a uridine nucleotide analogue pro-drug that appears to have a high barrier to drug resistance based on in vitro studies. It is designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. In vitro studies of the compound showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 through an exclusive licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

About INCIVEK

INCIVEK® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.10 The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.11 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.12,13 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including HCV, RSV, Influenza and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the third paragraph of this press release and statements regarding (i) data supporting the advancement of ALS-2200 into Phase 2 all-oral studies this year and (ii) Vertex's plans regarding the design of these Phase 2 studies. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the initiation of Phase 2 studies of ALS-2200 may be delayed or prevented, outcomes from any future studies of ALS-2200 may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)

References:

1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed September 21, 2012.

2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

9 Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.

10 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed September 21, 2012.

11 Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.

12 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

13 S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.

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FDA Gets New Authority Over Clinical Trial Reporting

By Ed Silverman // September 25th, 2012 // 12:12 pm

Here is an interesting development in the ongoing controversy over reporting clinical trial data in all its glory to the federal government. The US Department of Health & Human Services has transferred authority to the FDA to oversee information that is filed with ClinicalTrials.gov – the clinical trial registry data bank – and seek out those who fail to file, or file misleading or false data, according to a statement in the Federal Register (see here).

Of course, the FDA reports to the HHS, but the move is likely to be more than symbolic, given the scandals that have ensued in recent years over a failure to provide complete trial data. Examples include the Avandia diabetes pill sold by GlaxoSmithKline, which recently paid a $3 billion settlement, partly for failing to report safety data (read this). And evidence that Merck hid risks associated with its Vioxx painkiller continues to emerge (look here).

The notice says that the FDA now has a green light to pursue “…any clinical trial information (that) was not submitted as required under (federal law) or was submitted but is false or misleading in any particular, and to notify the responsible party and give such party an opportunity to remedy non-compliance by submitting required revised clinical trial information not later than 30 days after such notification.” The transfer of authority was first reported by Regulatory Focus.

In recent years, studies have shown that some clinical trial data often goes unreported. A 2009 analysis published in PLoS Medicine found that data mandated for reporting to ClinicalTrials.gov was nearly 100 percent, but reporting of optional data and publication rates were low. For instance, 53 percent reported trial end dates, 66 percent reported primary outcomes and 87 percent reported trial start dates.

Among a subsample of trials examined, those primarily sponsored by industry, or 40 percent, were less likely to be published when compared with trials not sponsored by industry or government sponsored trials, or 56 percent, but there was no significant difference when compared with government-sponsored trials. “Without greater attention to reporting of all data elements, the potential for ClinicalTrials.gov to address selective publication of clinical trials will be limited,” the authors wrote (read here).

Earlier this year, a series of papers in BMJ found a host of problems with reported trial data. One paper examined unpublished evidence of existing meta-analyses of nine drugs approved by the FDA in 2001 and 2002, but found identical estimates of drug efficacy in only three of 41 cases, or 7 percent. Estimates of efficacy were split evenly split in the remaining cases when unpublished FDA trial data was examined.

Another example: The Food and Drug Administration Amendments Act (FDAAA) requires mandatory reporting of summary clinical trial results within one year of completion on ClinicalTrials.gov. But one BMJ paper found that only 22 percent adhered to the mandate. Generally, later phase trials and industry-funded trials were more likely to report results. Another recent study found even lower compliance.

Still another paper looked at trials that were funded by the National Institutes of Health between 2005 and 2008, and found that only 46 percent were published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. And three years later, one third still remained unpublished.

In a widely quoted accompanying editorial, BMJ wrote that “there is an ‘Alice in Wonderland’ feel to these investigators’ efforts – acting on the public’s behalf, searching over hill and dale and among the paperwork of regulatory bodies and drug companies to put together pieces of data that should have been freely available in the first place” (here is the back story with links to the various papers).

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Scientists Probe How Some HIV Patients Resist AIDS

Last Updated: September 30, 2012.

Understanding immune response in these 'elite controllers' might help pave way to vaccine.

SUNDAY, Sept. 30 (HealthDay News) -- Researchers who discovered an immune system mechanism that seems to provide some people with a natural defense against HIV say their finding could help efforts to develop a vaccine for HIV/AIDS.

In most people, HIV infection without treatment almost always progresses to AIDS. But about one in 300 HIV-infected people remain AIDS-free without having to take medications. These people are called "elite controllers."

After conducting experiments with laboratory animals, the researchers concluded that elite controllers suppress HIV by generating a powerful CD8+ T killer cell response against just two or three small regions of the virus.

"By focusing on these selected regions, the immune response successfully controls the virus," David Watkins, a professor of pathology at the University of Miami Miller School of Medicine, said in a university news release.

"Understanding this mechanism may shed light on how to develop an effective vaccine to eradicate the global HIV/AIDS crisis," he added.

Scientists, however, note that research with animals often fails to provide similar results in humans.

The study was published Sept. 30 in the journal Nature.

The next step is to determine why these particular killer cells are so effective, Watkins said.

Watkins and his colleagues recently received a $10 million grant from the U.S. National Institute of Allergy and Infectious Diseases to develop an HIV vaccine from the yellow fever vaccine.

More information

The U.S. Centers for Disease Control and Prevention has questions and answers about HIV/AIDS.

SOURCE: University of Miami Miller School of Medicine, news release, Sept. 30, 2012

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Drug Abuse Office Offers Videos for Docs

By David Pittman, Washington Correspondent, MedPage Today

Published: October 01, 2012

WASHINGTON -- The White House has launched another salvo in its war on prescription drug abuse and diversion: training videos for physicians.

The Office of National Drug Control Policy (ONDCP) on Monday released two online modules it developed to provide clinicians with training material and video vignettes modeling doctor-patient conversations on the safe use of opioid analgesics for pain.

Lack of training in prescribing such medication is a barrier to reducing medication abuse, ONDCP Director Gil Kerlikowske said at a press conference Monday morning. Opioid analgesics were implicated in more than 15,000 overdose deaths in 2009, according to the CDC -- four times the number they were involved in a decade prior.

The modules contain lessons for providers on various topics, including:

• Educating patients on the drugs' risks
• Screening patients for risk factors to identify those a greater risk for abuse
• Discarding unused medicine safely
• Spotting patients who may be forming an addiction

"The videos show the way that the physicians interact with these patients, asking them questions that are sensitive and many physicians feel uncomfortable asking," said Nora Volkow, MD, director of the National Institute on Drug Abuse. "Those that are viewing the videos, by seeing the examples, will feel more comfortable so that when they are faced with that situation they can use what they've learned."

One video is a woman visiting a primary care doctor after receiving opioids from an emergency department for an ankle injury. The physician monitors the pain and discontinues medication when it is no longer needed.

The other video is of a middle-age man taking opioids for chronic back pain, whom the physician suspects may be abusing the drugs.

Providers can receive 1.25 CME credits per module and each takes about an hour to complete, Volkow said.

More than 5,000 physicians already have taken the online training. "It is quite impressive, but I think it also highlights the sense that there's a need for training materials that clinicians can use that can help guide them to screen their patients who are being treated with opioid medication for the management of pain," Volkow said.

Providers provide an important line of defense in stopping prescription drug abuse, Kerlikowske said.

"Too often I hear from the medical community that there are very few hours in medical school devoted to safe and effective pain management," Kerlikowske said. "Unfortunately, this lack of training can lead to improper prescribing of powerful painkillers and a lack of understanding about the disease of addiction and how it can be prevented and treated."

Kerlikowske called on professional medical societies to let their membership know of the online modules.

"We still believe that training in proper opioid prescribing should be a prerequisite for anyone who prescribes certain types of prescription drugs," Kerlikowske said.

Last week, the White House released a report showing prescription drug abuse was down among 18- to 25-year-olds 14 percent from 2011 to 2010. However, that same report showed heroin use was up.

When asked Monday if prescription drug abusers were simply shifting from one substance to another, Volkow said physicians and policymakers need to focus on the abuse of opioid prescriptions.

"If you can mount a very aggressive prevention strategy to avoid the abuse of prescription medication, then you will not have that transition into injection use of heroin," Volkow said. Patients become addicted to opioids and then shift to less-expensive heroin to feed their addition, she said.

The White House's plan to cut prescription drug diversion and abuse, released last year, calls on supporting provider education, expanding state-based monitoring programs, and reducing the prevalence of "pill mills" and doctor-shopping through enforcement actions.

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