REVIEW ARTICLE
By Richard Kim, MD 1, Michael T. Byrne, DO 2, Ann Tan, MD 3, Federico Aucejo, MD 2
March 17, 2011
1 H. Lee Moffitt Cancer Center, Tampa, Florida
2 Cleveland Clinic, Cleveland, Ohio
3 British Columbia Cancer Agency, Vancouver, British Columbia, Canada
ABSTRACT: The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib(Drug information on sorafenib) (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The US Food and Drug Administration (FDA) authorized use of sorafenib for “unresectable HCC,” an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.
Hepatocellular carcinoma (HCC) in the United States accounts for approximately 23,000 new cases annually.[1] The incidence of HCC continues to increase, partly as a result of the unsolved problem of hepatitis C and deficient screening in high-risk patients. Globally, HCC is the fifth most common cancer worldwide and the third most common cause of cancer mortality.[2] The only potentially curative options for patients with HCC are liver resection, radiofrequency ablation (RFA), and liver transplantation (LT). Patients who are fortunate enough to undergo LT have a 4-year survival rate of 85% if the tumors are within the Milan criteria. Recurrence rates in this patient population range from about 8% to 12%.[3] However, among patients undergoing hepatic resection in whom the procarcinogenic liver is not replaced, the disease recurrence rate can exceed 70% at 5 years.[4] Other noncurative options include local therapies such as transarterial chemoembolization (TACE), radioembolization, RFA, and systemic therapy.[5] Advanced HCC carries a very poor prognosis, and use of cytotoxic agents has provided only marginal benefit.[6,7]
In 2007, sorafenib was approved in United States and Europe for ad- vanced HCC based on results from the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial.[8] Sorafenib is an oral multikinase inhibitor that blocks tumor cell proliferation by targeting multiple pathways including the Raf/mitogen-activated protein kinase/extracellular signal–regulated kinase (Raf/MEK/ERK) signaling pathway, along with tyrosine kinases (TKs), VEGF receptor 2 (VEGFR-2), VEGFR-3, and the platelet-derived growth factor receptor β (PDGFR-β) pathway.[9] In the landmark SHARP trial, 602 patients with advanced HCC were randomized to either sorafenib at 400 mg twice a day or to placebo.[8] The final result showed that sorafenib had overall survival (OS) and time to tumor progression (TTP) benefits in patients with advanced HCC, compared with placebo. Median OS was 10.7 months in the sorafenib group and 7.9 months in the placebo group. In Asia, a similar phase III trial was being conducted simultaneously. This trial also showed a similar magnitude of benefit in the sorafenib arm compared with the placebo arm.[8,10] Based on these two phase III trials, sorafenib became the first molecularly targeted therapy to show an OS benefit, establishing it as the first new standard treatment for advanced HCC.
The new data are now being met with cautious optimism, but there are several unanswered questions. The US Food and Drug Administration (FDA) authorized use of sorafenib for patients with “unresectable hepatocellular carcinoma,” a very vague and broad indication. In Europe, the indication is even broader, as sorafenib is indicated for “hepatocellular carcinoma.” Therefore, the exact indication for sorafenib in advanced HCC is confusing and gives rise to many uncertainties, including use of sorafenib in patients with decompensated liver disease, use in conjunction with local therapy, or use in a transplant setting.
Most of the patients enrolled in these large phase III trials had well-compensated liver function (Child-Pugh A cirrhosis); therefore the utility of sorafenib in Child-Pugh class B or C cirrhotic patients remains unknown. Also unclear is the potential role of sorafenib in combination with locoregional therapies, as well as its potential use in liver-transplant settings. The safety and feasibility of the implementation of sorafenib as a pretransplant neoadjuvant agent, or as an adjuvant therapy for posttransplant HCC recurrence, are uncertain. These practical questions have to be addressed as we deal with a complex disease in which an oncologic state evolves from conditions of liver dysfunction or immunosuppression. In this review article we will discuss the current data on, and future role of, sorafenib in the treatment of HCC beyond Child-Pugh A cirrhosis, in conjunction with local therapy, and in a transplant setting. The role of sorafenib in combination with other targeted therapies or other promising agents in the treatment of advanced HCC is beyond the scope of this article and will not be discussed.
Sorafenib in Child-Pugh B or C Cirrhosis
The safety and efficacy of sorafenib have been proven in patients with Child-Pugh A cirrhosis based on the aforementioned two large phase III trials. Little is known about the safety and efficacy of sorafenib in patients with Child-Pugh class B or C cirrhosis. Nevertheless, since there are no other effective treatments for cirrhotic patients with advanced disease, many single institutions have used sorafenib in these patients.
Prior to the SHARP study, a phase II trial by Abou-Alfa et al analyzed use of sorafenib in both Child-Pugh A and B cirrhotic patients.[11,12] In this trial, out of 137 patients, 38 had Child-Pugh B cirrhosis and 99 had Child-Pugh A cirrhosis. In the analysis of the study, toxicity profiles for Child-Pugh A and B cirrhosis, drug discontinuation rates, and dose reduction rates were similar in both groups. Nevertheless, overall outcome was much worse in the Child-Pugh B group, with an overall survival (OS) outcome of 3.5 months and time to tumor progression (TTP) of 3.3 months. Another large retrospective study from the Western Hemisphere, by Pinter et al, included 23 patients with Child-Pugh B cirrhosis and 10 with Child-Pugh-C cirrhosis.[13] Results revealed an OS of 4.3 months and a TTP of 2.9 months in the Child-Pugh B group, similar to findings from the phase II trial by Abou-Alfa et al. In the Child-Pugh C group, however, OS was only 1.5 months, and the authors concluded that sorafenib should not be used in patients with advanced-stage cirrhosis.
Two of the largest Asian experiences in patients with Child-Pugh B cirrhosis are described in studies from Korea, where hepatitis B is the number one risk factor for HCC. Lee et al reported on 29 patients with Child-Pugh B cirrhosis who received sorafenib and exhibited an OS of 3.7 months.[14] Another series included 23 patients with Child-Pugh B cirrhosis; TTP was 2 months but OS was not reported.[15] Results of other small series that included patients with Child-Pugh B cirrhosis are listed in Table 1.
In terms of drug-related toxicity profiles, most of these retrospective analyses did not distinguish between Child-Pugh A and B cirrhosis. Four of the studies did attempt to make a distinction, however, and the toxicities are outlined in Table 2.
There are data showing no statistically significant difference in the pharmacokinetics (PK) of sorafenib in Child-Pugh A versus Child-Pugh B patients.[11] A phase I trial conducted in Japan also showed no substantial differences in the incidence of adverse events or clinically relevant differences in PK between the Child-Pugh A and B groups.[16] Overall, toxicity profiles for Child-Pugh B patients seem to be similar to or slightly worse than those for Child-Pugh A patients (see Table 2). However, toxicity reflecting worsening hepatic dysfunction, such as hyperbilirubinemia, encephalopathy, and ascites, appears to be to be greater in Child-Pugh B patients. Notably worsening bilirubin levels were reported in 40% of Child-Pugh B patients, compared with 18% of Child-Pugh A patients.[11] Nevertheless, because direct bilirubin levels were not reported, it is unclear if the rise in total bilirubin was related to sorafenib as a result of decreased bilirubin glucuronidation; this can increase indirect bilirubin or cause pre-existing hepatic dysfunction to worsen, which usually increases direct bilirubin levels. Interestingly, it seems that patients with hepatitis B may have a higher chance of developing liver toxicity from treatment with sorafenib. A phase II trial by Yao et al did not break down all of the toxicity findings by Child-Pugh class, but it did report a 73% rate of grade 3 or 4 liver toxicity among patients with Child-Pugh B or C cirrhosis.[17] Even though this finding was not statically significant compared with the high rate of liver toxicity seen in Child-Pugh A patients, it does raise an eyebrow. One of the hypotheses that may explain this result is that administration of targeted therapy can lead to reactivation of the underlying hepatitis B infection and, consequently, can worsen liver function.[18,19]
Efficacy of sorafenib in Child-Pugh B patients in the small series reported in the medical literature seems to be very modest, with OS ranging from 2–5 months. Difficulty in evaluating survival in Child-Pugh B patients has to do with the coexistence of HCC and advanced-stage liver disease. Patients who have Child-Pugh B cirrhosis without HCC have a 1-year survival rate of about 80%.[20] Therefore, deaths from cirrhosis could potentially mask treatment-related antitumor efficacy. The potential for a clinically meaningful gain in OS with use of sorafenib in Child-Pugh B patients can only be evaluated in a prospective, randomized, placebo-controlled trial. However, placebo-controlled trials in Child-Pugh B patients will be very difficult in an era in which drug regulatory agencies allow sorafenib to be used to treat patients with HCC and any degree of liver failure.
These retrospective analyses, therefore, give us important insights into use of sorafenib in Child-Pugh B patients, despite their obvious limitations. It is hoped that, as more institutions publish their experiences with incorporating sorafenib into the treatment of patients with advanced cirrhosis, we will gain further knowledge about its efficacy and toxicity profiles in a variety of patient settings.
In the future, instead of lumping all Child-Pugh B cirrhosis patients together in the outcomes analysis, we should consider categorizing them into subgroups. For example, Child-Pugh B patients with a Child-Pugh score of 7 may have a better outcome with sorafenib than those with a score of 8 or 9. Unfortunately, HCC patients who are classified as having Child-Pugh C disease will most likely not benefit from any therapeutic options except for LT secondary to liver cirrhosis. Quality of life also should be part of the assessment, given that OS in most patients with HCC and Child-Pugh C disease is measured in months.
GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib) is an ongoing global, prospective, noninterventional study of patients with unresectable HCC and for whom the decision has been taken to treat with sorafenib under real-life practice conditions.[21] The purpose of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially in patients with Child-Pugh B disease, or in conjunction with local therapy, a treatment option for which data are limited. The plan is to accrue more than 3,000 patients, and the findings are likely to provide us with valuable information about certain HCC patient subgroups.
Meanwhile, until more definitive data become available, it is imperative that clinicians employ caution and their best judgment when using sorafenib in patients with Child-Pugh B cirrhosis. As expected, patients with Child-Pugh C cirrhosis had a very poor outcome despite being on sorafenib, with median survival times between 2 and 3 months.[13,22] The poor outcome is most likely related to underlying liver cirrhosis, so it is highly unlikely that sorafenib or any other therapy will provide those patients with clinically meaningful benefits. Biomarker development or new information about tumor characteristics that identify subgroups of patients who may respond to sorafenib independent of Child-Pugh stage may be helpful in the future.
Sorafenib Plus Local Therapy
There is a good rationale for using sorafenib(Drug information on sorafenib) in conjunction with local therapy such as transarterial chemoembolization (TACE) or radioembolization. A study from China showed that TACE before hepatic resection enhances angiogenesis in HCC cells by upregulating the expression of vascular endothelial growth factor (VEGF).[23] Importantly, however, it has been shown that after the TACE procedure there is a rise in serum VEGF levels, which can feed the residual cancerous tissue and allow tumor cell proliferation.[24] Because of this, it might be beneficial to add an antiangiogenic agent to repress tumor angiogenesis after the patient has received therapies to induce tissue ischemia, such as TACE. Another potential advantage of these combinations is that use of an antiangiogenic systemic agent might enable control of systemic tumor cell spread. In the SHARP study, about 50% of patients did receive some form of local therapy prior to treatment with sorafenib.[8]
TACE is the most common local therapy used in patients with HCC. Transarterial radioembolization has been implemented in recent years, and even more recently, drug-eluting beads loaded with doxorubicin(Drug information on doxorubicin) (Adriamycin) have been used. TACE involves the injection of chemotherapeutic agents into the artery feeding the tumor, using lipiodol (Ethiodol) as a carrier. It is traditionally used for treatment of large unresectable HCCs that are not eligible for other treatments such as resection, RFA, or liver transplantation. Although data on TACE are controversial, there are two randomized controlled trials and a meta-analysis that support use of TACE in patients with advanced HCC.[25-27] Drug-eluting beads loaded with doxorubicin have an advantage over standard TACE in that they can deliver higher levels of chemotherapy released to the target over time, thereby decreasing potential systemic side effects. A recent randomized phase II trial comparing conventional TACE versus drug-eluting-bead (DEB) embolization showed that DEB embolization was associated with better response and better patient tolerance than standard TACE.[28]
Another local mode of therapy that is gaining popularity is radioembolization using intrahepatic arterial administration of yttrium 90 (Y90)-tagged glass (TheraSphere) or resin (SIR-Spheres) microspheres. Because HCC is a hypervascular tumor, micropsheres injected intraarterially will preferentially deliver to the tumor-bearing area and selectively emit high energy, high-penetrating-power radiation to the tumor. One of the advantages of radioembolization is that it can be used safely in patients with portal vein thrombosis, because it is less embolic and spares the arterial blood flow to the treated liver parenchyma. While multiple trials show that radioembolization has some antitumor activity, there are no prospective data showing improved survival benefits compared with placebo or TACE.[29,30]
Table 3 provides currently available information about the combination of sorafenib with local therapy. As one can see, most of the trials are small retrospective or prospective studies in only abstract forms, with the exception of one phase III trial. This trial was presented at the 2010 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology.[31] Investigators randomized patients with advanced HCC to TACE alone versus TACE plus sorafenib. In this trial, sorafenib was started a mean of 9.1 weeks after TACE. The primary endpoint was TTP. Despite the sound rationale for administering combination therapy, the trial did not meet its primary endpoint. There were several study limitations, however: Most patients only received one course of TACE despite the fact that most had bilobar disease; the rationale for this is unclear. The duration of treatment with sorafenib was relatively short, with a high rate of discontinuation (45%) secondary to adverse events. Inclusion criteria in this study were very heterogeneous, with patients having fewer than 3 lesions or up to 10 lesions. In addition, definitions of complete response and progression were unclear in the study. It is hoped that the investigators will answer some of these questions in the published manuscript.
Combination of radioembolization using Y-90 SIR-Spheres or DEB embolization and sorafenib also has been studied (seeTable 3). The largest series using radioembolization with sorafenib was done in Asia.[32] The trial included 35 patients with Barcelona Clinic Liver Cancer (BCLC) stage B and C disease. Results were a cause for optimism, with 33% of patients achieving a complete or partial response. The combination was well tolerated, as there were only three treatment-related adverse events of grade 3 and above reported. The largest series assessing combination of sorafenib with DEB was presented by a group from Johns Hopkins.[33] Preliminary analysis reveals that the combination appears to be safe, as it did not result in any greater toxicities than were seen with either therapy alone. The outcomes of this trial have not been reported.
In conclusion, trials evaluating local therapy with and without sorafenib are very small and too premature. Most have been communicated only in the form of study abstracts, leaving many questions unanswered. Primary endpoints and response criteria were not well defined in most of these studies. Because of these factors, no robust conclusion can be drawn in regard to the combined therapies investigated thus far. The critical question that needs to be answered is whether the addition of sorafenib to local therapy induces a better outcome than local therapy alone. Okita et al attempted to answer this question in a phase III trial,[31] but failed to do so because of several limitations.
There are other lingering questions as well. For example, when should we initiate treatment with sorafenib? Maybe it makes sense to start sorafenib prior to TACE in order to block upregulation of VEGF in the tumor as well as in serum. Should we stop sorafenib 1 to 2 days prior to initiating local therapy, given the concerns about toxicity? As one can see in Table 3, the schedule of sorafenib administration is different in each trial. Another major problem is the lack of consistency regarding the frequency of scheduling TACE procedures and the type of chemotherapy agent or embolic material used. In the past, TACE has been given as frequently as two courses per month, but under this schedule it has induced hepatic decompensation in 7.5% of patients.[26,34] Clearly, the toxicity profile needs to be closely looked at with these combinations. Large phase II and III studies underway are using a combination of local therapy plus sorafenib; the outcomes of these trials are eagerly awaited. It is hoped that, as these data become more mature and as these studies are developed into full manuscripts, we will have better insights into these trials. In oncology, we have learned from the past that one plus one does not always equal two, and sometimes can equal zero. Therefore, careful consideration must be given prior to combining sorafenib with local therapy in patients with HCC.
Sorafenib and Liver Transplantation
The neoadjuvant setting
If disease is caught at an early stage, then LT is a potential curative option. However, the shortage of donor organs leaves waitlisted patients at risk for disease progression beyond transplant criteria. Prevention of waitlist dropout has fueled investigation into a wide array of locoregional therapies as “bridging therapy” or neoadjuvant therapy prior to LT. The purpose of these therapies would be to decrease the dropout rate, to prevent tumor progression, and possibly to increase overall survival. Currently most of the transplant institutions are implementing some form of neoadjuvant therapy despite the lack of randomized prospective data.[35]
Sorafenib potentially can be used as a neoadjuvant therapy in patients awaiting LT, since the drug can extend the time to disease progression. Another possible use of sorafenib would be in patients who are not candidates for local therapy secondary to elevated bilirubin levels. There is a phase I trial showing that sorafenib can be used in patients with bilirubin levels > 1.5 times but < 3 times the upper limit of normal (ULN) with dose reduction.[36] Using sorafenib in patients with bilirubin levels > 3 times the ULN may be problematic, however, as patients in the phase I trial could not even tolerate a dosage of 200 mg every other day.
One analysis by Vitale et al, using the Markov model, showed that sorafenib given as neoadjuvant therapy can be cost-effective in comparison with no therapy for Milan criteria HCC patients waiting for LT, particularly for median times to LT that are < 6 months.[37] There is concern associated with the use of sorafenib in pretransplant patients, however.
Because sorafenib is a VEGF inhibitor, there is an associated risk of bleeding and/or wound healing complications. Bevacizumab (Avastin), a monoclonal antibody to VEGF, has been used as neoadjuavnt therapy prior to liver resection for advanced colorectal cancer.[38] Yet the antiangiogenic effects of bevacizumab(Drug information on bevacizumab), coupled with its long half-life (approximately 21 days), have led to concern that preoperative bevacizumab may affect liver regeneration and wound healing, requiring a waiting period of at least 6 weeks after the last dose of bevacizumab before performing surgical resection.[38-40] Sorafenib has an advantage over bevacizumab in that it has a much shorter half-life, but safety data prior to surgery are sorely lacking. The only prospective data that we have are in renal cell carcinoma patients who received sorafenib prior to nephrectomy; sorafenib was held at 24–48 hours prior to surgery, and no surgical complications were seen.[41] In a transplant setting, waiting 24 hours after sorafenib intake is not feasible, as a donor liver can become available at any time.
Therefore, the treatment safety profile is of the utmost importance. Currently there are no prospective trials reported, but several case reports have been published in which sorafenib has been used as a neoadjuvant agent in the pretransplant setting.[42,43] In those small case reports, there were no unforeseen surgical complications. Currently there is a small pilot study ongoing at the Cleveland Clinic to investigate the safety and feasibility of using sorafenib in HCC pretransplant patients.
The adjuvant setting
Patients whose HCC falls within the Milan criteria and who undergo LT tend to have a favorable outcome, but patients with high-risk tumor features (HCC beyond the Milan criteria, poorly differentiated tumors, presence of microvascular spread or satellite lesions) have a significantly higher rate of posttransplant tumor relapse.[44] Naturally, therefore, it will make sense to conduct a trial using an effective systemic agent in an adjuvant setting to prevent tumor recurrences. An ongoing multicenter international trial (STORM: Sorafenib as Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma) is evaluating the efficacy of sorafenib in preventing tumor recurrence after liver resection or RFA. This trial does not include transplant patients, however, owing to safety concerns associated with the interaction with immunosuppressive agents. There is an ongoing pilot study assessing the safety of sorafenib as an adjuvant therapy in patients with high-risk features of recurrence after LT. The main concern would be the short-term and long-term toxicities associated with the use of sorafenib in immunosuppressed patients.
Sorafenib for post-transplant recurrent HCC
Another area of interest is the use of sorafenib in patients with recurrence of HCC after LT. Currently no standard therapy is available for these patients. In the large phase III SHARP and Asia Pacific trials, patients who experienced a recurrence after transplant were excluded. The use of this drug in recurrent HCC after LT has therefore never been studied prospectively. Similar to the adjuvant setting after LT, a concern in transplant patients with recurrent HCC is the potential interaction between immunosuppressive medications and sorafenib. Even though there are no prospective trials in this setting, many institutions have reported their experience with the use of sorafenib in posttransplant patients who have tumor recurrences. Table 4 describes those findings. So far, only a few published reports exist, with little detailed information. In terms of its safety profile, however, it definitely seems feasible to use sorafenib concomitantly with immunosuppressive medications. The largest series, which have been published by investigators from Korea, the University of Miami, and the Cleveland Clinic, show that toxicities of sorafenib were quite manageable with dose reduction.[45-47] The main difference was that the data from Korea only included patients who had HCC recurrence after living donor transplantation; this reflects a difference in the practice pattern in Korea, as most of the transplants in the United States are from cadaveric livers. Overall results seem to be promising, but based on the small sample sizes of these studies, conclusions cannot be made regarding efficacy in this setting. It would be ideal, then, to conduct a randomized prospective trial to determine the efficacy of sorafenib versus placebo in patients who have disease recurrence after LT, since there is no standard therapy.
For a variety of reasons, however, it will be difficult to conduct a randomized prospective trial of sorafenib against placebo. First, the number of recurrences after transplant is quite small compared with advanced HCC patients in the pretransplant setting; thus, a much longer time would be required for the trial to accrue patients, which might not be feasible. Second, there is the issue of randomizing patients to a placebo arm when sorafenib is already available in the market. To begin, it would be reasonable to conduct a phase I trial to find out the correct dose of sorafenib to use in this setting, since most of the retrospective studies have required dose reduction secondary to toxicity. Then, a small phase II trial could be conducted with a single arm of sorafenib and comparing OS data against historical data, or a randomized phase II study could compare sorafenib against placebo, with patients on the placebo arm allowed to cross over upon progression. These trials would still require collaboration from many institutions in order to accrue in a timely fashion, and PK studies would be helpful as well.
Conclusion
In summary, the approval of sorafenib marks a major advance in the treatment of advanced HCC. Even though the indication for sorafenib is for patients with unresectable HCC, the published data and clinical experience thus far do not provide definitive conclusions about the use of sorafenib in advanced HCC patients with cirrhosis beyond Child-Pugh A classification. Most of the data reviewed in this article were from small-scale prospective or retrospective studies, resulting in a low level of evidence.
It is important that clinicians continue to exercise caution and their best judgment when treating patients with HCC beyond Child-Pugh A, until more definitive data become available. Ideally we would like to have prospective data for each Child-Pugh classification. While there are ongoing prospective trials—for example, those investigating sorafenib in combination with local regional treatment, as previously noted—for various reasons there are certain circumstances in which prospective trials will not be conducted. Indeed, there are many limitations to the current retrospective data, including lack of randomization to specific treatment arms and the lack of a placebo-control arm. These factors limit robust evaluation of the efficacy of any treatments received by these patients. Despite the limitations of retrospectively designed studies, information from retrospective/single-institution studies provides us with important insights to aid in decision-making when treating patients with end-stage liver disease complicated by HCC. In the future, as more retrospective and prospective data become available, we will be able to determine the best treatment options in a variety of settings and stages of liver disease, in order to maximize the outcome and benefits for our patients.
Financial Disclosure: Dr. Kim receives an honorarium from Bayer/Onyx. Dr. Byrne, Dr. Tan, and Dr. Aucejo have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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37. Vitale A, Volk ML, Pastorelli D, et al. Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost-benefit analysis while awaiting data on sorafenib safety. Hepatology. 2010;51:165-73.
38. Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol. 2008;26:5254-60.
39. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1-7.
40. Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol. 2005;23:4853-5.
41. Cowey CL, Amin C, Pruthi RS, et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol. 2010;28:1502-7.
42. Vagefi PA, Hirose R. Downstaging of hepatocellular carcinoma prior to liver transplant: is there a role for adjuvant sorafenib in locoregional therapy? J Gastrointest Cancer. 2010;41:217-20.
43. Kim R, Menon N, Aucejo F. Safe use of sorafenib in a patient undergoing salvage liver transplantation for recurrent hepatocellular carcinoma after hepatic resection. Med Oncol. 2010; Jul 16. [Epub ahead of print]
44. Molmenti EP, Klintmalm GB. Liver transplantation in association with hepatocellular carcinoma: an update of the international tumor registry. Liver Transpl. 2002;8:736-48.
45. Feun LG, Levi D, Moon J, et al. Sorafenib in hepatocellular carcinoma (HCC) patients after liver transplantation (Abstract e15579).. J Clin Oncol. 2009;27.
46. Yoon DH, Ryoo BY, Ryu MH, et al. Sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Jpn J Clin Oncol. 2010;40:768-73.
47. Kim R, El-Gazzaz G, Tan A, et alet al. Safety and feasibility of using sorafenib in recurrent hepatocellular carcinoma after orthotopic liver transplantation. Oncology (Williston Park). 2010. 25:XXXX-XXXX.
48. Del Prete S, Montella L, Addeo R, et al. Sorafenib plus long-acting octreotide in advanced hepatocellular carcinoma. Preliminary results of a multicenter ongoing study (Abstract 15624). J Clin Oncol. 2008;26(15 May 20 Suppl).
49. Schuette K, Zimmermann L, Bornschein J, et al. Tolerability of sorafenib in the treatment of hepatocellular carcinoma (HCC) in patients with Child A and B liver cirrhosis (Abstract e15593). J Clin Oncol. 2009;27 Suppl)
50. Balsom SM, Li X, Trolli E, et al. A single-institute experience with sorafenib in untreated and previously treated patients with advanced hepatocellular carcinoma. Oncology. 2010;78:210-2.
51. Ozenne V, Paradis V, Pernot S, et al. Tolerance and outcome of patients with unresectable hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2010;22:1106-10.
52. Xu L, Li P, Lin XJ, et al. Clinical observation of sorafenib monotherapy in Chinese patients with advanced hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi. 2009;31:58-61.
53. Sinakos E, Dedes I, Papalavrentios L, et al. Safety of transarterial chemoembolization plus sorafenib combination treatment in unresectable hepatocellular carcinoma. Scand J Gastroenterol. 2010;45:511-2.
54. Duan F, Wang MQ, Liu FY, et al. Clinical observation of the treatment with combination of transcatheter arterial chemoembolization and sorafenib for hepatocellular carcinoma with lung metastasis. Zhonghua Zhong Liu Za Zhi. 2009;31:716-8.
55. Cabrera R, George T, Soldevila-Pico C, et al. Safety of sorafenib alone or in combination with locoregional therapy in patients with advanced hepatocellular carcinoma (HCC) and decompensated cirrhosis (Abstract 147). Presented at the 2008 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 25-27, 2008.
56. Martin II RC, Keck G, Robbins K, et al. Evaluation of sorafenib in combination with doxorubicin-loaded DC bead as a combination treatment option for HCC (Abstract 216). Presented at the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, Jan 22-24, 2010.
57. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transcatheter arterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma (HCC) trial (START): second interim safety and efficacy analysis (Abstract 4026). J Clin Oncol. 2010;28(15 May 20 Suppl).
58. Valdivieso A, Bustamante J, Gastaca M, et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transplant Proc. 2010;42:660-2.
59. Yeganeh M, Finn RS, Saab S. Apparent remission of a solitary metastatic pulmonary lesion in a liver transplant recipient treated with sorafenib. Am J Transplant. 2009;9:2851-4.
Source
March 17, 2011
FDA hearing set for Vertex Hep C drug
Boston Business Journal - by Julie M. Donnelly
Date: Thursday, March 17, 2011, 4:26pm EDT - Last Modified: Thursday, March 17, 2011, 4:57pm EDT
Vertex Pharmaceuticals Inc. (Nasdaq: VRTX) will glean some important insight into the fate of its closely-watched potential treatment for hepatitis C on April 28. The U.S. Food and Drug Administration has announced it will hold an advisory panel meeting on the drug candidate, called telaprevir, on that date. A positive report from the panel would be a good indication that telaprevir is likely to gain approval from the regulatory agency as a whole on May 23.
The drug aims to treat chronic hepatitis C genotype 1 infection, in combination with two already-approved drugs, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
Vertex executives, investors and analysts are waiting with bated breath, because the approval of telaprevir would likely catapult Vertex into the elite of profitable biotech companies. Also waiting anxiously for an FDA decision is the city of Boston, which currently has a non-binding agreement with the Cambridge, Mass.-based biotechnology company to move across the river to the South Boston waterfront — but only if the drug is approved.
Vertex faces stiff competition in the hepatitis C space. The FDA advisory committee will discuss another potential treatment for hepatitis C, developed by Whitehouse Station, N.J.-based Merck & Co Inc (NYSE: MRK), on April 27.
In addition, Vertex saw its stock fall almost 5 percent March 8, after Princeton, N.J.-based Pharmasset Inc. (Nasdaq: VRUS) released positive late-stage data for its potential rival to Vertex’s drug candidate
Source
Also See: FDA Hepatitis Update - FDA Advisory Committee meeting to consider boceprevir and telaprevir, April 27 and April 28, 2011
Date: Thursday, March 17, 2011, 4:26pm EDT - Last Modified: Thursday, March 17, 2011, 4:57pm EDT
Vertex Pharmaceuticals Inc. (Nasdaq: VRTX) will glean some important insight into the fate of its closely-watched potential treatment for hepatitis C on April 28. The U.S. Food and Drug Administration has announced it will hold an advisory panel meeting on the drug candidate, called telaprevir, on that date. A positive report from the panel would be a good indication that telaprevir is likely to gain approval from the regulatory agency as a whole on May 23.
The drug aims to treat chronic hepatitis C genotype 1 infection, in combination with two already-approved drugs, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
Vertex executives, investors and analysts are waiting with bated breath, because the approval of telaprevir would likely catapult Vertex into the elite of profitable biotech companies. Also waiting anxiously for an FDA decision is the city of Boston, which currently has a non-binding agreement with the Cambridge, Mass.-based biotechnology company to move across the river to the South Boston waterfront — but only if the drug is approved.
Vertex faces stiff competition in the hepatitis C space. The FDA advisory committee will discuss another potential treatment for hepatitis C, developed by Whitehouse Station, N.J.-based Merck & Co Inc (NYSE: MRK), on April 27.
In addition, Vertex saw its stock fall almost 5 percent March 8, after Princeton, N.J.-based Pharmasset Inc. (Nasdaq: VRUS) released positive late-stage data for its potential rival to Vertex’s drug candidate
Source
Also See: FDA Hepatitis Update - FDA Advisory Committee meeting to consider boceprevir and telaprevir, April 27 and April 28, 2011
Hepatitis C transmission still high among injection drug users
Nicole Blazek
March 17, 2011
Efforts to control blood-borne infections have dramatically reduced HIV incidence among injection drug users (IDUs), but declines in hepatitis C virus (HCV) infection have been less substantial, prompting health officials to call for better prevention and treatment strategies.
Incidence of HIV infection decreased from 5.5 cases per 100 person-years in a cohort of injection drug users recruited from 1988 to 1989 to zero cases per 100 person-years in a cohort recruited between 2005 and 2008.
In contrast, HCV infections declined from 22 cases per 100 person-years in the 1988 to 1989 cohort, to 17.2 per 100 person-years in a cohort recruited in 1994 and 1995. A slight increase to 17.9 cases was reported in another group recruited in 1998, before infections rates declined to 7.8 cases per 100 person-years from 2005 to 2008 (P=0.07).
The disparity in HIV and HCV reduction rates may be due to the fact that HCV is 10-times more transmissible than HIV, according to study researcher Shruti H. Mehta, MD, of the Johns Hopkins Bloomberg School of Public Health, in Baltimore, and colleagues.
Because HCV can be acquired after just one instance of needle-sharing, hazard reduction interventions such as needle exchange and substance abuse treatment programs that have been effective at reducing HIV, may have less of an impact. CDC estimates indicate that approximately one-third of IUDs share needles.
“Efforts need to be intensified on both the prevention and treatment fronts to reduce the reservoir of HCV-infected IDUs,” the researchers wrote in the March 1 issue of the Journal of Infectious Diseases.
To get a better understanding of HCV incidence in IDUs, they analyzed data from four cohorts of IDUs during a 20-year period (1988-1989, n=2,946; 1994-1995, n=391; 1998, n=244; 2005-2008, n=875).
The researchers found that compared with the 1988-1989 cohort, HCV incidence significantly declined among patients younger than 39 years in each subsequent cohort (adjusted prevalence ration=0.73; 95% CI: 0.65-0.81).
However, the same decreases were not observed in patients older than 39 years — among that age group HCV infection rates only declined in the most recent cohort (adjusted prevalence ratio=0.87; 95% CI: 0.77 to 0.99).
“For many persons, the interval between initiation and injection simply remains too brief for prevention strategies to be successful,” the researchers wrote.
They emphasized the importance of targeting prevention efforts towards very young IDUs and drug users who have not yet begun injecting. The other strategy for reducing the HCV reservoir is treatment, the efficacy of HCV treatment regimens is often limited among certain subpopulations including blacks with genotype-1 HCV and those with HIV coinfection, the researchers noted.
“With new, more efficacious therapeutics on the horizon, it is critical that strategies to improve uptake and completion of HCV infection treatment of IDUs be implemented,” they wrote.
Jason Grebely, PhD, and Gregory J. Dore, MBBS, PhD, of the University of New South Wales in Sydney, Australia, offered several suggestions for improving treatment and prevention.
“The development and implmentation of national harm-reduction strategies including broader coverage, enhanced early access and intesnifcation and combination of interventions are probably all needed,” they wrote.
Grebely and Dore also emphasized the importance of conducting randomized clinical trials to evaluate new HCV interventions to ensure that they are successful.
Source
March 17, 2011
Efforts to control blood-borne infections have dramatically reduced HIV incidence among injection drug users (IDUs), but declines in hepatitis C virus (HCV) infection have been less substantial, prompting health officials to call for better prevention and treatment strategies.
Incidence of HIV infection decreased from 5.5 cases per 100 person-years in a cohort of injection drug users recruited from 1988 to 1989 to zero cases per 100 person-years in a cohort recruited between 2005 and 2008.
In contrast, HCV infections declined from 22 cases per 100 person-years in the 1988 to 1989 cohort, to 17.2 per 100 person-years in a cohort recruited in 1994 and 1995. A slight increase to 17.9 cases was reported in another group recruited in 1998, before infections rates declined to 7.8 cases per 100 person-years from 2005 to 2008 (P=0.07).
The disparity in HIV and HCV reduction rates may be due to the fact that HCV is 10-times more transmissible than HIV, according to study researcher Shruti H. Mehta, MD, of the Johns Hopkins Bloomberg School of Public Health, in Baltimore, and colleagues.
Because HCV can be acquired after just one instance of needle-sharing, hazard reduction interventions such as needle exchange and substance abuse treatment programs that have been effective at reducing HIV, may have less of an impact. CDC estimates indicate that approximately one-third of IUDs share needles.
“Efforts need to be intensified on both the prevention and treatment fronts to reduce the reservoir of HCV-infected IDUs,” the researchers wrote in the March 1 issue of the Journal of Infectious Diseases.
To get a better understanding of HCV incidence in IDUs, they analyzed data from four cohorts of IDUs during a 20-year period (1988-1989, n=2,946; 1994-1995, n=391; 1998, n=244; 2005-2008, n=875).
The researchers found that compared with the 1988-1989 cohort, HCV incidence significantly declined among patients younger than 39 years in each subsequent cohort (adjusted prevalence ration=0.73; 95% CI: 0.65-0.81).
However, the same decreases were not observed in patients older than 39 years — among that age group HCV infection rates only declined in the most recent cohort (adjusted prevalence ratio=0.87; 95% CI: 0.77 to 0.99).
“For many persons, the interval between initiation and injection simply remains too brief for prevention strategies to be successful,” the researchers wrote.
They emphasized the importance of targeting prevention efforts towards very young IDUs and drug users who have not yet begun injecting. The other strategy for reducing the HCV reservoir is treatment, the efficacy of HCV treatment regimens is often limited among certain subpopulations including blacks with genotype-1 HCV and those with HIV coinfection, the researchers noted.
“With new, more efficacious therapeutics on the horizon, it is critical that strategies to improve uptake and completion of HCV infection treatment of IDUs be implemented,” they wrote.
Jason Grebely, PhD, and Gregory J. Dore, MBBS, PhD, of the University of New South Wales in Sydney, Australia, offered several suggestions for improving treatment and prevention.
“The development and implmentation of national harm-reduction strategies including broader coverage, enhanced early access and intesnifcation and combination of interventions are probably all needed,” they wrote.
Grebely and Dore also emphasized the importance of conducting randomized clinical trials to evaluate new HCV interventions to ensure that they are successful.
Source
Girl versus virus: The 4 things I learned about journalism when I became the story
by Meg Heckman
Published Mar. 16, 2011 12:02 pm
Updated Mar. 17, 2011 12:20 pm
Nearly two years ago, my boss suggested that I turn myself into a story.
I was halfway through a grueling round of experimental treatment for hepatitis C, a potentially-fatal liver disease I contracted as an infant. My experience had all the trappings of compelling journalism. There was a simple central tension — girl versus virus — and a simple, central question: Will she be cured? Plus, HCV is a sweeping, under-reported epidemic with the potential to cost billions of dollars and millions of lives.
The journalist in me knew all this was newsworthy, but it was Concord Monitor Editor Felice Belman who urged me to use myself as a source.
Over lunch one day, she sketched out her idea: a heavily researched, first-person narrative told in short, serial installments. The piece would explore the epidemic, the idea of medical research on humans and the reasons why so few people know about a virus that affects four times as many Americans as AIDS.
It was an ambitious project for many reasons. For starters, I felt awful. Antiviral medication can cause brutal side effects, and keeping up with my normal workload was already a struggle. Plus, the Monitor’s newsroom is small, and the demands on our time seem to grow every day.
The research and writing took months longer than expected, but we finished the project, called “My Epidemic,” last December. Each day for a week, we published a new chapter in print and online, and used social media to promote the series and to invite feedback.
The result was a profound reminder of the power of storytelling and an illustration of the potential for new media to allow our stories to live on.
Lesson 1: Share your story in a way that works for both print and online.
Yes, journalism has changed, but narrative is still effective, especially if it’s structured to work in print and online. We picked a serial format for reasons both practical and organic. The ups and downs and cliffhangers inherent in serial narratives mimic the reality of living with a chronic disease.
In print, multiple chapters were also easier to place in a tight news hole, and we had multiple opportunities to find space for graphics and photos. Online, each chapter gave us another chance to invite readers into the story through Facebook and Twitter, and to promote HCV resources we’d assembled on our website.
The project was a boon for online traffic. Visits to our website shot up 12 percent compared to December 2009 — by far the largest month-to-month increase in recent memory.
Lesson 2: Find documents, include details for context.
Writing about myself demanded more research than writing about someone else.
When I’m writing about other people, I try to climb inside their heads, which means many hours of watching them just live their lives. In this case, I needed to do just the opposite and place myself in the context of the broader epidemic.
My brother, a doctor, directed me to medical journals and helped me decipher the articles. A database at the local public library supplied archival information about media coverage of HCV, and the Congressional record revealed how public health officials are — or are not — responding to the epidemic.
The most important documents were my own medical records. They included detailed doctors’ notes about all the tests I’d undergone as a teenager and a time-stamped transfusion report that revealed exactly when I’d contracted HCV.
One of the hardest parts was choosing what to include, particularly when it came to describing my birth. There were so many details: my hurried baptism, my father sleeping on the waiting room floor, my parents in their Jeep following the ambulance from one hospital to another, not knowing if I was dead or alive. Those are all important pieces of family lore, but they didn’t advance the story. Including them would have been indulgent, a disservice to the reader.
Lesson 3: Be honest about your fears, discomfort.
I was a crummy photo subject.
For more than a decade, I’ve been trained to collaborate, collaborate and collaborate some more with visual journalists. That’s what I planned to do with this story, but it didn’t quite work out that way.
Photographer Katie Barnes joined the Monitor newsroom a few months after I’d started working on the project and was soon assigned to my story. I was hesitant to drag Katie through my medical hell, and I (irrationally) didn’t trust anyone but myself to get it right.
There were logistical challenges, too. One of the side effects of antiviral medication is temporary absentmindedness. In my case, that meant showing up to work with mismatched shoes, getting lost in the grocery store and forgetting to tell Katie when something important was happening.
Finally, she made me a list of things I might do — walk the dog, cook dinner, visit the acupuncturist — that would help her tell the story.
I know now what it means, what it feels like, to be the subject of someone else’s journalism. Our sources have so much at stake: their reputations, their public images, the truth of how they view themselves. Building trust with the people we cover is everything, and that’s why honest storytelling requires so much time.
Katie ultimately made my discomfort a part of the story, producing a video focused on my feelings about the project. I was terrified when I sat down in front of that camera, but we’d been working together for almost a year, and I understood that this was part of the story only she could tell.
Lesson 4: Tend the seeds you sow.
The response to the series was overwhelming. By the time the last installment was published, I had Twitter followers from Russia and my e-mail and voicemail were full of messages from other people living with HCV.
My editors and I decided to turn some of those responses into an impromptu seventh installment. As I was writing, I found myself wondering if such a swift, multifaceted (and international) reader response would have been possible a decade ago.
The story continues to live on. I receive new e-mails every week from people who have discovered the series, often through Facebook or Twitter. More often than not, they have a personal connection to HCV. Take, for instance, the teenage girl in California who, like me, contracted the virus as a baby and who, like me, has faced cruel judgment from her peers.
As I read the e-mail, I was devastated that another young woman had endured such fear, shame and humiliation. Then she told me that she showed her family and friends my stories and, at last, people began to understand.
Meg Heckman splits her time at the Concord Monitor between writing and exploring digital storytelling. She is a 2001 Poynter summer fellow and a graduate of the University of New Hampshire, where she now works as an adjunct instructor in the journalism program
Source
Also See: My Epidemic.....Shared and Written by Meg Heckman of the Concord Monitor
Published Mar. 16, 2011 12:02 pm
Updated Mar. 17, 2011 12:20 pm
Nearly two years ago, my boss suggested that I turn myself into a story.
I was halfway through a grueling round of experimental treatment for hepatitis C, a potentially-fatal liver disease I contracted as an infant. My experience had all the trappings of compelling journalism. There was a simple central tension — girl versus virus — and a simple, central question: Will she be cured? Plus, HCV is a sweeping, under-reported epidemic with the potential to cost billions of dollars and millions of lives.
The journalist in me knew all this was newsworthy, but it was Concord Monitor Editor Felice Belman who urged me to use myself as a source.
Over lunch one day, she sketched out her idea: a heavily researched, first-person narrative told in short, serial installments. The piece would explore the epidemic, the idea of medical research on humans and the reasons why so few people know about a virus that affects four times as many Americans as AIDS.
It was an ambitious project for many reasons. For starters, I felt awful. Antiviral medication can cause brutal side effects, and keeping up with my normal workload was already a struggle. Plus, the Monitor’s newsroom is small, and the demands on our time seem to grow every day.
The research and writing took months longer than expected, but we finished the project, called “My Epidemic,” last December. Each day for a week, we published a new chapter in print and online, and used social media to promote the series and to invite feedback.
The result was a profound reminder of the power of storytelling and an illustration of the potential for new media to allow our stories to live on.
Lesson 1: Share your story in a way that works for both print and online.
Yes, journalism has changed, but narrative is still effective, especially if it’s structured to work in print and online. We picked a serial format for reasons both practical and organic. The ups and downs and cliffhangers inherent in serial narratives mimic the reality of living with a chronic disease.
In print, multiple chapters were also easier to place in a tight news hole, and we had multiple opportunities to find space for graphics and photos. Online, each chapter gave us another chance to invite readers into the story through Facebook and Twitter, and to promote HCV resources we’d assembled on our website.
The project was a boon for online traffic. Visits to our website shot up 12 percent compared to December 2009 — by far the largest month-to-month increase in recent memory.
Lesson 2: Find documents, include details for context.
Writing about myself demanded more research than writing about someone else.
When I’m writing about other people, I try to climb inside their heads, which means many hours of watching them just live their lives. In this case, I needed to do just the opposite and place myself in the context of the broader epidemic.
My brother, a doctor, directed me to medical journals and helped me decipher the articles. A database at the local public library supplied archival information about media coverage of HCV, and the Congressional record revealed how public health officials are — or are not — responding to the epidemic.
The most important documents were my own medical records. They included detailed doctors’ notes about all the tests I’d undergone as a teenager and a time-stamped transfusion report that revealed exactly when I’d contracted HCV.
One of the hardest parts was choosing what to include, particularly when it came to describing my birth. There were so many details: my hurried baptism, my father sleeping on the waiting room floor, my parents in their Jeep following the ambulance from one hospital to another, not knowing if I was dead or alive. Those are all important pieces of family lore, but they didn’t advance the story. Including them would have been indulgent, a disservice to the reader.
Lesson 3: Be honest about your fears, discomfort.
I was a crummy photo subject.
For more than a decade, I’ve been trained to collaborate, collaborate and collaborate some more with visual journalists. That’s what I planned to do with this story, but it didn’t quite work out that way.
Photographer Katie Barnes joined the Monitor newsroom a few months after I’d started working on the project and was soon assigned to my story. I was hesitant to drag Katie through my medical hell, and I (irrationally) didn’t trust anyone but myself to get it right.
There were logistical challenges, too. One of the side effects of antiviral medication is temporary absentmindedness. In my case, that meant showing up to work with mismatched shoes, getting lost in the grocery store and forgetting to tell Katie when something important was happening.
Finally, she made me a list of things I might do — walk the dog, cook dinner, visit the acupuncturist — that would help her tell the story.
I know now what it means, what it feels like, to be the subject of someone else’s journalism. Our sources have so much at stake: their reputations, their public images, the truth of how they view themselves. Building trust with the people we cover is everything, and that’s why honest storytelling requires so much time.
Katie ultimately made my discomfort a part of the story, producing a video focused on my feelings about the project. I was terrified when I sat down in front of that camera, but we’d been working together for almost a year, and I understood that this was part of the story only she could tell.
Lesson 4: Tend the seeds you sow.
The response to the series was overwhelming. By the time the last installment was published, I had Twitter followers from Russia and my e-mail and voicemail were full of messages from other people living with HCV.
My editors and I decided to turn some of those responses into an impromptu seventh installment. As I was writing, I found myself wondering if such a swift, multifaceted (and international) reader response would have been possible a decade ago.
The story continues to live on. I receive new e-mails every week from people who have discovered the series, often through Facebook or Twitter. More often than not, they have a personal connection to HCV. Take, for instance, the teenage girl in California who, like me, contracted the virus as a baby and who, like me, has faced cruel judgment from her peers.
As I read the e-mail, I was devastated that another young woman had endured such fear, shame and humiliation. Then she told me that she showed her family and friends my stories and, at last, people began to understand.
Meg Heckman splits her time at the Concord Monitor between writing and exploring digital storytelling. She is a 2001 Poynter summer fellow and a graduate of the University of New Hampshire, where she now works as an adjunct instructor in the journalism program
Source
Also See: My Epidemic.....Shared and Written by Meg Heckman of the Concord Monitor
Achillion wins patent for anti-hepatitis compound
By Gregory Seay
gseay@HartfordBusiness.com
New Haven drug developer Achillion Pharmaceuticals Inc. says its new U.S. patent covering a key compound in its treatment for hepatitis C protects it while undergoing clinical trials to bring the drug to market but also widens the door to a takeover.
Achieving patent status for its "cornerstone compound'' also elevates Achillion's attractiveness as a partner to other drug developers as well as a more attractive takeover target for pharmaceutical giants, the CEO says.
"The answer is a pretty hard 'yes,''' said Michael D. Kishbauch, a veteran pharma executive and investor who also is Achillion's chairman. "We're probably a reasonable acquisition to begin with.''
Kishbauch said the company has had previous discussions with potential partners and suitors. He did not elaborate.
Achillion has three small-molecule drugs under development to treat blood-borne ailments, including HIV.
Drug giants, such as Pfizer Inc., which has R&D operations in Connecticut, face the loss of billions in annual sales to generics as patents on their popular drugs begin to expire.
Achillion's U.S. Patent No. 7,906,619 covers composition-of-matter and method of use claims for its ACH-1625 and structurally related compounds. The patent, entitled "4-amino-4-oxobutanoyl peptides as inhibitors of viral replication," expires in 2029.
Kishbauch said patent removes the air of uncertainty among other drug developers who might want to partner with, or license from Achillion, the intellectual property at the root of the compound.
d Achillion is currently in phase 2 clinical trials with its small-molecule protease inhibitor to treat the hepatitis C virus. It is racing against other drug makers to be the first to market with an effective treatment.
"This key patent grant provides a cornerstone for Achillion's intellectual property portfolio [and] ... will make this a transformational year for Achillion," Kishbauch said.
Source
gseay@HartfordBusiness.com
New Haven drug developer Achillion Pharmaceuticals Inc. says its new U.S. patent covering a key compound in its treatment for hepatitis C protects it while undergoing clinical trials to bring the drug to market but also widens the door to a takeover.
Achieving patent status for its "cornerstone compound'' also elevates Achillion's attractiveness as a partner to other drug developers as well as a more attractive takeover target for pharmaceutical giants, the CEO says.
"The answer is a pretty hard 'yes,''' said Michael D. Kishbauch, a veteran pharma executive and investor who also is Achillion's chairman. "We're probably a reasonable acquisition to begin with.''
Kishbauch said the company has had previous discussions with potential partners and suitors. He did not elaborate.
Achillion has three small-molecule drugs under development to treat blood-borne ailments, including HIV.
Drug giants, such as Pfizer Inc., which has R&D operations in Connecticut, face the loss of billions in annual sales to generics as patents on their popular drugs begin to expire.
Achillion's U.S. Patent No. 7,906,619 covers composition-of-matter and method of use claims for its ACH-1625 and structurally related compounds. The patent, entitled "4-amino-4-oxobutanoyl peptides as inhibitors of viral replication," expires in 2029.
Kishbauch said patent removes the air of uncertainty among other drug developers who might want to partner with, or license from Achillion, the intellectual property at the root of the compound.
d Achillion is currently in phase 2 clinical trials with its small-molecule protease inhibitor to treat the hepatitis C virus. It is racing against other drug makers to be the first to market with an effective treatment.
"This key patent grant provides a cornerstone for Achillion's intellectual property portfolio [and] ... will make this a transformational year for Achillion," Kishbauch said.
Source
March 16, 2011
Outcomes Differ Among Hepatitis C-Related Vasculitides
Last Updated: March 16, 2011
Among patients with hepatitis C virus-related vasculitis, those with polyarteritis nodosa have a more severe and acute clinical presentation and a higher rate of clinical remission, according to a study published online Feb. 25 in Arthritis Care & Research.
WEDNESDAY, March 16 (HealthDay News) -- Among patients with hepatitis C virus (HCV)-related vasculitis, those with polyarteritis nodosa (PAN) have a more severe and acute clinical presentation and a higher rate of clinical remission, according to a study published online Feb. 25 in Arthritis Care & Research.
David Saadoun, M.D., Ph.D., of Groupe Hospitalier Pitié-Salpêtrière in Paris, and colleagues investigated the prevalence and characteristics of PAN in a cohort of 161 patients with chronic HCV-related vasculitis. The features and outcomes of 31 patients with HCV-PAN were compared with those patients with HCV-associated mixed cryoglobulinemia (HCV-MC).
The researchers found that, compared to HCV-MC, a more severe and acute presentation was seen in patients with HCV-PAN. They had more frequent fever and weight loss, severe hypertension, involvement of the gastrointestinal tract, severe and acute multifocal neuropathy, kidney and liver microaneurysms, and elevated C-reactive protein. However, clinical remission occurred in 79.3 percent of those with HCV-PAN compared to 57.5 percent of those with HCV-MC. A complete clinical response of HCV vasculitis was independently correlated with skin involvement and PAN-type vasculitis; whereas, a glomerular filtration rate less than 70 mL per minute was negatively correlated with the clinical response. Among the entire HCV-related vasculitis cohort, the five-year survival rate was 86 percent, irrespective of the type of vasculitis.
"HCV-PAN accounts for 19.3 percent of our cohort of HCV-related vasculitis. HCV-PAN compared to HCV-MC displays a more severe and acute clinical presentation, a distinct pathogenic pathway, and a higher rate of clinical remission," the authors write.
One of the study authors disclosed financial ties with several pharmaceutical companies.
Abstract
Full Text (subscription or payment may be required)
Source
Among patients with hepatitis C virus-related vasculitis, those with polyarteritis nodosa have a more severe and acute clinical presentation and a higher rate of clinical remission, according to a study published online Feb. 25 in Arthritis Care & Research.
WEDNESDAY, March 16 (HealthDay News) -- Among patients with hepatitis C virus (HCV)-related vasculitis, those with polyarteritis nodosa (PAN) have a more severe and acute clinical presentation and a higher rate of clinical remission, according to a study published online Feb. 25 in Arthritis Care & Research.
David Saadoun, M.D., Ph.D., of Groupe Hospitalier Pitié-Salpêtrière in Paris, and colleagues investigated the prevalence and characteristics of PAN in a cohort of 161 patients with chronic HCV-related vasculitis. The features and outcomes of 31 patients with HCV-PAN were compared with those patients with HCV-associated mixed cryoglobulinemia (HCV-MC).
The researchers found that, compared to HCV-MC, a more severe and acute presentation was seen in patients with HCV-PAN. They had more frequent fever and weight loss, severe hypertension, involvement of the gastrointestinal tract, severe and acute multifocal neuropathy, kidney and liver microaneurysms, and elevated C-reactive protein. However, clinical remission occurred in 79.3 percent of those with HCV-PAN compared to 57.5 percent of those with HCV-MC. A complete clinical response of HCV vasculitis was independently correlated with skin involvement and PAN-type vasculitis; whereas, a glomerular filtration rate less than 70 mL per minute was negatively correlated with the clinical response. Among the entire HCV-related vasculitis cohort, the five-year survival rate was 86 percent, irrespective of the type of vasculitis.
"HCV-PAN accounts for 19.3 percent of our cohort of HCV-related vasculitis. HCV-PAN compared to HCV-MC displays a more severe and acute clinical presentation, a distinct pathogenic pathway, and a higher rate of clinical remission," the authors write.
One of the study authors disclosed financial ties with several pharmaceutical companies.
Abstract
Full Text (subscription or payment may be required)
Source
In New York, A Rare Case of HIV Transmission From a Live Organ Donor
March 16, 2011, 5:38 PM ET
By Laura Landro
The New York State Department of Health alerted hospitals and transplant centers Tuesday that an organ recipient recently contracted the virus that causes AIDS from a live kidney donor in an unnamed city hospital. It’s the nation’s first documented case of HIV transmission via a transplant from a living donor since a sensitive test for the virus was approved and implemented for donor screening in 1985, according to the health department.
A department spokeswoman tells the Health Blog that the hospital followed acceptable protocols in an initial screening of the donor, but that he apparently had “unsafe sex” after the test and prior to donating the organ. “Of course this is a rare case, but we felt like we needed to alert centers to this possibility so they can talk to potential donors about risks and do testing closer to the time of surgery,” she says.
The state declined to name the hospital in the interest of protecting the privacy of the patient.
The department is now recommending that hospitals test donors for HIV and the hepatitis C and B viruses within 14 days before the organ donation, using nucleic acid testing. NAT can detect viral infections weeks to months before antibodies are detectable by standard serologic tests. It hasn’t been recommended for testing organs from deceased donors because of the time pressure of transplanting the organs before they deteriorate, but that time crunch shouldn’t apply to potential living donors, the state notes in its advisory.
Testing for infectious disease has all but eliminated the transmission of HIV through organ, tissue and blood donation. The Centers for Disease Control and Prevention last issued HIV-specific organ-donation screening recommendations in 1994 and is expected to update its recommendation this year.
The state is advising hospitals to question living organ donors about risky behavior, including the use of non-medical injectable drugs. Compliance with the specific recommendation is voluntary but the department is urging all centers to update their policies for screening living donors as necessary.
The transplant community’s most recent testing recommendations, which appeared in the American Journal of Transplantation last year, said that average-risk donors do not require NAT screening; they didn’t address the timing of screening. The health department says it doesn’t believe those recommendations are sufficiently protective because of the challenges of detecting behavioral risks and learning about the infection status of a donor’s sexual partners.
Source
By Laura Landro
The New York State Department of Health alerted hospitals and transplant centers Tuesday that an organ recipient recently contracted the virus that causes AIDS from a live kidney donor in an unnamed city hospital. It’s the nation’s first documented case of HIV transmission via a transplant from a living donor since a sensitive test for the virus was approved and implemented for donor screening in 1985, according to the health department.
A department spokeswoman tells the Health Blog that the hospital followed acceptable protocols in an initial screening of the donor, but that he apparently had “unsafe sex” after the test and prior to donating the organ. “Of course this is a rare case, but we felt like we needed to alert centers to this possibility so they can talk to potential donors about risks and do testing closer to the time of surgery,” she says.
The state declined to name the hospital in the interest of protecting the privacy of the patient.
The department is now recommending that hospitals test donors for HIV and the hepatitis C and B viruses within 14 days before the organ donation, using nucleic acid testing. NAT can detect viral infections weeks to months before antibodies are detectable by standard serologic tests. It hasn’t been recommended for testing organs from deceased donors because of the time pressure of transplanting the organs before they deteriorate, but that time crunch shouldn’t apply to potential living donors, the state notes in its advisory.
Testing for infectious disease has all but eliminated the transmission of HIV through organ, tissue and blood donation. The Centers for Disease Control and Prevention last issued HIV-specific organ-donation screening recommendations in 1994 and is expected to update its recommendation this year.
The state is advising hospitals to question living organ donors about risky behavior, including the use of non-medical injectable drugs. Compliance with the specific recommendation is voluntary but the department is urging all centers to update their policies for screening living donors as necessary.
The transplant community’s most recent testing recommendations, which appeared in the American Journal of Transplantation last year, said that average-risk donors do not require NAT screening; they didn’t address the timing of screening. The health department says it doesn’t believe those recommendations are sufficiently protective because of the challenges of detecting behavioral risks and learning about the infection status of a donor’s sexual partners.
Source
FDA Hepatitis Update - FDA Advisory Committee meeting to consider boceprevir and telaprevir, April 27 and April 28, 2011
From: U.S. Food & Drug Administration (FDA)
You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.
The Food and Drug Administration will convene its Antiviral Drugs Advisory Committee on April 27 and 28, 2011 to provide advice and recommendations to the Agency on two drugs intended to treat hepatitis C.
On April 27, 2011, from 8 a.m. to 5 p.m., the Committee will discuss a new drug application (NDA) 202–258, boceprevir (a hepatitis C virus protease inhibitor), manufactured by Merck & Co., Inc., with a proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
On April 28, 2011, the committee will discuss a new drug application (NDA) 201–917, telaprevir (a hepatitis C virus protease inhibitor), manufactured by Vertex Pharmaceuticals, Inc., with a proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
Compensated liver disease is a stage in which the liver is damaged but maintains ability to function.
The meeting will be held on both days from 8 a.m. to 5 p.m. at the FDA White Oak Campus, located at
10903 New Hampshire Ave., Building 31 Conference Center, the Great Room (rm. 1503), Silver Spring, MD 20993-0002.
Please note that visitors to the White Oak Campus must enter through Building 1, which is located at the circle at the entrance to the campus via Mahan Road from New Hampshire Avenue. (Google Maps)
FDA intends to make background material about these meetings available to the public no later than 2 business days before the meeting at http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm.
Scroll down to the link for the Antiviral Drug Committee, and click on appropriate meeting dates.
If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA’s Web site after the meeting.
Public Participation Information
This FDA advisory committee meeting is free and open to the public without prior registration.
Interested persons may present data, information, or views, orally at the meeting, or in writing, on issues pending before the committee.
Written submissions may be made to
Paul Tran, R.Ph
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
WO31-2417
Silver Spring, MD 20993-0002
Phone: 301-796-9001
Fax: 301-847-8533
E-mail: Paul.Tran@fda.hhs.gov
on or before April 14, 2011.
Oral presentations from the public will be scheduled between approximately 1:00 p.m. to 2:00 p.m., on April 28, 2011. Those desiring to make formal oral presentations should notify Paul Tran and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before April 6, 2011.
Time allotted for each presentation may be limited. If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by April 7, 2011.
Please call the FDA Advisory Committee Information Line for up-to-date information on this meeting at
1-800-741-8138
(301-443-0572 in the Washington DC area)
Enter code: 3014512531
FDA welcomes the attendance of the public at its advisory committee meetings and will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Paul Tran at (301) 796-9001 at least 7 days in advance of the meeting.
Information regarding special accommodations due to a disability, or information about visitor parking and transportation may be accessed at: Public Meetings at the FDA White Oak Campus
Please visit our Web site at Public Conduct During FDA Advisory Committee Meetings for procedures on public conduct during advisory committee meetings. FDA is committed to the orderly conduct of its advisory committee meetings.
Persons attending FDA’s advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.
The Food and Drug Administration will convene its Antiviral Drugs Advisory Committee on April 27 and 28, 2011 to provide advice and recommendations to the Agency on two drugs intended to treat hepatitis C.
On April 27, 2011, from 8 a.m. to 5 p.m., the Committee will discuss a new drug application (NDA) 202–258, boceprevir (a hepatitis C virus protease inhibitor), manufactured by Merck & Co., Inc., with a proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
On April 28, 2011, the committee will discuss a new drug application (NDA) 201–917, telaprevir (a hepatitis C virus protease inhibitor), manufactured by Vertex Pharmaceuticals, Inc., with a proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C infection) in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
Compensated liver disease is a stage in which the liver is damaged but maintains ability to function.
The meeting will be held on both days from 8 a.m. to 5 p.m. at the FDA White Oak Campus, located at
10903 New Hampshire Ave., Building 31 Conference Center, the Great Room (rm. 1503), Silver Spring, MD 20993-0002.
Please note that visitors to the White Oak Campus must enter through Building 1, which is located at the circle at the entrance to the campus via Mahan Road from New Hampshire Avenue. (Google Maps)
FDA intends to make background material about these meetings available to the public no later than 2 business days before the meeting at http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm.
Scroll down to the link for the Antiviral Drug Committee, and click on appropriate meeting dates.
If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA’s Web site after the meeting.
Public Participation Information
This FDA advisory committee meeting is free and open to the public without prior registration.
Interested persons may present data, information, or views, orally at the meeting, or in writing, on issues pending before the committee.
Written submissions may be made to
Paul Tran, R.Ph
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
WO31-2417
Silver Spring, MD 20993-0002
Phone: 301-796-9001
Fax: 301-847-8533
E-mail: Paul.Tran@fda.hhs.gov
on or before April 14, 2011.
Oral presentations from the public will be scheduled between approximately 1:00 p.m. to 2:00 p.m., on April 28, 2011. Those desiring to make formal oral presentations should notify Paul Tran and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before April 6, 2011.
Time allotted for each presentation may be limited. If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by April 7, 2011.
Please call the FDA Advisory Committee Information Line for up-to-date information on this meeting at
1-800-741-8138
(301-443-0572 in the Washington DC area)
Enter code: 3014512531
FDA welcomes the attendance of the public at its advisory committee meetings and will make every effort to accommodate persons with physical disabilities or special needs. If you require special accommodations due to a disability, please contact Paul Tran at (301) 796-9001 at least 7 days in advance of the meeting.
Information regarding special accommodations due to a disability, or information about visitor parking and transportation may be accessed at: Public Meetings at the FDA White Oak Campus
Please visit our Web site at Public Conduct During FDA Advisory Committee Meetings for procedures on public conduct during advisory committee meetings. FDA is committed to the orderly conduct of its advisory committee meetings.
Persons attending FDA’s advisory committee meetings are advised that the agency is not responsible for providing access to electrical outlets.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Hepatitis C virus infection in USA: an estimate of true prevalence
Liver International
Early View (Articles online in advance of print)
Eric Chak 1, Andrew H. Talal 2, Kenneth E. Sherman 3, Eugene R. Schiff 4, Sammy Saab 5
Article first published online: 15 MAR 2011
DOI: 10.1111/j.1478-3231.2011.02494.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Medicine, UCLA-Olive View Medical Center, University of California at Los Angeles, Sylmar, CA, USA
2 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA
3 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
4 Department of Medicine, University of Miami School of Medicine, Miami, FL, USA
5 Department of Medicine and Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
* Correspondence: Correspondence Sammy Saab, MD, MPH, AGAF, UCLA Pfleger Liver Institute, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA Tel: +1 310-206-6705 Fax: +1 310-206-4197 e-mail: ssaab@mednet.ucla.edu
Abstract
Keywords :hepatitis C virus;prevalence
The recent National Health and Nutrition Examination Survey (NHANES) sampled only the civilian, non-institutionalized population of USA and may have underestimated the prevalence of hepatitis C virus (HCV) in this country. We searched the database MEDLINE, the Bureau of Justice Statistics, Center for Medicare and Medicaid and individual states Department of Corrections for all epidemiological studies regarding the prevalence of HCV in populations not sampled by the NHANES survey namely the incarcerated, homeless, nursing home residents, hospitalized and those on active military duty. Because of their relatively low frequency in the NHANES sample, we also expanded our search to include healthcare workers and long-term dialysis patients. Although included in the NHANES sample, we also performed searches on drug users (injection and non-injection) and veterans to confirm the findings of the NHANES study. Based on the prevalence of studies identified meeting our inclusion criteria, our most conservative estimates state that there at least 142 761 homeless persons, 372 754 incarcerated persons and 6805 persons on active military duty unaccounted for in the NHANES survey. While the NHANES estimates of drug users (both injection and non-injection) appear to be reasonable, the survey seems to have underestimated the number of HCV-positive veterans. Our most conservative estimates suggest that there are at least 5.2 million persons living with HCV in USA today, approximately 1.9 million of whom were unaccounted for in the NHANES survey.
Source
Early View (Articles online in advance of print)
Eric Chak 1, Andrew H. Talal 2, Kenneth E. Sherman 3, Eugene R. Schiff 4, Sammy Saab 5
Article first published online: 15 MAR 2011
DOI: 10.1111/j.1478-3231.2011.02494.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Medicine, UCLA-Olive View Medical Center, University of California at Los Angeles, Sylmar, CA, USA
2 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA
3 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
4 Department of Medicine, University of Miami School of Medicine, Miami, FL, USA
5 Department of Medicine and Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
* Correspondence: Correspondence Sammy Saab, MD, MPH, AGAF, UCLA Pfleger Liver Institute, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA Tel: +1 310-206-6705 Fax: +1 310-206-4197 e-mail: ssaab@mednet.ucla.edu
Abstract
Keywords :hepatitis C virus;prevalence
The recent National Health and Nutrition Examination Survey (NHANES) sampled only the civilian, non-institutionalized population of USA and may have underestimated the prevalence of hepatitis C virus (HCV) in this country. We searched the database MEDLINE, the Bureau of Justice Statistics, Center for Medicare and Medicaid and individual states Department of Corrections for all epidemiological studies regarding the prevalence of HCV in populations not sampled by the NHANES survey namely the incarcerated, homeless, nursing home residents, hospitalized and those on active military duty. Because of their relatively low frequency in the NHANES sample, we also expanded our search to include healthcare workers and long-term dialysis patients. Although included in the NHANES sample, we also performed searches on drug users (injection and non-injection) and veterans to confirm the findings of the NHANES study. Based on the prevalence of studies identified meeting our inclusion criteria, our most conservative estimates state that there at least 142 761 homeless persons, 372 754 incarcerated persons and 6805 persons on active military duty unaccounted for in the NHANES survey. While the NHANES estimates of drug users (both injection and non-injection) appear to be reasonable, the survey seems to have underestimated the number of HCV-positive veterans. Our most conservative estimates suggest that there are at least 5.2 million persons living with HCV in USA today, approximately 1.9 million of whom were unaccounted for in the NHANES survey.
Source
March 15, 2011
Gilead's Hepatitis C Therapy Called Successful
CDC 3-14-11
Abstract
In early-stage study results reported recently to investors, Gilead Sciences Inc. said its four-drug combination eliminated hepatitis C virus in patients. The trial examined the use of Gilead GS-9256 and GS-9190 with the standard drugs ribavirin and peginterferon. The researchers plan to present their findings at the annual meeting of the European Association for the Study of the Liver, which begins March 30 in Berlin.
Source
http://www.sfgate.com/
Date of Publication
03/09/2011
Author
Kristen Hallam, Bloomberg News
Article Type
General media
Article Category
News Briefs
Source
Abstract
In early-stage study results reported recently to investors, Gilead Sciences Inc. said its four-drug combination eliminated hepatitis C virus in patients. The trial examined the use of Gilead GS-9256 and GS-9190 with the standard drugs ribavirin and peginterferon. The researchers plan to present their findings at the annual meeting of the European Association for the Study of the Liver, which begins March 30 in Berlin.
Source
http://www.sfgate.com/
Date of Publication
03/09/2011
Author
Kristen Hallam, Bloomberg News
Article Type
General media
Article Category
News Briefs
Source
The relationship between body mass index and age at hepatocellular carcinoma onset
Public release date: 15-Mar-2011
Contact: Ye-Ru Wang
wjg@wjgnet.com
86-105-908-0039
World Journal of Gastroenterology
The incidence and mortality associated with hepatocellular carcinoma (HCC) have been increasing worldwide, and hepatitis C virus (HCV) infection plays an important role in the pathogenesis of HCC. Previous studies have suggested that host factors, such as sex, alcohol consumption, smoking, diabetes mellitus, and obesity, are important risk factors for HCC. Meanwhile, it has been reported that HCV infection causes insulin resistance and leads to oxidative stress, potentiating fibrosis and hepatic carcinogenesis. However, the factors that influence the development of HCC in HCV-infected patients remain largely unknown.
A research article published on February 21, 2011 in the World Journal of Gastroenterology addresses this question. The authors hypothesized that obesity influences the time to onset of HCC related to HCV infection, which is reflected in the patient's age at onset. To test this hypothesis, they investigated the relationship between body mass index (BMI) and lifestyle factors and age at onset of HCC in HCV-infected patients.
The research showed that the underweight patients (BMI < 18.5 kg/m2), tended to be older at HCC onset than patients within the normal weight range (BMI 18.5 kg/m2).
The results suggest that achieving an adequate body weight along with a reduction of alcohol intake in patients with chronic hepatitis C could help prevent hepatic carcinogenesis.
###
Reference: Akiyama T, Mizuta T, Kawazoe S, Eguchi Y, Kawaguchi Y, Takahashi H, Ozaki I, Fujimoto K. Body mass index is associated with age-at-onset of HCV-infected hepatocellular carcinoma patients. World J Gastroenterol 2011; 17(7): 914-921
http://www.wjgnet.com/1007-9327/full/v17/i7/914.htm
Correspondence to: Toshihiko Mizuta, MD, PhD, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 8498501, Japan. mizutat@med.saga-u.ac.jp
Telephone: +81-952-342362 Fax: +81-952-342017
About World Journal of Gastroenterology
World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H. pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2009 IF: 2.092. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.
Source
Contact: Ye-Ru Wang
wjg@wjgnet.com
86-105-908-0039
World Journal of Gastroenterology
The incidence and mortality associated with hepatocellular carcinoma (HCC) have been increasing worldwide, and hepatitis C virus (HCV) infection plays an important role in the pathogenesis of HCC. Previous studies have suggested that host factors, such as sex, alcohol consumption, smoking, diabetes mellitus, and obesity, are important risk factors for HCC. Meanwhile, it has been reported that HCV infection causes insulin resistance and leads to oxidative stress, potentiating fibrosis and hepatic carcinogenesis. However, the factors that influence the development of HCC in HCV-infected patients remain largely unknown.
A research article published on February 21, 2011 in the World Journal of Gastroenterology addresses this question. The authors hypothesized that obesity influences the time to onset of HCC related to HCV infection, which is reflected in the patient's age at onset. To test this hypothesis, they investigated the relationship between body mass index (BMI) and lifestyle factors and age at onset of HCC in HCV-infected patients.
The research showed that the underweight patients (BMI < 18.5 kg/m2), tended to be older at HCC onset than patients within the normal weight range (BMI 18.5 kg/m2).
The results suggest that achieving an adequate body weight along with a reduction of alcohol intake in patients with chronic hepatitis C could help prevent hepatic carcinogenesis.
###
Reference: Akiyama T, Mizuta T, Kawazoe S, Eguchi Y, Kawaguchi Y, Takahashi H, Ozaki I, Fujimoto K. Body mass index is associated with age-at-onset of HCV-infected hepatocellular carcinoma patients. World J Gastroenterol 2011; 17(7): 914-921
http://www.wjgnet.com/1007-9327/full/v17/i7/914.htm
Correspondence to: Toshihiko Mizuta, MD, PhD, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 8498501, Japan. mizutat@med.saga-u.ac.jp
Telephone: +81-952-342362 Fax: +81-952-342017
About World Journal of Gastroenterology
World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H. pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2009 IF: 2.092. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.
Source
iTherX Initiates Phase 1b Study of First-in-Class Hepatitis C Virus Entry Inhibitor ITX-5061
-- Preclinical Studies Show that ITX-5061 Prevents Hepatitis C from Invading Liver Cells --
SAN DIEGO, March 15, 2011 /PRNewswire/ -- iTherX, a pharmaceutical company dedicated to discovering and developing a new class of therapies for hepatitis C, today announced that it has commenced patient recruitment in an open-label, proof-of-concept Phase 1b study of its lead compound ITX-5061 in liver transplant patients with hepatitis C virus infection (HCV). ITX-5061 represents a first-in-class compound that inhibits entry of the hepatitis C virus into liver cells.
"ITX-5061 possesses a unique mechanism of action that prevents the hepatitis C virus from entering liver cells and has demonstrated potent preclinical antiviral activity against all HCV genotypes.In addition, it has already demonstrated safety in more than 280 subjects," said Jeffrey McKelvy, PhD, MD, President and Chief Executive Officer of iTherX. "We hope ITX-5061 will significantly improve long-term transplant outcomes."
The primary objective of the Phase 1b clinical trial will be to assess the safety and tolerability of ITX-5061 in liver transplant patients. The study will also assess HCV viral load for three months after liver transplantation to determine if ITX-5061 has any immediate and/or sustained impact on viral kinetics in treated patients. Approximately 20 patients will be enrolled into one of two cohorts: one group will receive supportive care only, while the second cohort will also receive ITX-5061 at a150 mg daily dose for seven days. The trial is being conducted at the University of Birmingham, UK under the direction of David Mutimer, MBBS, MD, FRACP, FRCP, Reader in Hepatology at Birmingham University and Consultant Hepatologist to the Birmingham QE Hospital Liver and Hepatobiliary Unit.
Preclinical studies have shown ITX-5061 to be a potent and selective inhibitor of HCV entry into hepatocytes, capable of preventing virus binding/fusion and cell to cell spread, suggesting ITX-5061 may reduce re-infection rates following liver transplant.
"Recurrence of HCV infection among liver transplant patients is universal and immediate. Clinicians have long sought ways to prevent re-infection by HCV, improve transplant patient outcomes and extend survival," said Dr. Mutimer. "The potential of ITX-5061 to prevent or reduce viral infection of the new liver by halting viral-entry into healthy cells represents an extraordinarily novel approach, and we are excited to advance the clinical development of this promising antiviral compound."
The Phase 1b trial of ITX-5061 in liver transplant recipients is funded through an educational grant from iTherX with the National Institute of Health Research Biomedical Research Unit (NIH-BRU Birmingham).
This is a second clinical study for ITX-5061 in hepatitis C. The first study, a single agent placebo-controlled dose response study commenced in August 2010, is being conducted in treatment naïve chronic HCV patients by the AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases.
About Hepatitis C
Hepatitis C virus (HCV) infection, a disease that attacks the liver, affects 170 million people worldwide. The majority of individuals develop chronic infection and up to 20 percent of infected individuals will develop cirrhosis with the attendant risks of liver failure and liver cell cancer. The current standard of care is combination antiviral treatment with pegylated interferon-alpha and ribavirin, which results in a cure for approximately half of all patients. Unfortunately, many patients present with clinically silent infection or advanced disease, at which time antiviral treatment is generally ineffective. For these patients, liver transplantation may be the only option. End-stage liver disease due to chronic HCV infection has become the leading indication for liver transplantation in the United States. Recurrence of hepatitis C virus after liver transplantation is inevitable and disease progression is rapid when compared with disease in the non-transplanted liver.
About iTherX
iTherX is a pharmaceutical company focused on the discovery and development of a novel class of antiviral therapeutics that act by blocking entry of the hepatitis C virus into liver cells to halt the spread of infection. The company's lead program, ITX-5061, is currently in Phase 1b clinical studies intended to evaluate antiviral activity and safety in patients with HCV infection. In addition to ITX-5061, iTherX is leveraging its proprietary expertise in molecular virology and medicinal chemistry to establish a pipeline of viral entry inhibitors, with additional candidates currently undergoing preclinical testing.
CONTACTS:
BCC Partners
Karen Bergman or Susan Pietropaolo, +1.650.575.1509 or +1.845.638.6290
SOURCE iTherX
Source
SAN DIEGO, March 15, 2011 /PRNewswire/ -- iTherX, a pharmaceutical company dedicated to discovering and developing a new class of therapies for hepatitis C, today announced that it has commenced patient recruitment in an open-label, proof-of-concept Phase 1b study of its lead compound ITX-5061 in liver transplant patients with hepatitis C virus infection (HCV). ITX-5061 represents a first-in-class compound that inhibits entry of the hepatitis C virus into liver cells.
"ITX-5061 possesses a unique mechanism of action that prevents the hepatitis C virus from entering liver cells and has demonstrated potent preclinical antiviral activity against all HCV genotypes.In addition, it has already demonstrated safety in more than 280 subjects," said Jeffrey McKelvy, PhD, MD, President and Chief Executive Officer of iTherX. "We hope ITX-5061 will significantly improve long-term transplant outcomes."
The primary objective of the Phase 1b clinical trial will be to assess the safety and tolerability of ITX-5061 in liver transplant patients. The study will also assess HCV viral load for three months after liver transplantation to determine if ITX-5061 has any immediate and/or sustained impact on viral kinetics in treated patients. Approximately 20 patients will be enrolled into one of two cohorts: one group will receive supportive care only, while the second cohort will also receive ITX-5061 at a150 mg daily dose for seven days. The trial is being conducted at the University of Birmingham, UK under the direction of David Mutimer, MBBS, MD, FRACP, FRCP, Reader in Hepatology at Birmingham University and Consultant Hepatologist to the Birmingham QE Hospital Liver and Hepatobiliary Unit.
Preclinical studies have shown ITX-5061 to be a potent and selective inhibitor of HCV entry into hepatocytes, capable of preventing virus binding/fusion and cell to cell spread, suggesting ITX-5061 may reduce re-infection rates following liver transplant.
"Recurrence of HCV infection among liver transplant patients is universal and immediate. Clinicians have long sought ways to prevent re-infection by HCV, improve transplant patient outcomes and extend survival," said Dr. Mutimer. "The potential of ITX-5061 to prevent or reduce viral infection of the new liver by halting viral-entry into healthy cells represents an extraordinarily novel approach, and we are excited to advance the clinical development of this promising antiviral compound."
The Phase 1b trial of ITX-5061 in liver transplant recipients is funded through an educational grant from iTherX with the National Institute of Health Research Biomedical Research Unit (NIH-BRU Birmingham).
This is a second clinical study for ITX-5061 in hepatitis C. The first study, a single agent placebo-controlled dose response study commenced in August 2010, is being conducted in treatment naïve chronic HCV patients by the AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases.
About Hepatitis C
Hepatitis C virus (HCV) infection, a disease that attacks the liver, affects 170 million people worldwide. The majority of individuals develop chronic infection and up to 20 percent of infected individuals will develop cirrhosis with the attendant risks of liver failure and liver cell cancer. The current standard of care is combination antiviral treatment with pegylated interferon-alpha and ribavirin, which results in a cure for approximately half of all patients. Unfortunately, many patients present with clinically silent infection or advanced disease, at which time antiviral treatment is generally ineffective. For these patients, liver transplantation may be the only option. End-stage liver disease due to chronic HCV infection has become the leading indication for liver transplantation in the United States. Recurrence of hepatitis C virus after liver transplantation is inevitable and disease progression is rapid when compared with disease in the non-transplanted liver.
About iTherX
iTherX is a pharmaceutical company focused on the discovery and development of a novel class of antiviral therapeutics that act by blocking entry of the hepatitis C virus into liver cells to halt the spread of infection. The company's lead program, ITX-5061, is currently in Phase 1b clinical studies intended to evaluate antiviral activity and safety in patients with HCV infection. In addition to ITX-5061, iTherX is leveraging its proprietary expertise in molecular virology and medicinal chemistry to establish a pipeline of viral entry inhibitors, with additional candidates currently undergoing preclinical testing.
CONTACTS:
BCC Partners
Karen Bergman or Susan Pietropaolo, +1.650.575.1509 or +1.845.638.6290
SOURCE iTherX
Source
March 14, 2011
A wild ride in Hepatitis C treatment
A wild ride in Hepatitis C treatment: Vertex stock gives investors whiplash
March 14th, 2011 5:56 pm ET
Elisabeth Morris
Boston Health News Examiner
Has anyone noticed that Vertex Pharmaceuticals, Cambridge MA (VRTX, Nasdaq) stock has been bouncing around like a ping pong ball during the last months? Traders have been consistently excited about the positive news from Vertex’s Hepatitis C virus (HCV) treatment telaprevir. And some news about a treatment for cystic fibrosis pushed the stock to it’s 52 week high on March 4. But investors reacted (or should we say over-reacted) quite strikingly to some extremely early, positive (but as yet unpublished) results from a very short and small study testing efficacy of Pharmaset’s Hepatitis C treatment, and Vertex’s stock lost 12% of it’s value abruptly last week. Now Vertex stock is undergoing a small uptick based on positive results from it’s anti-inflammatory to treat epilepsy. What a roller coaster ride! It is really very unlikely that any of these results justify such large changes in the value of the company’s stock.
Let’s go back to telaprevir, the treatment for Hepatitis C that is the foundation of Vertex’s value at this point. Hepatitis C virus is a leading cause of chronic liver disease in the United States, and it is estimated that 170 million people worldwide have clinical signs from Hepatitis C virus infection. HCV can cause acute liver disease with severe symptoms, but about 75% of patients develop chronic HCV which can vary from asymptomatic to chronic liver failure and cirrhosis over a course of 10-20 years. HCV is a enveloped, single stranded RNA virus which infects liver cells, proliferates in the cell and then goes on to infect many more cells with each replication process. The end result is destruction of the liver. The viral replication process requires the virus to make an enzyme called NS3/4A. When telaprevir is in the circulation, it binds to the NS3/4A enzyme and prevents the virus from proliferating in the liver cell.
Present standard of care for Hepatitis C infection is a combination therapy of pegylated interferon alpha plus ribavirin for 24-48 weeks. Approximately 70-80% of patients infected with Hepatitis Virus type 2 and type 3 respond to this treatment, whereas Hepatitis Virus type 1 is only successfully treated in 40% of patients. Success is measured as ‘sustained virological response’ or SVR, where the virus is undetectable 24 weeks after therapy has ended. The treatment plan for telaprevir is to add it to the combination of interferon and ribavirin, and the desired result is an improvement in the per cent of patients with SVR in Hepatitis Virus type 1 patients previously untreated. In addition, Vertex investigated whether treatment of patients who did not respond to interferon and ribavirin, or who responded and then relapsed would achieve SVR by repeat treatment with the addition of telaprevir.
Vertex filed a NDA in November 2010, and was granted a 6 month priority review by the FDA, which reduced the time for the FDA to evaluate the submission from 10 months to 6 months. The data in the NDA was based on three studies. Two recruited people never before treated for Hepatitis C and treated them with a combination of pegylated interferon, ribavirin and telaprevir. 75% achieved a viral cure (SVR) with telaprevir-based combination therapy, compared to 44% of people who received pegylated-interferon and ribavirin alone; The data showed there was no benefit to extending total treatment from 24 weeks to 48 weeks in people who responded quickly, so treatment time was cut in half for many patients. The third study was done in people with hepatitis C who had not achieved a viral cure with a prior course of treatment. 83% of prior relapsers and 29% of prior non-responders achieved a viral cure with telaprevir-based combination therapy compared to 24%, and 5% of people in these subgroups, respectively, who received pegylated-interferon and ribavirin alone. This result, in particular, is quite exciting, as prior to the availability of telaprevir, non-responders or relapsers had only a tiny hope of improved response with a second course of ribavirin/pegylated interferon therapy. In March, Vertex reported that telaprevir helped eliminate the hepatitis C virus in 70 percent of patients who were also infected with HIV, according to interim analysis from a small midstage clinical trial. The interim analysis looked for a rapid viral response (RVR), meaning the hepatitis C virus was undetectable in the blood after four weeks of treatment.
Vertex has stiff competition from Merck, who also filed an NDA for boceprevir for treatment of Hepatitis C in studies designed similarly to those for telaprevir. Boceprevir has the same mechanism of action against the Hepatitic C virus as telaprevir. Efficacy was similar for boceprevir and telaprevir, but Merck is grappling with anemia as a side effect of boceprevir, and the anemia is severe enough to require treatment with recombinant erythropoietin. Although more than 20 other drugs are in development for Hepatitis C, the advanced state of telaprevir and boceprevir, and the good results with both will require that any new drugs differentiate themselves by complete elimination of the virus, or an advance that would not require combination with pegylated interferon and ribavirin, both of which cause clinically important side effects.
Back to Vertex and it’s wild stock ride. In May 2009, Vertex stock was trading at $29, and it slowly rose to $37 in May 2010 after phase 2 results for telaprevir were reported. The stock hit $47 after the filing of the NDA and then the release of the recent study in patients co-infected with Hepatitis C and HIV. In February Vertex released some results for VX-770, a genetic treatment for 4% of cystic fibrosis patients (1) with a genetic mutation known as G551D. Patients with the G551D mutation have sufficient cystic fibrosis transporter proteins on the surface of cells but the proteins are damaged and don't work correctly. VX-770 is a "potentiator" designed to improve the function of the damaged CFTR proteins, thereby fixing the root cause of cystic fibrosis in these patients. Although this drug will be targeted to a very small subpopulation of cystic fibrosis patients, those with the gene mutation G551D sustained a 10.6% improvement in lung function. Vertex had designated a 4.5% improvement as a positive endpoint for this study, so these results are solidly positive. Based on this result, Vertex’s stock rose to a 52 week high of 51.07 on March 4.
Just last week, at the International Liver Congress in Berlin, Pharmaset, a Princeton, NJ biotech company presented a poster which claimed that combination therapy with 2 nucleotide analogs resulted in 95-100% of patients with no detectable Hepatitis C virus 4 weeks after initiation of treatment. While quite promising, this type of viral therapy has been around since the development of AZT which was approved by the FDA for treatment of HIV in 1987. While Pharmaset’s dual therapies demonstrated increased efficacy compared to treatment with either drug alone, the study reported results in only 30 patients. Nucleotide analogs are well understood, and typically induce viral resistance with sustained use. The use of 2 different analogs together may circumvent this problem, but much longer studies are needed to be able to predict the success of the Pharmaset drugs for treatment of Hepatitis C. But this study does generate excitement centered around the fulfilling of the 2 remaining goals for Hepatitis C virus treatment: Complete elimination of the virus, and removal of requirement for treatment with interferon and ribavirin. But based on this very early, very short study in 30 patients, Vertex’s stock plummeted 12% to $44.80 on March 10. It is way too premature to predict what effect the Pharmaset drugs will have on the market for telaprevir.
Luckily, on that same day, Vertex fought back by releasing positive safety and tolerability goals in a midstage study of an anti-inflammatory for treatment-resistant epilepsy, a type of epilepsy where seizures start and occur in a specific part of the brain. The study enrolled and dosed people who had not benefitted from the use of at least two currently available medicines. While the drug was safe, efficacy was not significant. But, greater improvements were observed in the last two weeks of the treatment phase and first two weeks of the follow-up period, which suggests that a longer-duration study may be needed to evaluate the effectiveness of the drug. Vertex expects to begin this study as early as the fourth quarter.
Source
March 14th, 2011 5:56 pm ET
Elisabeth Morris
Boston Health News Examiner
Has anyone noticed that Vertex Pharmaceuticals, Cambridge MA (VRTX, Nasdaq) stock has been bouncing around like a ping pong ball during the last months? Traders have been consistently excited about the positive news from Vertex’s Hepatitis C virus (HCV) treatment telaprevir. And some news about a treatment for cystic fibrosis pushed the stock to it’s 52 week high on March 4. But investors reacted (or should we say over-reacted) quite strikingly to some extremely early, positive (but as yet unpublished) results from a very short and small study testing efficacy of Pharmaset’s Hepatitis C treatment, and Vertex’s stock lost 12% of it’s value abruptly last week. Now Vertex stock is undergoing a small uptick based on positive results from it’s anti-inflammatory to treat epilepsy. What a roller coaster ride! It is really very unlikely that any of these results justify such large changes in the value of the company’s stock.
Let’s go back to telaprevir, the treatment for Hepatitis C that is the foundation of Vertex’s value at this point. Hepatitis C virus is a leading cause of chronic liver disease in the United States, and it is estimated that 170 million people worldwide have clinical signs from Hepatitis C virus infection. HCV can cause acute liver disease with severe symptoms, but about 75% of patients develop chronic HCV which can vary from asymptomatic to chronic liver failure and cirrhosis over a course of 10-20 years. HCV is a enveloped, single stranded RNA virus which infects liver cells, proliferates in the cell and then goes on to infect many more cells with each replication process. The end result is destruction of the liver. The viral replication process requires the virus to make an enzyme called NS3/4A. When telaprevir is in the circulation, it binds to the NS3/4A enzyme and prevents the virus from proliferating in the liver cell.
Present standard of care for Hepatitis C infection is a combination therapy of pegylated interferon alpha plus ribavirin for 24-48 weeks. Approximately 70-80% of patients infected with Hepatitis Virus type 2 and type 3 respond to this treatment, whereas Hepatitis Virus type 1 is only successfully treated in 40% of patients. Success is measured as ‘sustained virological response’ or SVR, where the virus is undetectable 24 weeks after therapy has ended. The treatment plan for telaprevir is to add it to the combination of interferon and ribavirin, and the desired result is an improvement in the per cent of patients with SVR in Hepatitis Virus type 1 patients previously untreated. In addition, Vertex investigated whether treatment of patients who did not respond to interferon and ribavirin, or who responded and then relapsed would achieve SVR by repeat treatment with the addition of telaprevir.
Vertex filed a NDA in November 2010, and was granted a 6 month priority review by the FDA, which reduced the time for the FDA to evaluate the submission from 10 months to 6 months. The data in the NDA was based on three studies. Two recruited people never before treated for Hepatitis C and treated them with a combination of pegylated interferon, ribavirin and telaprevir. 75% achieved a viral cure (SVR) with telaprevir-based combination therapy, compared to 44% of people who received pegylated-interferon and ribavirin alone; The data showed there was no benefit to extending total treatment from 24 weeks to 48 weeks in people who responded quickly, so treatment time was cut in half for many patients. The third study was done in people with hepatitis C who had not achieved a viral cure with a prior course of treatment. 83% of prior relapsers and 29% of prior non-responders achieved a viral cure with telaprevir-based combination therapy compared to 24%, and 5% of people in these subgroups, respectively, who received pegylated-interferon and ribavirin alone. This result, in particular, is quite exciting, as prior to the availability of telaprevir, non-responders or relapsers had only a tiny hope of improved response with a second course of ribavirin/pegylated interferon therapy. In March, Vertex reported that telaprevir helped eliminate the hepatitis C virus in 70 percent of patients who were also infected with HIV, according to interim analysis from a small midstage clinical trial. The interim analysis looked for a rapid viral response (RVR), meaning the hepatitis C virus was undetectable in the blood after four weeks of treatment.
Vertex has stiff competition from Merck, who also filed an NDA for boceprevir for treatment of Hepatitis C in studies designed similarly to those for telaprevir. Boceprevir has the same mechanism of action against the Hepatitic C virus as telaprevir. Efficacy was similar for boceprevir and telaprevir, but Merck is grappling with anemia as a side effect of boceprevir, and the anemia is severe enough to require treatment with recombinant erythropoietin. Although more than 20 other drugs are in development for Hepatitis C, the advanced state of telaprevir and boceprevir, and the good results with both will require that any new drugs differentiate themselves by complete elimination of the virus, or an advance that would not require combination with pegylated interferon and ribavirin, both of which cause clinically important side effects.
Back to Vertex and it’s wild stock ride. In May 2009, Vertex stock was trading at $29, and it slowly rose to $37 in May 2010 after phase 2 results for telaprevir were reported. The stock hit $47 after the filing of the NDA and then the release of the recent study in patients co-infected with Hepatitis C and HIV. In February Vertex released some results for VX-770, a genetic treatment for 4% of cystic fibrosis patients (1) with a genetic mutation known as G551D. Patients with the G551D mutation have sufficient cystic fibrosis transporter proteins on the surface of cells but the proteins are damaged and don't work correctly. VX-770 is a "potentiator" designed to improve the function of the damaged CFTR proteins, thereby fixing the root cause of cystic fibrosis in these patients. Although this drug will be targeted to a very small subpopulation of cystic fibrosis patients, those with the gene mutation G551D sustained a 10.6% improvement in lung function. Vertex had designated a 4.5% improvement as a positive endpoint for this study, so these results are solidly positive. Based on this result, Vertex’s stock rose to a 52 week high of 51.07 on March 4.
Just last week, at the International Liver Congress in Berlin, Pharmaset, a Princeton, NJ biotech company presented a poster which claimed that combination therapy with 2 nucleotide analogs resulted in 95-100% of patients with no detectable Hepatitis C virus 4 weeks after initiation of treatment. While quite promising, this type of viral therapy has been around since the development of AZT which was approved by the FDA for treatment of HIV in 1987. While Pharmaset’s dual therapies demonstrated increased efficacy compared to treatment with either drug alone, the study reported results in only 30 patients. Nucleotide analogs are well understood, and typically induce viral resistance with sustained use. The use of 2 different analogs together may circumvent this problem, but much longer studies are needed to be able to predict the success of the Pharmaset drugs for treatment of Hepatitis C. But this study does generate excitement centered around the fulfilling of the 2 remaining goals for Hepatitis C virus treatment: Complete elimination of the virus, and removal of requirement for treatment with interferon and ribavirin. But based on this very early, very short study in 30 patients, Vertex’s stock plummeted 12% to $44.80 on March 10. It is way too premature to predict what effect the Pharmaset drugs will have on the market for telaprevir.
Luckily, on that same day, Vertex fought back by releasing positive safety and tolerability goals in a midstage study of an anti-inflammatory for treatment-resistant epilepsy, a type of epilepsy where seizures start and occur in a specific part of the brain. The study enrolled and dosed people who had not benefitted from the use of at least two currently available medicines. While the drug was safe, efficacy was not significant. But, greater improvements were observed in the last two weeks of the treatment phase and first two weeks of the follow-up period, which suggests that a longer-duration study may be needed to evaluate the effectiveness of the drug. Vertex expects to begin this study as early as the fourth quarter.
Source
Incidence and Risk Factors for Steatosis Progression in Adults Coinfected With HIV and Hepatitis C Virus
Gastroenterology
Volume 140, Issue 3 , Pages 809-817, March 2011
Tinsay A. Woreta, Catherine G. Sutcliffe, Shruti H. Mehta, Todd T. Brown, Yvonne Higgins, David L. Thomas, Michael S. Torbenson, Richard D. Moore, Mark S. Sulkowski
Received 24 May 2010; accepted 22 November 2010. published online 06 December 2010.
Abstract
Background & Aims
Hepatic steatosis is a common histologic finding in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), although little is known about its natural history. We prospectively examined the natural history of steatosis in patients coinfected with HIV and HCV who attended an urban HIV clinic.
Methods
The study cohort consisted of 222 coinfected patients (87% black, 94% with HCV genotype 1 infection) who had at least 2 liver biopsies performed between 1993 and 2008. Biopsy specimens were scored by a single pathologist; samples were classified as having trivial (<5% of hepatocytes affected) or significant (>5%) levels of fat (steatosis). We characterized progression to significant levels of fat among patients whose first biopsy samples had no or trivial levels of fat, and regression among those with significant fat, using logistic regression.
Results
Initial biopsy specimens from most patients (88%) had no or trivial amounts of fat. Among second biopsy samples, 74% had no or trivial fat and 13% had significant amounts of fat. The strongest risk factors for progression of steatosis were alcohol abuse and overweight/obesity; cumulative exposure to antiretroviral therapy between biopsies and high counts of CD4+ T cells were associated with reduced progression of steatosis. Among the 28 patients whose initial biopsy specimen had significant fat levels, most (75%) regressed.
Conclusions
Antiretroviral therapy and high counts of CD4+ T cells are associated with reduced progression of steatosis in patients coinfected with HIV and HCV. Efforts to diagnose and prevent steatosis should focus on persons with a high body mass index and excessive alcohol intake.
Keywords: Pathology, Cirrhosis, AIDS, Liver Disease
Source
Volume 140, Issue 3 , Pages 809-817, March 2011
Tinsay A. Woreta, Catherine G. Sutcliffe, Shruti H. Mehta, Todd T. Brown, Yvonne Higgins, David L. Thomas, Michael S. Torbenson, Richard D. Moore, Mark S. Sulkowski
Received 24 May 2010; accepted 22 November 2010. published online 06 December 2010.
Abstract
Background & Aims
Hepatic steatosis is a common histologic finding in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), although little is known about its natural history. We prospectively examined the natural history of steatosis in patients coinfected with HIV and HCV who attended an urban HIV clinic.
Methods
The study cohort consisted of 222 coinfected patients (87% black, 94% with HCV genotype 1 infection) who had at least 2 liver biopsies performed between 1993 and 2008. Biopsy specimens were scored by a single pathologist; samples were classified as having trivial (<5% of hepatocytes affected) or significant (>5%) levels of fat (steatosis). We characterized progression to significant levels of fat among patients whose first biopsy samples had no or trivial levels of fat, and regression among those with significant fat, using logistic regression.
Results
Initial biopsy specimens from most patients (88%) had no or trivial amounts of fat. Among second biopsy samples, 74% had no or trivial fat and 13% had significant amounts of fat. The strongest risk factors for progression of steatosis were alcohol abuse and overweight/obesity; cumulative exposure to antiretroviral therapy between biopsies and high counts of CD4+ T cells were associated with reduced progression of steatosis. Among the 28 patients whose initial biopsy specimen had significant fat levels, most (75%) regressed.
Conclusions
Antiretroviral therapy and high counts of CD4+ T cells are associated with reduced progression of steatosis in patients coinfected with HIV and HCV. Efforts to diagnose and prevent steatosis should focus on persons with a high body mass index and excessive alcohol intake.
Keywords: Pathology, Cirrhosis, AIDS, Liver Disease
Source
FDA Panel To Review Merck, Vertex Hepatitis Drugs In Late April
March 14, 2011, 11:52 A.M. ET
By Thomas Gryta
Of DOW JONES NEWSWIRES
NEW YORK (Dow Jones)--A U.S. Food and Drug Administration panel will review two hepatitis C drugs in development from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April, as the companies race to compete against each other in a potentially lucrative market.
The agency's Antiviral Drugs Advisory Committee will review Merck's boceprevir on April 27 and Vertex's telaprevir on April 28. The widely expected reviews will have outside experts recommend whether the agency should allow the drugs on the market.
Both drugs have shown success in increasing the cure rates of the liver disease when added to current treatments.
They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting a similar review and expects a decision by May 23.
Many on Wall Street believe that clinical trials show Vertex's telaprevir is the preferable drug, although Merck's Chief Executive Kenneth Frazier has repeatedly stated his confidence in boceprevir's prospects.
Wells Fargo recently projected $1.4 billion in U.S. sales next year for telaprevir. Vertex owns the North American rights to the drug and would get a royalty on overseas sales from partner Johnson & Johnson (JNJ).
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment.
- By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com
Source
By Thomas Gryta
Of DOW JONES NEWSWIRES
NEW YORK (Dow Jones)--A U.S. Food and Drug Administration panel will review two hepatitis C drugs in development from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April, as the companies race to compete against each other in a potentially lucrative market.
The agency's Antiviral Drugs Advisory Committee will review Merck's boceprevir on April 27 and Vertex's telaprevir on April 28. The widely expected reviews will have outside experts recommend whether the agency should allow the drugs on the market.
Both drugs have shown success in increasing the cure rates of the liver disease when added to current treatments.
They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting a similar review and expects a decision by May 23.
Many on Wall Street believe that clinical trials show Vertex's telaprevir is the preferable drug, although Merck's Chief Executive Kenneth Frazier has repeatedly stated his confidence in boceprevir's prospects.
Wells Fargo recently projected $1.4 billion in U.S. sales next year for telaprevir. Vertex owns the North American rights to the drug and would get a royalty on overseas sales from partner Johnson & Johnson (JNJ).
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment.
- By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com
Source
New Hepatitis C Data from Boehringer Ingelheim HCV Portfolio to Be Presented at EASL
March 14, 2011 03:00 AM Eastern Daylight Time
INGELHEIM, Germany--(BUSINESS WIRE)--For Non- U.S. Media only
New data from the Boehringer Ingelheim hepatitis C virus (HCV) portfolio will be presented in oral scientific sessions at the International Liver CongressTM 2011, the 46th Annual Meeting of the European Association for the Study of the Liver (EASL), taking place 30 March-3 April in Berlin, Germany. The data will include final results from SILEN-C1 and SILEN-C2, two Phase IIb studies evaluating one of Boehringer Ingelheim’s investigational compounds for Hepatitis C treatment, the once-daily, oral protease inhibitor BI 201335 in combination with the current standard-of-care (pegylated-interferon and ribavirin).
Oral presentations (Friday, 1 April, 2011; Parallel Session: HCV Drug Development, Hall 1)
• SILEN-C1: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype 1 HCV infection
(Abstract 60. M. Sulkowski, et al. 16:00h - 16:15h)
• SILEN-C2: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R
(Abstract 66. M. Sulkowski, et al. 17:30h - 17:45h)
Boehringer Ingelheim is continuing its long heritage in virology and is dedicated to developing new medicines to improve treatment for HCV patients. BI 201335 is part of a growing HCV portfolio that is being investigated with the aim of identifying a simpler HCV cure, overcoming the challenges of current treatments.
Additional HCV studies to be presented at EASL
• SVR and Pharmacokinetics of the HCV protease inhibitor BI201335 with PegIFN/RBV in HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV
(Poster 1231. S. Pol, et al.; Saturday, 2 April, 2011, 09:00h - 18:00h)
• Mechanisms of isolated unconjugated hyperbilirubinemia induced by the HCV NS3/4A protease inhibitor BI201335 (Poster 1236. R. Sane, et al.;Saturday, 2 April, 2011, 09:00h - 18:00h)
• BI201335 Pharmacokinetics and early effect on viral load in HCV genotype-1 patients
(Poster 1249. C. Yong, et al.;Saturday, April 2, 2011, 09:00h - 18:00h)
• Preclinical Characterization of the hepatitis C virus NS5B polymerase non-nucleoside inhibitor BILB 1941 (Poster 1215. G. Kukolj et. al.; Friday, 30 March, 2011, 09:00h - 18:00h)
The abstracts can be accessed through the EASL website, http://www.easl.eu/.
For more information on BI’s hepatitis portfolio, please visit www.boehringer-ingelheim.com and follow us on Twitter. www.twitter.com/boehringer.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
Within the company’s global research network, Virology is one of the seven R&D areas with focus on Hepatitis C.
In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro (US $17.7 billion) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.
Contacts
Boehringer Ingelheim GmbH
Julia Meyer-Kleinmann
Director Corporate Communications
55216 Ingelheim/Germany
Phone: + 49 - 6132 – 77 8271 / Fax: + 49 - 6132 – 77 70 77
E-mail: press@boehringer-ingelheim.com
Source
INGELHEIM, Germany--(BUSINESS WIRE)--For Non- U.S. Media only
New data from the Boehringer Ingelheim hepatitis C virus (HCV) portfolio will be presented in oral scientific sessions at the International Liver CongressTM 2011, the 46th Annual Meeting of the European Association for the Study of the Liver (EASL), taking place 30 March-3 April in Berlin, Germany. The data will include final results from SILEN-C1 and SILEN-C2, two Phase IIb studies evaluating one of Boehringer Ingelheim’s investigational compounds for Hepatitis C treatment, the once-daily, oral protease inhibitor BI 201335 in combination with the current standard-of-care (pegylated-interferon and ribavirin).
Oral presentations (Friday, 1 April, 2011; Parallel Session: HCV Drug Development, Hall 1)
• SILEN-C1: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype 1 HCV infection
(Abstract 60. M. Sulkowski, et al. 16:00h - 16:15h)
• SILEN-C2: Sustained Virologic Response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R
(Abstract 66. M. Sulkowski, et al. 17:30h - 17:45h)
Boehringer Ingelheim is continuing its long heritage in virology and is dedicated to developing new medicines to improve treatment for HCV patients. BI 201335 is part of a growing HCV portfolio that is being investigated with the aim of identifying a simpler HCV cure, overcoming the challenges of current treatments.
Additional HCV studies to be presented at EASL
• SVR and Pharmacokinetics of the HCV protease inhibitor BI201335 with PegIFN/RBV in HCV genotype-1 patients with compensated liver cirrhosis and non-response to previous PegIFN/RBV
(Poster 1231. S. Pol, et al.; Saturday, 2 April, 2011, 09:00h - 18:00h)
• Mechanisms of isolated unconjugated hyperbilirubinemia induced by the HCV NS3/4A protease inhibitor BI201335 (Poster 1236. R. Sane, et al.;Saturday, 2 April, 2011, 09:00h - 18:00h)
• BI201335 Pharmacokinetics and early effect on viral load in HCV genotype-1 patients
(Poster 1249. C. Yong, et al.;Saturday, April 2, 2011, 09:00h - 18:00h)
• Preclinical Characterization of the hepatitis C virus NS5B polymerase non-nucleoside inhibitor BILB 1941 (Poster 1215. G. Kukolj et. al.; Friday, 30 March, 2011, 09:00h - 18:00h)
The abstracts can be accessed through the EASL website, http://www.easl.eu/.
For more information on BI’s hepatitis portfolio, please visit www.boehringer-ingelheim.com and follow us on Twitter. www.twitter.com/boehringer.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
Within the company’s global research network, Virology is one of the seven R&D areas with focus on Hepatitis C.
In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro (US $17.7 billion) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.
Contacts
Boehringer Ingelheim GmbH
Julia Meyer-Kleinmann
Director Corporate Communications
55216 Ingelheim/Germany
Phone: + 49 - 6132 – 77 8271 / Fax: + 49 - 6132 – 77 70 77
E-mail: press@boehringer-ingelheim.com
Source
Inovio Pharmaceuticals' Partner ChronTech Initiates Phase II Clinical Trial of Hepatitis C Virus DNA Vaccine Using Inovio's Electroporation Delivery Technology
In Phase I trial 83% of patients showed undetectable hepatitis C virus levels
BLUE BELL, Pa., March 14, 2011 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE Amex: INO), a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that its partner, ChronTech Pharma AB (formerly Tripep AB), has initiated a Phase IIb clinical study of its ChronVac-C® DNA vaccine for hepatitis C virus (HCV), delivered by Inovio's proprietary electroporation DNA vaccine delivery technology, in combination with standard of care.
In a Phase I clinical trial of ChronVac-C using Inovio's MedPulser® electroporation device the therapy resulted in a robust increase in T-cell immune responses against HCV and was safe and well-tolerated. Post-study observation of subjects who completed the protocol and then entered into standard of care (SOC) treatment using interferon and ribavirin showed a complete and rapid viral response (four weeks) in 70% of those participants (5 of 7 patients). More significantly, 83% of the participants (5 of 6 patients) who were monitored for an extended period of time, continued to be free of the virus six months after they completed SOC. SOC treatment alone usually results in about 40-50% of patients reaching undetectable virus levels after six months of treatment.
This Phase II follow-on trial is an open-label, single-dose, randomized trial of 32 patients to further explore the effect of the ChronVac-C® DNA vaccine administered by Inovio's MedPulser® electroporation delivery device. The therapy will be given two times, with four weeks in between, followed by SOC treatment after the final vaccine dose in treatment-naïve chronic HCV infected genotype-1 subjects. This trial will assess the level of immune responses, levels of HCV viral load, and further assess the response to the delivery technology. Twenty patients will receive ChronVac-C® vaccine delivered with Inovio's electroporation device; the 12-patient comparison group will receive standard-of-care treatment alone. The study has received approval from the Swedish Medical Products Agency and local ethical committee.
"If we can repeat the Phase I results in this phase IIb study there is certainly a possibility that vaccination with ChronVac-C® before drug therapy could become a part of the standard of care therapy for patients with chronic hepatitis C-virus infection. In particular, we hope that vaccination with this novel therapy will result in a considerable shortening of the duration of interferon and ribavirin treatment," said Anders Vahlne, CEO of ChronTech Pharma AB.
Dr. J. Joseph Kim, Inovio's president and CEO, said: "We are encouraged by the phase I results showing the improved cure rate in patients who received the HCV vaccine followed by a SOC drug therapy. Any improvement to the HCV standard of care response rates would be well-received by HCV patients and practitioners. We are pleased to collaborate in this advancement of ChronVac-C®, using Inovio's innovative delivery technology, into Phase II."
About Hepatitis C Virus
Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States, where approximately 3.5 million persons have been chronically infected. Worldwide, about 300 million people have been infected with HCV. Based on current statistics for hepatitis C, it is estimated that 8,000 to 10,000 people die each year from chronic liver disease caused by this condition. Chronic HCV infection is the leading indication for liver transplants in the United States. Total health costs associated with hepatitis C virus in the U.S. are estimated at more than $15 billion per year. No vaccine for HCV is currently available.
About Inovio's Electroporation-Based Delivery Technology
Inovio's electroporation-based DNA delivery systems can increase the cellular uptake of an agent by 1,000 times or more. When used to deliver DNA vaccines, Inovio's systems can increase levels of gene expression (i.e. production of the coded protein) and immune responses by 100 times or more compared to plasmid DNA delivered without other delivery enhancements. Inovio has recently reported best-in-class immune responses with DNA vaccines for cervical dysplasias/cancers and HIV. Inovio has also shown the safety and tolerability of its electroporation devices in many hundreds of patients and continues to advance device innovations to further enhance the utility of these devices for mass vaccinations.
About Inovio Pharmaceuticals, Inc.
Inovio is developing a new generation of vaccines, called DNA vaccines, to treat and prevent cancers and infectious diseases. These SynCon™ vaccines are designed to provide broad cross-strain protection against known as well as newly emergent strains of pathogens such as influenza. These vaccines, in combination with Inovio's proprietary electroporation delivery devices, have been shown to be safe and generate significant immune responses. Inovio's clinical programs include HPV/cervical dysplasia and cancer (therapeutic), avian flu (preventive), and HIV vaccines (both preventive and therapeutic). Inovio is developing universal influenza and other vaccines in collaboration with scientists from the University of Pennsylvania. Other partners and collaborators include Merck, National Cancer Institute, U.S. Military HIV Research Program, NIH, HIV Vaccines Trial Network, University of Southampton, and PATH Malaria Vaccine Initiative. More information is available at http://www.inovio.com/.
* * *
This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, our ability to successfully integrate Inovio and VGX Pharmaceuticals, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2009, our Form 10-Q for the nine months ended September 30, 2010, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.
CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals 858-410-3101 bhertel@inovio.com
Media: Jeff Richardson, Richardson & Associates 805-491-8313 jeff@richardsonglobalpr.com
SOURCE Inovio Pharmaceuticals, Inc.
RELATED LINKS
http://www.inovio.com/
Source
Also See: An unusually high cure rate recorded after ChronVac-C® vaccination followed by standard treatment in patients with genotype 1 chronic hepatitis C
BLUE BELL, Pa., March 14, 2011 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE Amex: INO), a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that its partner, ChronTech Pharma AB (formerly Tripep AB), has initiated a Phase IIb clinical study of its ChronVac-C® DNA vaccine for hepatitis C virus (HCV), delivered by Inovio's proprietary electroporation DNA vaccine delivery technology, in combination with standard of care.
In a Phase I clinical trial of ChronVac-C using Inovio's MedPulser® electroporation device the therapy resulted in a robust increase in T-cell immune responses against HCV and was safe and well-tolerated. Post-study observation of subjects who completed the protocol and then entered into standard of care (SOC) treatment using interferon and ribavirin showed a complete and rapid viral response (four weeks) in 70% of those participants (5 of 7 patients). More significantly, 83% of the participants (5 of 6 patients) who were monitored for an extended period of time, continued to be free of the virus six months after they completed SOC. SOC treatment alone usually results in about 40-50% of patients reaching undetectable virus levels after six months of treatment.
This Phase II follow-on trial is an open-label, single-dose, randomized trial of 32 patients to further explore the effect of the ChronVac-C® DNA vaccine administered by Inovio's MedPulser® electroporation delivery device. The therapy will be given two times, with four weeks in between, followed by SOC treatment after the final vaccine dose in treatment-naïve chronic HCV infected genotype-1 subjects. This trial will assess the level of immune responses, levels of HCV viral load, and further assess the response to the delivery technology. Twenty patients will receive ChronVac-C® vaccine delivered with Inovio's electroporation device; the 12-patient comparison group will receive standard-of-care treatment alone. The study has received approval from the Swedish Medical Products Agency and local ethical committee.
"If we can repeat the Phase I results in this phase IIb study there is certainly a possibility that vaccination with ChronVac-C® before drug therapy could become a part of the standard of care therapy for patients with chronic hepatitis C-virus infection. In particular, we hope that vaccination with this novel therapy will result in a considerable shortening of the duration of interferon and ribavirin treatment," said Anders Vahlne, CEO of ChronTech Pharma AB.
Dr. J. Joseph Kim, Inovio's president and CEO, said: "We are encouraged by the phase I results showing the improved cure rate in patients who received the HCV vaccine followed by a SOC drug therapy. Any improvement to the HCV standard of care response rates would be well-received by HCV patients and practitioners. We are pleased to collaborate in this advancement of ChronVac-C®, using Inovio's innovative delivery technology, into Phase II."
About Hepatitis C Virus
Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States, where approximately 3.5 million persons have been chronically infected. Worldwide, about 300 million people have been infected with HCV. Based on current statistics for hepatitis C, it is estimated that 8,000 to 10,000 people die each year from chronic liver disease caused by this condition. Chronic HCV infection is the leading indication for liver transplants in the United States. Total health costs associated with hepatitis C virus in the U.S. are estimated at more than $15 billion per year. No vaccine for HCV is currently available.
About Inovio's Electroporation-Based Delivery Technology
Inovio's electroporation-based DNA delivery systems can increase the cellular uptake of an agent by 1,000 times or more. When used to deliver DNA vaccines, Inovio's systems can increase levels of gene expression (i.e. production of the coded protein) and immune responses by 100 times or more compared to plasmid DNA delivered without other delivery enhancements. Inovio has recently reported best-in-class immune responses with DNA vaccines for cervical dysplasias/cancers and HIV. Inovio has also shown the safety and tolerability of its electroporation devices in many hundreds of patients and continues to advance device innovations to further enhance the utility of these devices for mass vaccinations.
About Inovio Pharmaceuticals, Inc.
Inovio is developing a new generation of vaccines, called DNA vaccines, to treat and prevent cancers and infectious diseases. These SynCon™ vaccines are designed to provide broad cross-strain protection against known as well as newly emergent strains of pathogens such as influenza. These vaccines, in combination with Inovio's proprietary electroporation delivery devices, have been shown to be safe and generate significant immune responses. Inovio's clinical programs include HPV/cervical dysplasia and cancer (therapeutic), avian flu (preventive), and HIV vaccines (both preventive and therapeutic). Inovio is developing universal influenza and other vaccines in collaboration with scientists from the University of Pennsylvania. Other partners and collaborators include Merck, National Cancer Institute, U.S. Military HIV Research Program, NIH, HIV Vaccines Trial Network, University of Southampton, and PATH Malaria Vaccine Initiative. More information is available at http://www.inovio.com/.
* * *
This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, our ability to successfully integrate Inovio and VGX Pharmaceuticals, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2009, our Form 10-Q for the nine months ended September 30, 2010, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.
CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals 858-410-3101 bhertel@inovio.com
Media: Jeff Richardson, Richardson & Associates 805-491-8313 jeff@richardsonglobalpr.com
SOURCE Inovio Pharmaceuticals, Inc.
RELATED LINKS
http://www.inovio.com/
Source
Also See: An unusually high cure rate recorded after ChronVac-C® vaccination followed by standard treatment in patients with genotype 1 chronic hepatitis C
EASL schedules press conference and news briefings during International Liver Congress 2011
Published on March 14, 2011 at 10:22 AM
The EASL International Liver Congress is an opportunity for over 6,000 clinicians and scientists from around the world to hear the latest research, perspectives and treatments for liver diseases from principal experts in the field. It features a high-calibre and multi-disciplinary scientific programme covering groundbreaking information and in-depth examination of the most essential topics.
EASL will hold an international press conference and two morning news briefings during its International Liver Congress 2011 in Berlin.
EASL Press Conference
Date: Thursday 31st March 2011
Time: 11:00am - 12:00am
Location: Room 43
Leading experts will highlight new developments in the future management of viral hepatitis C. A question and answer session will follow the presentations.
Speakers will also be available for informal discussions and interviews following the presentations.
Due to limited space, please confirm your attendance at the press conference with the EASL press office now.
Morning News Briefings
To ensure you get the best out of ILC, news briefings will be held to provide you with the latest news and data on the following topics
Friday 1st April - Liver transplantation & Wilson's disease
Saturday 2nd April 2011 - Hepatocellular carcinoma & Fatty liver disease
Times: 8:00am - 8:45am
Location: The Press Centre
Onsite Press Office staff will be able to assist you in organising interviews with the relevant experts. Wi-Fi access will be available in the press working room.
• Abstracts can be viewed at: http://www1.easl.eu/easl2011/program/Orals/
• Details of the scientific programme are available at: http://www2.kenes.com/liver-congress/scientific/Pages/Timetable.aspx
• Stay up-to-date with all of the latest news and information, follow us @ILCpress!
Source: European Association for the Study of the Liver
Source
The EASL International Liver Congress is an opportunity for over 6,000 clinicians and scientists from around the world to hear the latest research, perspectives and treatments for liver diseases from principal experts in the field. It features a high-calibre and multi-disciplinary scientific programme covering groundbreaking information and in-depth examination of the most essential topics.
EASL will hold an international press conference and two morning news briefings during its International Liver Congress 2011 in Berlin.
EASL Press Conference
Date: Thursday 31st March 2011
Time: 11:00am - 12:00am
Location: Room 43
Leading experts will highlight new developments in the future management of viral hepatitis C. A question and answer session will follow the presentations.
Speakers will also be available for informal discussions and interviews following the presentations.
Due to limited space, please confirm your attendance at the press conference with the EASL press office now.
Morning News Briefings
To ensure you get the best out of ILC, news briefings will be held to provide you with the latest news and data on the following topics
Friday 1st April - Liver transplantation & Wilson's disease
Saturday 2nd April 2011 - Hepatocellular carcinoma & Fatty liver disease
Times: 8:00am - 8:45am
Location: The Press Centre
Onsite Press Office staff will be able to assist you in organising interviews with the relevant experts. Wi-Fi access will be available in the press working room.
• Abstracts can be viewed at: http://www1.easl.eu/easl2011/program/Orals/
• Details of the scientific programme are available at: http://www2.kenes.com/liver-congress/scientific/Pages/Timetable.aspx
• Stay up-to-date with all of the latest news and information, follow us @ILCpress!
Source: European Association for the Study of the Liver
Source
March 12, 2011
Lack of health insurance limits hepatitis C patients' access to latest antiviral therapy
Public release date: 24-Feb-2011
Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell
High costs, insurance status, and eligibility issues restrict treatment options
New research has determined that patients in the U.S. with hepatitis C virus (HCV) are twice as likely to not have health insurance coverage compared with those without the disease. In fact researchers found only a third of HCV infected Americans have access to antiviral therapy; the remaining are either uninsured or not candidates for therapy due to treatment contraindications. Details of this study are published in the March issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).
HCV is the most common cause of chronic liver disease, hepatocellular (liver) cancer, and liver transplantation in the U.S., with up to 85% of HCV-positive individuals (3.5 million) developing chronic HCV infection. Symptoms of chronic HCV are non-specific which can inhibit diagnosis and as many as 75% of patients are unaware of their HCV infection (Hagan et al., 2006). Furthermore, the Centers for Disease Control and Prevention (CDC) estimates that HCV causes 12,000 deaths in the U.S. each year.
"Successful treatment with antiviral therapy improves health-related quality of life in patients with HCV and could potentially reduce morbidity and mortality in patients," said Zobair Younossi, MD, MPH, from the Center of Liver Diseases at Inova Fairfax Hospital in Virginia and lead author of the study. "A significant number of HCV patients, however, may not even have access to antiviral therapy due to lack of adequate health insurance coverage." It is estimated to cost up to $48,000 per year for monitoring and treatment of HCV.
For the current study, researchers analyzed health insurance status and treatment candidacy of HCV-positive individuals using 2005-2008 data collected from the National Health and Nutritional Examination Survey (NHANES). This information was collected via household interviews, physical examinations and extensive laboratory sample data from subjects who were 18 years of age or older and living in the U.S.
Analysis showed that 1.16% of study subjects were infected with HCV. Among those with HCV only 61% were insured compared to 81% of HCV-negative individuals. HCV infection was an independent predictor of being uninsured even after adjusting for demographic disparity in the HCV-positive group. Approximately 67% of HCV-positive patients were eligible for treatment, however only 54% of those treatment candidates had insurance coverage.
Some individuals with HCV may not be eligible for antiviral therapy due to contraindications to treatment. Previous studies have found that only half of HCV patients exhibit a positive response to peginterferon/ribavirin treatment. "The side effect profile of the current antiviral therapy requires careful selection of treatment candidates with a number of chronic conditions," said Dr. Younossi. The authors noted that patients with comorbidities such as active cardiac disease, severe depression, or renal failure are typically ineligible for antiviral therapy due to severe adverse events that may occur with treatment.
Research showed that only 36% of HCV-positive patients who were eligible for antiviral therapy had health insurance. "Access to care for HCV patients is critical. Our results have important implications for HCV-infected patients and should be considered as new health care reform legislation takes effect," Dr. Younossi concluded.
###
Article: "Insurance Status and Treatment Candidacy of Hepatitis C Patients: Analysis of Population-based Data from the United States." Maria Stepanova, Fasiha Kanwal, Hashem B. El-Serag, Zobair M. Younossi. Hepatology; Published Online: February 11, 2011 (DOI: 10.1002/hep.24131); Print Issue Date: March 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24131/abstract.
This study is published in Hepatology. Media wishing to receive a PDF of the articles may contact healthnews@wiley.com.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
Source
Also See: Many Hepatitis C-Positive Patients Are Uninsured
Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell
High costs, insurance status, and eligibility issues restrict treatment options
New research has determined that patients in the U.S. with hepatitis C virus (HCV) are twice as likely to not have health insurance coverage compared with those without the disease. In fact researchers found only a third of HCV infected Americans have access to antiviral therapy; the remaining are either uninsured or not candidates for therapy due to treatment contraindications. Details of this study are published in the March issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).
HCV is the most common cause of chronic liver disease, hepatocellular (liver) cancer, and liver transplantation in the U.S., with up to 85% of HCV-positive individuals (3.5 million) developing chronic HCV infection. Symptoms of chronic HCV are non-specific which can inhibit diagnosis and as many as 75% of patients are unaware of their HCV infection (Hagan et al., 2006). Furthermore, the Centers for Disease Control and Prevention (CDC) estimates that HCV causes 12,000 deaths in the U.S. each year.
"Successful treatment with antiviral therapy improves health-related quality of life in patients with HCV and could potentially reduce morbidity and mortality in patients," said Zobair Younossi, MD, MPH, from the Center of Liver Diseases at Inova Fairfax Hospital in Virginia and lead author of the study. "A significant number of HCV patients, however, may not even have access to antiviral therapy due to lack of adequate health insurance coverage." It is estimated to cost up to $48,000 per year for monitoring and treatment of HCV.
For the current study, researchers analyzed health insurance status and treatment candidacy of HCV-positive individuals using 2005-2008 data collected from the National Health and Nutritional Examination Survey (NHANES). This information was collected via household interviews, physical examinations and extensive laboratory sample data from subjects who were 18 years of age or older and living in the U.S.
Analysis showed that 1.16% of study subjects were infected with HCV. Among those with HCV only 61% were insured compared to 81% of HCV-negative individuals. HCV infection was an independent predictor of being uninsured even after adjusting for demographic disparity in the HCV-positive group. Approximately 67% of HCV-positive patients were eligible for treatment, however only 54% of those treatment candidates had insurance coverage.
Some individuals with HCV may not be eligible for antiviral therapy due to contraindications to treatment. Previous studies have found that only half of HCV patients exhibit a positive response to peginterferon/ribavirin treatment. "The side effect profile of the current antiviral therapy requires careful selection of treatment candidates with a number of chronic conditions," said Dr. Younossi. The authors noted that patients with comorbidities such as active cardiac disease, severe depression, or renal failure are typically ineligible for antiviral therapy due to severe adverse events that may occur with treatment.
Research showed that only 36% of HCV-positive patients who were eligible for antiviral therapy had health insurance. "Access to care for HCV patients is critical. Our results have important implications for HCV-infected patients and should be considered as new health care reform legislation takes effect," Dr. Younossi concluded.
###
Article: "Insurance Status and Treatment Candidacy of Hepatitis C Patients: Analysis of Population-based Data from the United States." Maria Stepanova, Fasiha Kanwal, Hashem B. El-Serag, Zobair M. Younossi. Hepatology; Published Online: February 11, 2011 (DOI: 10.1002/hep.24131); Print Issue Date: March 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24131/abstract.
This study is published in Hepatology. Media wishing to receive a PDF of the articles may contact healthnews@wiley.com.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
Source
Also See: Many Hepatitis C-Positive Patients Are Uninsured
Treatment failure and resistance with direct acting antiviral drugs against hepatitis C virus
Hepatology. 2011 Mar 3. doi: 10.1002/hep.24262. [Epub ahead of print]
Pawlotsky JM.
National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France. jean-michel.pawlotsky@hmn.aphp.fr.
Abstract
Current treatment of chronic hepatitis C virus infection is based on the combination of pegylated interferon-α and ribavirin. The recent development of direct-acting antiviral molecules active on hepatitis C virus, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on direct acting antivirals. A new standard-of-care treatment will soon be available for both treatment-naïve and -experienced patients infected with hepatitis C virus genotype 1, based on a triple combination of pegylated interferon-α, ribavirin and a protease inhibitor, either telaprevir or boceprevir. With this therapy, most failures to eradicate infection in treatment-adherent patients are due to an inadequate response to pegylated interferon-α and ribavirin, in the context of a low genetic barrier to resistance of first-generation protease inhibitors. This article reviews patterns of resistance to hepatitis C virus direct acting antiviral drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon-α and ribavirin, the consequences of treatment failure, and possible means of optimizing therapies using direct acting antivirals in the future. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21374691 [PubMed - as supplied by publisher]
Source
Pawlotsky JM.
National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France. jean-michel.pawlotsky@hmn.aphp.fr.
Abstract
Current treatment of chronic hepatitis C virus infection is based on the combination of pegylated interferon-α and ribavirin. The recent development of direct-acting antiviral molecules active on hepatitis C virus, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on direct acting antivirals. A new standard-of-care treatment will soon be available for both treatment-naïve and -experienced patients infected with hepatitis C virus genotype 1, based on a triple combination of pegylated interferon-α, ribavirin and a protease inhibitor, either telaprevir or boceprevir. With this therapy, most failures to eradicate infection in treatment-adherent patients are due to an inadequate response to pegylated interferon-α and ribavirin, in the context of a low genetic barrier to resistance of first-generation protease inhibitors. This article reviews patterns of resistance to hepatitis C virus direct acting antiviral drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon-α and ribavirin, the consequences of treatment failure, and possible means of optimizing therapies using direct acting antivirals in the future. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21374691 [PubMed - as supplied by publisher]
Source
Second phase HCV RNA decline during telaprevir based therapy increases with drug effectiveness: Implications for treatment duration
Hepatology. 2011 Mar 7. doi: 10.1002/hep.24272. [Epub ahead of print]
Guedj J, Perelson AS.
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos 87545, USA.
Abstract
Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21384401 [PubMed - as supplied by publisher]
Source
Guedj J, Perelson AS.
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos 87545, USA.
Abstract
Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21384401 [PubMed - as supplied by publisher]
Source
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