June 23, 2011

22-Jun-11 Huddinge, Sweden - Medivir AB (OMX: MVIR), the emerging research-based specialty pharmaceutical company focused on infectious diseases, today announces the start of a phase Ib clinical trial with TMC649128 intended for the treatment of chronic hepatitis C virus (HCV) infection.

TMC649128 is a nucleoside NS5B polymerase inhibitor developed in collaboration with Tibotec Pharmaceuticals. TMC649128 has demonstrated an attractive pre-clinical profile and displays in vitro activity across multiple HCV genotypes and a high genetic barrier to resistance. A clinical phase Ia double-blind, randomized, placebo-controlled single-ascending dose trial to assess the safety, tolerability and pharmacokinetics in healthy volunteers has now successfully been completed.

The TMC649128 phase Ib study that now is underway is a double-blind, randomized and placebo-controlled trial in genotype 1 HCV-infected patients to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of multiple ascending doses of TMC649128 given as monotherapy and in combination with pegylated interferon and ribavirin.

It is anticipated that TMC649128 will be used in combination with other HCV direct acting antiviral agents, given its high genetic barrier to resistance and antiviral activity across multiple HCV genotypes.

“We are delighted to see TMC649128, our first HCV nucleoside inhibitor, advance into clinical phase Ib studies in HCV patients”, stated Bertil Samuelsson, CSO of Medivir. "The start of this phase Ib trial underscores our commitment to develop new and innovative treatments for hepatitis C infected patients. We view nucleoside inhibitors, such as TMC649128, and protease inhibitors, such as TMC435, as cornerstone components of future direct acting antiviral combinations for HCV therapy.”

For more information about Medivir, please contact;

Medivir (http://www.medivir.se/ (http://www.medivir.se/)) Mobile: +46 708 537 292
Rein Piir, CFO & VP Investor Relations
M:CommunicationsEurope: Mary-Jane Elliott / Amber Bielecka / Katja Toon Medivir@mcomgroup.com (Medivir@mcomgroup.com)
+44(0)20 7920 2330
USA: Roland Tomforde +1 212 232 2356

About Hepatitis C

Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir’s Commitment to HCV

Medivir and Tibotec are also jointly developing the once daily protease inhibitor TMC435 for treatment of hepatitis C virus infections (HCV).

About Medivir

Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese™/Xerclear®.

Medivir’s key pipeline asset, TMC435, a protease inhibitor, is in global phase 3 clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.

Xerese™/Xerclear® is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GlaxoSmithKline to be sold OTC in Europe and Russia and with Meda AB in North America. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.

For more information about Medivir, please visit the Company’s website: http://www.medivir.se/.

Source

Noninvasive assessment of liver fibrosis (and Biopsy)

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Hepatology
June 2011

Doris Nguyen1 and Jayant A. Talwalkar2,3

rom the 1Mayo Medical School, 2Center for Advanced Imaging Research, and 3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN

"The gold standard for detecting liver fibrosis remains percutaneous liver biopsy, although this procedure is not without its own inherent limitations.....Despite the proliferation of investigations and clinical experiences with noninvasive methods for detecting hepatic fibrosis, there remain a number of critical questions about the clinical effectiveness of these approaches"

Case Scenario

A 48-year-old male with a previous longstanding history of intravenous drug abuse is evaluated for a diagnosis of hepatitis C and elevated liver biochemical tests. The aspartate aminotransferase is 59 U/L, and the alanine aminotransferase is 68 U/L. The serum bilirubin is 0.8 mg/dL with an indirect fraction of 0.5 mg/dL, the serum creatinine is 1.1 mg/dL, and the international normalized ratio is 1.0. The serum albumin is 3.9 g/dL. Ultrasound imaging reveals a coarse echotexture without evidence of ascites or intra-abdominal collateral veins. The hepatitis C virus genotype is 1b, and the viral load is 5.6 x 106 IU. You recommend a liver biopsy to determine activity and the stage of fibrosis. The patient asks you whether you can get the same information with blood tests or noninvasive imaging, that is, he wants to know the role of serum markers, ultrasound-based transient elastography (TE), and magnetic resonance elastography (MRE) in such situations.

The Problem

In the United States alone, an estimated 150,000 persons annually are diagnosed with chronic liver disease with nearly 30,000 (20%) individuals having cirrhosis at initial presentation.1 Disease-related complications of cirrhosis, in turn, are mediated by the development and progression of hepatic fibrosis.

Hepatic fibrogenesis is a maladaptative wound-healing process that occurs in response to chronic, injurious stimuli affecting hepatocytes. This results in a stereotypical inflammatory response leading to hepatic stellate cell activation that produces a nonuniform accumulation of extracellular matrix complexes that constitute hepatic fibrosis. The crosslinking of collagen fibrils within extracellular matrix leads to fibrous scar formation and eventual distortion of the hepatic architecture. Notably, the progression of hepatic fibrosis is not a continuous, linear process but rather a discontinuous, stuttering phenomenon that is greatly influenced by factors such as age, sex, race, alcohol exposure, and obesity.2

The gold standard for detecting liver fibrosis remains percutaneous liver biopsy, although this procedure is not without its own inherent limitations. These include (1) a small but significant risk for procedure-related complications such as pain or bleeding, (2) inaccurate staging from sampling error in up to 25% of cases, and (3) inter- and intraobserver variability in biopsy interpretation.3, 4 Because of these reasons and wide availability of serum diagnostic tests, the use of diagnostic liver biopsy in clinical practice is declining.5

From a clinical perspective, the greatest limitation with liver biopsy is sampling variability and its effect on fibrosis staging. Several investigations have documented that sampling error is present in a variety of liver diseases.6, 7 Furthermore, the performance of biopsies involving the right and left liver lobes in the same patient does not reduce sampling error, because substantial discordance in fibrosis stage is observed.7 Although the optimal liver biopsy specimen characteristics (≥20 mm in length with ≥11 portal tracts) have been identified to minimize the effects from sampling error,8 the typical specimen obtained in clinical practice often fails to meet these standards.

Serum Markers and Elastography Imaging

Serum Markers.

A variety of serum markers have been developed for identifying patients who are at risk for clinically significant hepatic fibrosis (defined by stages F2-F4). These markers are classified as direct (representing components of extracellular matrix) or indirect (reflecting hepatic inflammation and function). Indirect markers may be used alone or combined with direct markers to form panels. The practical advantages of serum fibrosis markers include their noninvasiveness, potential for widespread availability, and reproducibility when serial examinations are performed using the same laboratory (Table 1).9

Among indirect serum marker panels, the most widely used and validated technique worldwide is called the FibroTest. This proprietary panel contains five variables including total bilirubin, haptoglobin, gamma glutamyl transpeptidase, α2-macroglobulin, and apolipoprotein A. Several independent and combined analyses have demonstrated excellent diagnostic performance for the detection of histological stage F4 fibrosis (i.e., cirrhosis) among patients with chronic hepatitis C. Additional studies in patients with chronic hepatitis B, alcoholic liver disease, nonalcoholic fatty liver disease, as well as studies conducted in the general population, are emerging in support of this method as well. However, serum markers including FibroTest are less accurate in detecting the presence of intermediate stages of fibrosis as compared to the detection of cirrhosis.9, 10

There are specific limitations associated with the use of FibroTest and serum marker panels in general. False positive results can be attributable to (1) decreases in haptoglobin from hemolysis, (2) increases in total bilirubin from conditions such as Gilbert's syndrome and cholestasis, and (3) increases in α2-macroglobulin and haptoglobin from systemic as well as hepatic inflammation.9, 10 Because of the variability of components in assays and analyzers, FibroTest can only be performed in validated reference laboratories as opposed to local outpatient or hospital-based labs where other testing is typically performed.

Ultrasound-Based TE.

This imaging modality uses a transducer probe which emits low-frequency (50 Hz) vibrations into the liver for measuring liver stiffness. The examination is performed over the right lateral intercostal spaces with the patient lying in the dorsal decubitus position and the right arm being in maximal abduction. The propagating shear wave induced by these vibrations is detected by a pulse-echo acquisition, and the velocity of the wave is then calculated. Liver stiffness is proportional to shear wave velocity as expressed by the equation for Young's modulus (expressed as E = 3pv2, where v is the shear velocity and p is the density of tissue, assumed to be constant). Liver stiffness is measured in kilopascals. Requirements for accurate TE measurement of mean liver stiffness include (1) an interquartile range for measurements within 30% of the median value and (2) a ratio of successful measurements to the total number of acquisitions ≥60%.11

In two meta-analyses,12, 13 the pooled estimates for the diagnosis of cirrhosis with TE were excellent, with sensitivity and specificity values approaching 90%. Reported diagnostic threshold (or cutoff) values for cirrhosis have ranged between 11 and 17 kPa in studies of patients with chronic hepatitis C. Results of TE from studies in other etiologies of liver disease such as chronic hepatitis B, alcohol, and nonalcoholic fatty liver disease are emerging. Despite its excellent accuracy for detecting cirrhosis, liver stiffness is an insensitive predictor for esophageal varices and should not dictate which patients should or should not be screened for esophageal varices by endoscopy.14 For the detection of hepatic fibrosis between stages 2-4, however, the pooled estimates of sensitivity and specificity are reduced to between 70% and 80%.12, 13

Magnetic Resonance Elastography.

MRE uses a modified phase-contrast imaging sequence to detect propagating shear waves within the liver. Acoustic shear waves are generated by a pneumatic driver placed directly over the upper abdomen for propagation into liver tissue. Subsequently, liver stiffness values are calculated from wave displacement patterns displayed as color-encoded images (elastograms). Region-of-interest analysis throughout four cross-sectional slices of liver (avoiding vascular structures) is then performed to calculate mean liver stiffness.15 Elasticity quantification by MRE is based on the formula representing shear modulus, which is equivalent to one-third of the Young's modulus used with TE.

Initial prospective studies have demonstrated the feasibility and diagnostic accuracy in detecting hepatic fibrosis with MRE. As with TE, the detection of cirrhosis by MRE is highly accurate with sensitivity and specificity values exceeding 90%, respectively. In contrast to TE, however, studies of MRE to date identify a higher diagnostic accuracy for detecting intermediate to severe fibrosis (F2-F4) with sensitivity and specificity values each in the 80%-85% range.16, 17

Although the reproducibility of TE is excellent within experienced centers, its accuracy is diminished when obesity and narrow rib interspaces are encountered.18 In a recent 5-year prospective study with 13,369 examinations, the probability of technical failure or generation of invalid results was independently associated with a body mass index > 30 kg/m2.19 The development of a specialized probe for obese patients may reduce the frequency of technically limited examinations in the future. The reproducibility of MRE is also excellent,20 yet reliance on individual operators does not exist, because imaging processes are essentially automated. Furthermore, MRE is not significantly affected by obesity or rib interspace width.

For both MRE and TE, it should also be noted that other pathophysiological processes including severe inflammation, cholestasis, and hepatic congestion may independently contribute to liver stiffness.12, 13, 18

Areas of Uncertainty

Despite the proliferation of investigations and clinical experiences with noninvasive methods for detecting hepatic fibrosis, there remain a number of critical questions about the clinical effectiveness of these approaches.

For both serum fibrosis markers and elastography imaging techniques, a number of investigators have proposed diagnostic algorithms to assist with defining the stage of fibrosis. For example, it has been suggested that liver biopsy may be deferred in patients with chronic hepatitis C and liver stiffness values from TE ≤ 6 kPa (which suggest nonsignificant fibrosis) or ≥12 kPa (which indicate advanced fibrosis). Intermediate values, however, would require liver biopsy for detecting fibrosis stage if relevant for individualized cases. Although these algorithms are intuitively helpful, they have yet to be externally validated among independent populations.

Studies of noninvasive tests to assess disease progression or prognosis with or without liver disease therapy are just beginning to emerge.21 These results are widely anticipated, because many believe the link between important clinical outcomes and results of noninvasive testing provide the highest level of validation for these methods.

Other potential areas for future research include (1) defining the role of combined versus sequential noninvasive test approaches to improve fibrosis detection, (2) further defining the role of noninvasive testing in special populations (i.e., pediatrics), and (3) determining the clinical utility of such testing as a screening tool for liver disease in general populations.

Regulatory & Cost Considerations

A major advantage of noninvasive testing is that no serious adverse effects from these techniques is recognized. Economic considerations apply for proprietary serum marker panels as well as TE and MRE. Regarding FibroTest, the U.S. Food and Drug Administration (FDA) has determined that approval is not currently required. FibroTest is currently available in the United States and is marketed as Fibrosure by LabCorp. Recent estimates of cost for this test are approximately US $300 to US $400, which typically includes shipping and processing of the blood sample as well as reporting the test result. At the moment, ultrasound-based TE is not approved for use in the United States by the FDA. In Europe, for example, the price of a TE unit is approximately 80,000 to 100,000 (US $100,000 to US $130,000), and the annual fees for calibrating measurement probes is approximately 3000 to 5000 (US $4000 to US $6500). MRE was first approved by the FDA in 2010, and is becoming available as a commercial upgrade for standard MRI systems. MRE requires less than a minute of acquisition time and can be added as part of a standard MRI examination of the abdomen. The estimated cost of MRE, if performed as a stand-alone examination, is unknown at this time, but is expected to be similar to that of TE.

Recommendations

There is no evidence for cirrhosis or severe inflammation based on routine clinical studies in the case presented here. The patient's hepatitis C viral genotype is not favorable in terms of probability of treatment response. Thus, obtaining further information about the degree of liver injury from hepatitis C could be an important factor in deciding to pursue or defer antiviral therapy. In this setting, the initial use of a noninvasive test over liver biopsy would be preferred, because it appears the patient may be reluctant to undergo invasive testing (Fig. 1). The use of FibroTest or TE or MRE imaging will be helpful if evidence for cirrhosis or minimal to no fibrosis is predicted by these tests. Should the results of noninvasive testing be indeterminate, then a liver biopsy may need to be performed for stage confirmation. If the patient is discovered to have no or minimal fibrosis and chooses not to pursue antiviral therapy, then longitudinal assessment with elastography imaging to detect fibrosis progression by an increase in liver stiffness is preferred.


Download the PDf here

N Engl J Med 2011; 364:2405-2416 June 23, 2011

"68%, 66%, and 9% in the three groups, respectively, had undetectable HCV RNA at week 4 (rapid virologic response); and 58%, 57%, and 8% in the three groups, respectively, had undetectable HCV RNA at weeks 4 and 12 (extended rapid virologic response). Among the patients with extended rapid virologic response assigned to receive a total of 24 weeks of therapy, 89% in the T12PR group and 83% in the T8PR group met the criteria for sustained virologic response.....A sustained virologic response occurred in 71% of the patients with HCV genotype 1a and 79% with genotype 1b in the T12PR group, in 66% and 74% of the patients with genotype 1a and genotype 1b, respectively, in the T8PR group, and in 41% and 48% in of the patients with genotype 1a and genotype 1b, respectively, in the PR group......Among black patients, 62% in the T12PR group and 58% in the T8PR group had a sustained virologic response, as compared with 25% in the PR group....An increase in sustained virologic response by a factor of more than 2 occurred with telaprevir in black patients, in whom low response rates to interferon have been reported. This finding has been associated with a high prevalence in black persons of the T allele at the rs1297860 locus in the region of the IL28B gene.....Among patients with bridging fibrosis or cirrhosis, 62% of patients in the T12PR group and 53% in the T8PR group, as compared with 33% in the PR group, had a sustained virologic response."

"Stopping rules were implemented to prevent the continuation of treatment in patients who did not have an adequate response. Patients receiving telaprevir who had HCV RNA levels greater than 1000 IU per milliliter at week 4 discontinued telaprevir but continued peginterferon-ribavirin. All patients with less than a 2 log10 decrease from baseline in HCV RNA levels at week 12 discontinued treatment. Patients discontinued treatment if HCV RNA was confirmed to be detectable at any time between weeks 24 and 40."

Ira M. Jacobson, M.D., John G. McHutchison, M.D., Geoffrey Dusheiko, M.D., Adrian M. Di Bisceglie, M.D., K. Rajender Reddy, M.D., Natalie H. Bzowej, M.D., Patrick Marcellin, M.D., Andrew J. Muir, M.D., Peter Ferenci, M.D., Robert Flisiak, M.D., Jacob George, M.D., Mario Rizzetto, M.D., Daniel Shouval, M.D., Ricard Sola, M.D., Ruben A. Terg, M.D., Eric M. Yoshida, M.D., Nathalie Adda, M.D., Leif Bengtsson, B.Sc., Abdul J. Sankoh, Ph.D., Tara L. Kieffer, Ph.D., Shelley George, M.D., Robert S. Kauffman, M.D., Ph.D., and Stefan Zeuzem M.D. for the ADVANCE Study Team

ABSTRACT

Background: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.

Methods: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response).

Results: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.

Conclusions: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.)

Results

Study Patients

Of the 1095 patients enrolled in the study, 1088 received at least one dose of a study drug and were included in the data set for the full analysis (Figure 1Figure 1Randomization and Sustained Virologic Response (SVR) in Study Patients.). Patients were well balanced with respect to major baseline demographic and disease characteristics (Table 1Table 1Baseline Characteristics of the Study Patients, According to Treatment Group.). A total of 58% of the patients were men, 9% were black, 11% were Hispanic, and 21% had bridging fibrosis or cirrhosis.

Efficacy

A significantly greater proportion of patients in each of the two groups receiving telaprevir than in the group receiving peginterferon-ribavirin alone met the criteria for a sustained virologic response (undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment): 75% in the T12PR group and 69% in the T8PR group, as compared with 44% in the PR group (P<0.001 for the comparison of either telaprevir group with the PR group) (Table 2Table 2Response during and after the Treatment Period, According to Treatment Group.). A total of 73% of patients in the T12PR group, 67% in the T8PR group, and 44% in the PR group had undetectable HCV RNA 72 weeks after starting treatment (P<0.001 for the comparison of either telaprevir group with the PR group); 68%, 66%, and 9% in the three groups, respectively, had undetectable HCV RNA at week 4 (rapid virologic response); and 58%, 57%, and 8% in the three groups, respectively, had undetectable HCV RNA at weeks 4 and 12 (extended rapid virologic response). Among the patients with extended rapid virologic response assigned to receive a total of 24 weeks of therapy, 89% in the T12PR group and 83% in the T8PR group met the criteria for sustained virologic response. Mean HCV RNA levels during treatment are shown in Figure 2 in the Supplementary Appendix, available at NEJM.org.

Analyses of subgroups according to various characteristics showed that there were higher rates of sustained virologic response with telaprevir than with peginterferon-ribavirin alone (Figure 2Figure 2Difference in Rates of Sustained Virologic Response (SVR) between the T12PR and Control Groups, According to Subgroups., and Fig. 1 in the Supplementary Appendix). A sustained virologic response occurred in 71% of the patients with HCV genotype 1a and 79% with genotype 1b in the T12PR group, in 66% and 74% of the patients with genotype 1a and genotype 1b, respectively, in the T8PR group, and in 41% and 48% in of the patients with genotype 1a and genotype 1b, respectively, in the PR group. Among black patients, 62% in the T12PR group and 58% in the T8PR group had a sustained virologic response, as compared with 25% in the PR group. Among patients with HCV RNA levels of 800,000 IU per milliliter or more at baseline, those who received telaprevir had a higher rate of response than did those who received peginterferon-ribavirin alone (74% of the patients in the T12PR group and 66% in the T8PR group vs. 36% in the PR group). Among patients with bridging fibrosis or cirrhosis, 62% of patients in the T12PR group and 53% in the T8PR group, as compared with 33% in the PR group, had a sustained virologic response.

Among patients who had undetectable HCV RNA levels after the last dose of study treatment, relapse occurred in 9% in the T12PR group, 9% in the T8PR group, and 28% in the PR group. Recipients of a telaprevir-based regimen who were assigned to 24 weeks of treatment and who met the criteria for sustained virologic response were assessed for relapse beyond 24 weeks after the last study dose. One of 357 patients evaluated through week 72 (<1%) had a confirmed late relapse after early discontinuation of the T8PR regimen at week 12. Three others had detectable HCV RNA below 25 IU per milliliter; in 2 of these patients, HCV RNA was subsequently undetectable, and in 1, there was no available confirmation of HCV RNA level. One patient had HCV RNA of more than 20 million IU per milliliter, but the sequencing assay (limit of detection, approximately 1000 IU per milliliter) was unsuccessful, raising the possibility of a sample error.

A patient was considered to have virologic failure during the treatment period if he or she met the criteria for a stopping rule, had HCV RNA greater than 1000 IU per milliliter at week 12 even if the HCV RNA decline was greater than 2 log10, or had detectable HCV RNA at the end of treatment (week 24 or 48). The rate of virologic failure during the treatment period was lower among patients who received telaprevir than among those who received peginterferon-ribavirin alone (8% in the T12PR group and 13% in the T8PR group, vs. 32% in the PR group). There were similar rates of virologic failure in the T12PR group and the T8PR group during the telaprevir treatment phase up to week 12 (3%), and the virologic failure was attributable primarily to higher-level resistant variants of the HCV virus (e.g., V36M+R155K). After week 12, the rates of virologic failure were higher in the T8PR group than in the T12PR group (10% vs. 5%), with more frequent emergence of wild-type and lower-level resistant variants (e.g., V36A/M, T54A, and R155K/T).11 Virologic failure was more common among patients with HCV genotype 1a infection than among those with HCV genotype 1b infection.

Safety

The incidence of gastrointestinal disorders (nausea and diarrhea), pruritus, rash, and anemia was at least 10 percentage points higher in either of the telaprevir groups than in the PR group (Table 3Table 3Incidence of Serious Adverse Events and Most Common Adverse Events, According to Treatment Group.). Other common adverse events are shown in Table 1 in the Supplementary Appendix. A total of 10% of the patients in the T12PR group, 10% in the T8PR group, and 7% in the PR group discontinued all treatment at some time during the study owing to adverse events (Table 2 in the Supplementary Appendix), whereas 7%, 8%, and 4% of the patients in the three groups, respectively, discontinued all treatment during the telaprevir (or placebo) phase of the study owing to adverse events. The rate of discontinuation of telaprevir (or placebo) only owing to adverse events was higher among the patients who received telaprevir than among those who received placebo (11% in the T12PR group and 7% in the T8PR group, vs. 1% in the PR group). Anemia and rash were the most frequently reported adverse events that led to the discontinuation of telaprevir-based regimens. A total of 7% of the patients in the T12PR group and 5% in the T8PR group discontinued telaprevir owing to rash, whereas 1.4% and 0.5% in the two groups, respectively, discontinued all treatment owing to rash during the telaprevir (or placebo) phase of the study. Rashes were primarily eczematous and were reversible with discontinuation of telaprevir. One case of the Stevens-Johnson syndrome occurred approximately 11 weeks after the last dose of telaprevir had been administered.

More patients in the telaprevir groups than in the PR group discontinued all treatment owing to anemia (1% in the T12PR group and 3% in the T8PR group, vs. <1% in the PR group), and 4%, 2%, and 0% of the patients in the three groups, respectively, discontinued telaprevir (or placebo) only. A total of 17 patients in the T12PR group, 17 in the T8PR group, and 6 in the PR group received blood transfusions during the study. The decrease in hemoglobin levels was more pronounced in patients receiving telaprevir-based regimens than in patients in the PR group and was reversed with the discontinuation of telaprevir (Fig. 3 in the Supplementary Appendix). The largest difference in mean hemoglobin levels between the T12PR group and the PR group (1.04 g per deciliter lower in the T12PR group) and between the T8PR group and the PR group (1.11 g per deciliter lower in the T8PR group) was observed at week 8 of treatment.

Four deaths occurred during the study: three after all study drugs had been discontinued and one (in the PR group) during the treatment phase. Two patients - one in the T12PR group and one in the PR group - died as a result of suicide, one patient in the T12PR group died from HCV infection and liver disease, and one in the T8PR group died from an unknown cause.

Discussion

These results confirm earlier studies and showed a significant increase in the rate of sustained virologic response among patients with HCV genotype 1 infection who are treated with a regimen combining peginterferon alfa-2a and ribavirin with telaprevir for 12 or 8 weeks, followed by peginterferon-ribavirin alone, for a total of 24 or 48 weeks of therapy, as compared with a standard regimen of peginterferon-ribavirin alone for 48 weeks. Among patients with HCV genotype 1 infection who have not previously received treatment, the potential to shorten the duration of therapy with peginterferon-ribavirin to less than 48 weeks without impairing the chance of a sustained virologic response is currently limited to the small number of patients with a low viral load who have undetectable HCV RNA at week 4.12-15 In contrast, in the current study, more than half the patients who received telaprevir had undetectable HCV RNA at weeks 4 and 12, indicating an extended rapid virologic response, and relapse occurred infrequently in these patients after 24 weeks of treatment, suggesting that a total treatment duration of 24 weeks is sufficient for these patients. A longer duration of peginterferon-ribavirin therapy is indicated for patients who do not have an extended rapid virologic response.

Patients in the T8PR group, as compared with those in the T12PR group, had a lower rate of response, and also a slightly lower rate of discontinuation of telaprevir. The lower rate of virologic failure during treatment in the T12PR group as compared with the T8PR group and the more frequent emergence of wild-type and lower-level resistant variants beyond week 12 in the T8PR group than in the T12PR group are probably attributable to more efficient elimination of these viral strains as a result of the additional 4 weeks of telaprevir therapy in the T12PR group.

The rates of sustained virologic response were substantially improved with the addition of telaprevir in patients with negative predictive factors for a response to peginterferon-ribavirin treatment, such as bridging fibrosis or cirrhosis, older age, diabetes, and HCV RNA levels of 800,000 IU per milliliter or more. An increase in sustained virologic response by a factor of more than 2 occurred with telaprevir in black patients, in whom low response rates to interferon have been reported.16-19 This finding has been associated with a high prevalence in black persons of the T allele at the rs1297860 locus in the region of the IL28B gene.20,21 Additional studies are needed to clarify the relationship between IL28B polymorphisms and the response to telaprevir or other direct-acting antiviral agents.

As suggested previously, telaprevir, as compared with peginterferon-ribavirin alone, was associated with a higher incidence of adverse events such as rash, gastrointestinal disorders, and anemia.8-10 In this study, rashes resolved with the discontinuation of telaprevir; 7 to 11% of patients discontinued telaprevir, and only 0.5 to 1.4% discontinued all therapy owing to rash. The implementation of managed, sequential discontinuation of medications for severe rash may have led to the lower rate of overall discontinuation of treatment in this study. Anemia led to the discontinuation of treatment in few patients.

In conclusion, telaprevir-containing regimens, as compared with a regimen of peginterferon-ribavirin alone, were associated with a significant increase in the rates of sustained virologic response, overall and in all the subgroups of patients that were analyzed. The majority of patients who were treated with telaprevir had undetectable HCV RNA at weeks 4 and 12 and received only 24 weeks of total therapy. Numerically higher response rates, with a small increment in reversible adverse events, were observed with a regimen of 12 weeks, as compared with 8 weeks, of telaprevir combined with peginterferon-ribavirin, followed by additional weeks of peginterferon-ribavirin alone. The significant improvement in the rates of sustained virologic response with telaprevir-based therapy and the capacity for response-guided therapy to shorten the duration of exposure to peginterferon-ribavirin among patients who have a rapid response represent important advances in the treatment of patients with HCV genotype 1 infection.

Supported by Vertex Pharmaceuticals and Tibotec.

Methods

Patients

We enrolled patients at 123 international sites. Eligible patients were 18 to 70 years of age and had HCV genotype 1 infection with evidence of chronic hepatitis, as confirmed by means of a liver biopsy within 1 year before screening for the study; patients with compensated liver cirrhosis were eligible. Additional eligibility criteria included seronegativity for hepatitis B surface antigen, and the absence of antibodies against human immunodeficiency virus types 1 and 2, absolute neutrophil counts of 1500 or more per cubic millimeter, platelet counts of 90,000 or more per cubic millimeter, and hemoglobin levels of at least 12 g per deciliter in the case of women or 13 g per deciliter in the case of men. Patients were excluded if they had decompensated liver disease, liver disease from other causes, or hepatocellular carcinoma.

Study Design

This study was a phase 3, randomized, double-blind trial, placebo-controlled for telaprevir. Patients were stratified according to genotype 1 subtype (a, b, or unknown) and baseline viral load (HCV RNA <800,000 IU per milliliter or ≥800,000 IU per milliliter) and were randomly assigned to one of three treatment groups. The study was designed to evaluate two regimens of telaprevir (Vertex Pharmaceuticals) of different durations, combined with peginterferon alfa-2a (Pegasys, Roche) and ribavirin (Copegus, Roche), as compared with a regimen of peginterferon alfa-2a and ribavirin alone. The total duration of treatment was either 24 or 48 weeks. During the first 12 weeks, patients assigned to one of the telaprevir groups received telaprevir and peginterferon-ribavirin either for the entire 12 weeks (T12PR group) or for 8 weeks followed by 4 weeks of placebo and peginterferon-ribavirin (T8PR group). Patients in the T12PR and T8PR groups who met the criteria for an extended rapid virologic response (defined as undetectable HCV RNA at weeks 4 and 12) received 12 additional weeks of treatment with peginterferon-ribavirin alone, for a total treatment period of 24 weeks. Patients in the T12PR and T8PR groups who had detectable HCV RNA either at week 4 or at week 12 received 36 additional weeks of treatment with peginterferon-ribavirin, for a total treatment period of 48 weeks. The group receiving peginterferon alfa-2a and ribavirin alone (PR group) received placebo plus peginterferon-ribavirin for 12 weeks, followed by peginterferon-ribavirin alone for 36 additional weeks. Telaprevir was administered orally at a dose of 750 mg every 8 hours with food, peginterferon alfa-2a by subcutaneous injection at a dose of 180 μg per week, and ribavirin orally at a dose of 1000 mg per day (in patients who weighed less than 75 kg) or 1200 mg per day (in patients who weighed 75 kg or more).

Stopping rules were implemented to prevent the continuation of treatment in patients who did not have an adequate response. Patients receiving telaprevir who had HCV RNA levels greater than 1000 IU per milliliter at week 4 discontinued telaprevir but continued peginterferon-ribavirin. All patients with less than a 2 log10 decrease from baseline in HCV RNA levels at week 12 discontinued treatment. Patients discontinued treatment if HCV RNA was confirmed to be detectable at any time between weeks 24 and 40.

Study Oversight

The protocol was designed by Vertex Pharmaceuticals and Tibotec in collaboration with one of the academic authors. The protocol, which is available with the full text of this article at NEJM.org, was approved by an independent or institutional review board at each participating center, and all patients provided written informed consent before participating in study-related activities. The corresponding author prepared the first draft of the manuscript and made the decision to submit the manuscript for publication, and all the authors, together with an employee of the sponsor, assisted in the revision of subsequent drafts. All the authors reviewed and approved the final draft of the manuscript and assume responsibility for the accuracy and completeness of the data and data analyses and for the fidelity of the study to the trial protocol.

Efficacy Assessments

Plasma HCV RNA levels were measured with the use of the COBAS TaqMan HCV RNA assay, version 2.0 (Roche), with a lower limit of quantification of 25 IU per milliliter and a lower limit of detection of 10 IU per milliliter. The lower limit of detection was used in the determination of extended rapid virologic response. HCV RNA levels were measured on day 1 and at weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 36, 40, and 48; at follow-up visits 4 weeks after the end of treatment; and at weeks 60 and 72.

Evaluation of HCV Sequence

Blood samples were obtained for viral sequencing at baseline and at every treatment and follow-up study visit. Sequencing samples from all the patients were analyzed at baseline, and those from patients who did not meet the criteria for a sustained virologic response were analyzed at all post-baseline time points at which HCV RNA levels were above the limit of detection of the sequencing assay (approximately 1000 IU per milliliter). HCV RNA was isolated from the plasma and amplified by reverse-transcriptase polymerase chain reaction, and the NS3/4A region of the HCV genome was analyzed with the use of population sequencing.

Safety Assessments

Chemical and hematologic assessments were performed at the same time as the efficacy assessments during the treatment period and at 4 weeks after the last dose of the study drug was administered. Data on adverse events were collected at each treatment visit and at the safety follow-up assessment. Full physical examinations were performed at the screening visit and at the safety follow-up assessment. Physical examinations were performed as needed for the assessment and treatment of symptoms during treatment visits.

Because an increased rate of rash had been observed in phase 2 studies,8-10 guidance regarding the grading and management of rash was incorporated into this study. Rash was classified as grade 1 (mild, localized), grade 2 (moderate, with a diffuse skin eruption involving up to 50% of the body surface), or grade 3 (severe, involving more than 50% of the body surface, or rash with the appearance of substantial systemic signs or symptoms). If a progressive grade 2 rash or any grade 3 rash developed, telaprevir or placebo was to be discontinued but the patient would continue to receive peginterferon-ribavirin. If the rash worsened within 7 days after discontinuation of telaprevir or placebo, ribavirin (with or without peginterferon) was to be discontinued (sequential discontinuation).

Anemia was to be managed by means of reductions in the dose of ribavirin in accordance with the product labeling. Erythropoietin-stimulating agents were prohibited according to the final amended study protocol, as were reductions in the dose of telaprevir. If ribavirin was discontinued owing to anemia, discontinuation of telaprevir (or placebo) was required.

An independent data and safety monitoring committee conducted regular planned reviews of the safety data to evaluate safety and side effects of the study regimens. The analyses and preparation of the safety data for each review of the committee were performed by a statistical group that was independent of the sponsor (Parexel International). No interim analyses were planned or conducted.

End Points

The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Secondary efficacy end points included the proportion of patients with undetectable HCV RNA at week 72; at week 4, week 12, or both weeks 4 and 12; at the end of treatment; and 12 weeks after the last planned dose of treatment. A patient was considered to have had a relapse if he or she had undetectable HCV RNA levels at the end of the treatment period but had confirmed detectable HCV RNA levels sometime between the end of treatment and 24 weeks after the last study dose.

Statistical Analysis

The analysis of the primary end point was based on a logistic-regression model, with sustained virologic response as the dependent variable and treatment, genotype 1 subtype, and baseline HCV RNA plasma level as factors. The primary end point was also evaluated by an analysis of the consistency of the treatment effect in prespecified subgroups according to 10 baseline variables (see the statistical analysis plan provided with the protocol at NEJM.org). We estimated that with a sample size of 350 patients in each treatment group, the study would have 92% power to show a significant difference among the treatments, with the use of a two-sided, continuity-corrected chi-square test, at an overall significance level of 5% (adjusted for multiple comparisons), assuming a 50% response rate in the control (PR) group and a 64% response rate in a telaprevir group. Efficacy and safety analyses included data from all patients who underwent random assignment and received at least one dose of any study drug.

Source
June 22, 2011, 4:07 p.m. EDT

NEW HAVEN, Conn., Jun 22, 2011 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. today announced that the Company has initiated patient dosing in segment 2 of its Phase 2 clinical trial of ACH-1625 for the treatment of hepatitis C virus (HCV) for genotype 1 treatment naïve HCV-infected patients. ACH-1625, discovered and advanced by Achillion, is a potent small molecule inhibitor of HCV protease, an enzyme necessary for viral replication.

The clinical trial has advanced into the second segment of a Phase 2a, randomized, double-blind trial evaluating the safety, tolerability and antiviral activity of oral ACH-1625 in combination with standard of care (SOC) consisting of pegylated interferon alfa-2a and ribavirin. Patients will be randomized to receive once daily doses of 200 mg, 400 mg or 800 mg of ACH-1625 in combination with SOC for 12 weeks of dosing. Patients will continue to receive an additional 12 weeks of pegylated interferon alfa-2a and ribavirin and eligible to discontinue treatment at week 24 if they achieve extended rapid virologic response (eRVR) at week 12. Patients who do not achieve an eRVR will continue to receive SOC until week 48.

The trial will take place in the United States and Europe and is designed to enroll approximately 60 HCV-infected patients. The 12-week complete early virologic response (cEVR) trial results are anticipated to be announced in the fourth quarter of 2011.

"Initiating the second segment of this Phase 2 clinical trial allows us to build upon the robust RVR results we observed with ACH-1625, and to further augment the safety and efficacy database by taking the opportunity to study multiple doses of ACH-1625," commented Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "We expect that the results will provide important insight to benchmark the activity of our once-daily protease inhibitor and we look forward to reporting cEVR results by the end of this year."

"This next study segment with ACH-1625 is yet another important milestone achieved for this potentially best-in-class protease inhibitor and for Achillion's broader HCV pipeline," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "It should be recalled that, very recently, we announced the start of Phase 1 on Achillion's high-potency, pan-genotypic protease inhibitor, ACH-2684, and with the upcoming start of Phase 1 on our first NS5A inhibitor, ACH-2928, Achillion remains poised to deliver on a number of clinical milestones over the next few quarters that we believe will significantly enhance our overall position within the important and promising HCV market."

About ACH-1625

ACH-1625 is a HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM.

In the first segment of a Phase 2a clinical study, HCV-infected patients receiving doses of 200 mg, 400 mg, or 800 mg of ACH-1625 in combination with SOC achieved a rapid viral response of 75 -- 81% compared to an RVR of 20% for patients receiving SOC only. ACH-1625 was well tolerated at all doses with no serious adverse events reported and adverse events which were reported as mild to moderate and transient.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit http://www.achillion.com/ or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration, and Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks and uncertainties that Achillion faces are described in greater detail in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings. All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.

This news release was distributed by GlobeNewswire, http://www.globenewswire.com/

SOURCE: Achillion Pharmaceuticals, Inc.

CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com
Media:
Christin Culotta Miller
Ogilvy PR
Tel. (646) 229-5178
christin.miller@ogilvypr.com

Source
Published on: 2011-06-23

The 9.6 kb long RNA genome of Hepatitis C virus (HCV) is under the control of RNA dependent RNA polymerase, an error-prone enzyme, for its transcription and replication. A high rate of mutation has been found to be associated with RNA viruses like HCV.

Based on genetic variability, HCV has been classified into 6 different major genotypes and 11 different subtypes. However this classification system does not provide significant information about the origin of the virus, primarily due to high mutation rate at nucleotide level.

HCV genome codes for a single polyprotein of about 3011 amino acids which is processed into structural and non-structural proteins inside host cell by viral and cellular proteases.

Results: We have identified a conserved NS4A protein sequence for HCV genotype 3a reported from four different continents of the world i.e. Europe, America, Australia and Asia.

We investigated 346 sequences and compared amino acid composition of NS4A protein of different HCV genotypes through Multiple Sequence Alignment and observed amino acid substitutions C22, V29, V30, V38, Q46 and Q47 in NS4A protein of genotype 1b. Furthermore, we observed C22 and V30 as more consistent members of NS4A protein of genotype 1a.

Similarly Q46 and Q47 in genotype 5, V29, V30, Q46 and Q47 in genotype 4, C22, Q46 and Q47 in genotype 6, C22, V38, Q46 and Q47 in genotype 3 and C22 in genotype 2 as more consistent members of NS4A protein of these genotypes. So the different amino acids that were introduced as substitutions in NS4A protein of genotype 1 subtype 1b have been retained as consistent members of the NS4A protein of other known genotypes.

Conclusion: These observations strongly indicate that NS4A protein of different HCV genotypes originally evolved from NS4A protein of genotype 1 subtype 1b, which in turn indicate that HCV genotype 1 subtype 1b established itself earlier in human population and all other known genotypes evolved later as a result of mutations in HCV genotype 1b.

These results were further confirmed through phylogenetic analysis by constructing phylogenetic tree using NS4A protein as a phylogenetic marker.

Author: Muhammad SarwarHumera KausarBushra IjazWaqar AhmadMuhammad AnsarAleena SumrinUsman AshfaqSultan AsadSana GullImran ShahidSajida Hassan

Credits/Source: Virology Journal 2011, 8:317

Source
Michael Carter
Published: 23 June 2011


Project ECHO care teams take part in a virtual care conference using teleconferencing to link remote primary care centres to the University of New Mexico

Specially trained primary care providers can offer effective and safe treatment hepatitis C infection, US investigators report in the New England Journal of Medicine.

Rates of sustained virological response were the same for patients who received therapy from primary care providers as individuals who received treatment at a specialist clinic.

The primary care providers were given specialist training and support using video and telephone conferencing. This training, called the Extension for Community Healthcare Outcomes (ECHO) model, was developed by doctors at the University of New Mexico (UNM) Health Sciences Center.

They were concerned that a large proportion of patients in New Mexico with chronic hepatitis C were not receiving therapy for their infection. Especially low rates of treatment were seen in patients living in rural areas, as well as those from minority populations, and those in prison.

“In 2004, patients from rural areas had to wait up to 6 months for an appointment at the HNM HCV clinic and had to travel up to 250 miles,” comment the authors, adding, “as of 2003, not a single patient in the correctional system had received treatment for HCV infection.”

Using state-of-the-art video and teleconfering facilities, specialist staff from the UNM HCV clinic trained primary care providers to deliver hepatitis C therapy.

Investigators wished to see if treatment provided according to the ECHO model was as effective and safe as therapy delivered at the specialist UNM clinic.

They therefore compared treatment outcomes (the proportion of patients achieving a sustained virological response) between the two types of service providers, and also gathered information on the frequency of side-effects.

“Our hypothesis was that when treatment for hepatitis C infection is delivered in the community (or prison) with the use of the ECHO model, it is as effective as that provided by an academic medical center,” comment the investigators.

The study involved 407 adult patients whose hepatitis was treated between 2004 and 2008. A total of 246 of these patients received therapy at the 21 ECHO centres (five in prisons) that participated in the research.

Almost identical proportions of patients at the ECHO sites and specialist clinic achieved a sustained virological response (58.2% vs. 57.5%).

Treatment outcomes were also comparable for patients with the hard-to-treat genotype-1 infection (rate of sustained virological response: ECHO, 49.7% vs. clinic, 45.8%).

Serious side-effects were more common among patients treated at the clinic than those cared for at ECHO sites (13.7 vs. 6.9%, p = 0.02). In addition, clinic patients were more likely to have side-effects leading to the termination of therapy (8.9% vs. 4.2%, p = 0.05).

“We found that treatment for HCV infection delivered with the use of the ECHO model was associated with high rates of cure,” write the authors, who also note “we met our goal of increasing treatment for minority and other underserved patients.”

They believe that the ECHO model can bring “to the rural clinician the expertise and clinical resources that may not otherwise be available, thus positively affecting the outcomes.”

The investigators conclude: “The ECHO model has the potential for being replicated elsewhere in the United States and abroad, with community providers and academic specialists collaborating to respond to an increasingly diverse range of chronic health issues.”

Reference
Arora S et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. New England Journal of Medicine 364:2199-2207, 2011 (click here for the free abstract).

Source

Telaprevir and Peginterferon–Ribavirin Improve HCV Outcomes

Laurie Barclay, MD

June 22, 2011 — Telaprevir added to peginterferon–ribavirin significantly improves rates of sustained virologic response in previously untreated patients with hepatitis C virus (HCV) genotype 1 infection and in those who require retreatment, according to the results of 2 randomized controlled trials reported in the June 23 issue of the New England Journal of Medicine. Most patients received only 24 weeks of therapy.

Medscape Medical News previously reported that the US Food and Drug Administration (FDA) had approved telaprevir, in combination with peginterferon alfa and ribavirin, to treat chronic HCV genotype 1 infection in patients at least 18 years old with compensated liver disease, including cirrhosis, who are previously untreated or who have been previously treated with interferon-based treatment.

Study 1: ADVANCE Study

"In phase 2 trials, telaprevir, [an HCV] genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients," write Ira M. Jacobson, MD, from the Weill Cornell Medical College and Center for the Study of Hepatitis C, New York, NY, and colleagues from the ADVANCE Study, an international, phase 3, randomized, double-blind, placebo-controlled trial.

Participants (n = 1088) with previously untreated HCV genotype 1 infection were randomly assigned to 1 of 3 treatment groups. The T12PR group received 12 weeks of telaprevir combined with peginterferon alfa-2a and ribavirin, followed by 12 weeks of peginterferon–ribavirin alone if HCV RNA level was undetectable at weeks 4 and 12 or by 36 weeks of peginterferon–ribavirin if HCV RNA level was detectable at either week 4 or 12.

The T8PR group received 8 weeks of telaprevir with peginterferon–ribavirin and 4 weeks of placebo with peginterferon–ribavirin, followed by 12 or 36 weeks of peginterferon–ribavirin according to the same HCV RNA criteria. The PR group received placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin. The main study outcome was the proportion of patients with sustained virologic response, defined as undetectable plasma HCV RNA levels 24 weeks after the last planned dose of study treatment.

Compared with the PR group, the T12PR and T8PR groups had significantly more patients with a sustained virologic response (75% and 69%, respectively, vs 44%; P < .001 for the T12PR or T8PR group vs the PR group). More than half (58%) of patients receiving telaprevir were eligible to receive 24 weeks of total treatment.

Compared with patients receiving peginterferon–ribavirin alone, those receiving telaprevir had higher rates of anemia, gastrointestinal tract adverse effects, and skin rashes. Overall rate of discontinuation of the study drugs because of adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.

"Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients," the study authors write.

Study 2: REALIZE Study

The REALIZE Study was a randomized, phase 3 trial led by Stefan Zeuzem, MD, from Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. The investigators examined the effects of adding telaprevir to peginterferon alfa-2a plus ribavirin in 663 patients with HCV genotype 1 infection who had no response or only a partial response to previous treatment, or who experienced a relapse after initially responding to treatment.

Participants were randomly assigned to the T12PR48 group (n = 266; telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks), the lead-in T12PR48 group (n = 264; 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks), or the control group (n = 132; PR48; peginterferon plus ribavirin for 48 weeks. The rate of sustained virologic response, defined as no detectable HCV RNA levels 24 weeks after the last planned dose of a study medication, was the main study outcome.

Among patients who had a previous relapse, the 2 telaprevir groups had significantly higher rates of sustained virologic response than the control group (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group). Among patients who had a previous partial response, rates were 59%, 54%, and 15%, respectively, and among patients who previously had no response, rates were 29%, 33%, and 5%, respectively (P < .001 for all comparisons). The telaprevir groups had more frequent grade 3 adverse events than the control group (37% vs 22%), and these events were mostly anemia, neutropenia, and leukopenia.

"Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase," the study authors write.

Clinical Practice Article

An accompanying Clinical Practice article, by Hugo R. Rosen, MD, at the Division of Gastroenterology and Hepatology, University of Colorado in Denver, discusses management of chronic HCV infection. He notes that liver biopsy remains the standard for assessment of hepatic fibrosis and facilitates prognostication and decision making.

Treatment goals are to prevent complications and death from HCV infection. Symptomatic extrahepatic HCV, such as cryoglobulinemia, is an indication for therapy regardless of the stage of fibrosis. On the basis of considerable evidence from randomized trials during the past decade, pegylated interferon (peginterferon) plus ribavirin became the standard of care for all HCV genotypes.

The protease inhibitors telaprevir and boceprevir were recently approved by the FDA. On-treatment viral kinetics can be used to predict the likelihood of response and to guide treatment duration.

"Although peginterferon–ribavirin is likely to remain the backbone of antiviral therapy for the foreseeable future, options for treating HCV are expected to expand rapidly in upcoming years," Dr. Rosen writes. "The optimal combination of agents (including nucleoside and nonnucleoside polymerase inhibitors, inhibitors of NS4B and NS5A proteases, modulators of the immune response, and medications that interfere with lipid metabolism, which is essential for the assembly and maturation of HCV particles) and duration of therapy will need to be defined, in order to maximize rates of sustained virologic response while minimizing the risk that resistance will develop. A recent pilot study of a combination of directly acting antiviral agents suggests the possibility of treating HCV infection with an interferon-free, oral approach."

Tibotec and Vertex Pharmaceuticals funded both studies. Financial relationships of the study authors are listed on the New England Journal of Medicine Web site with the full text of the journal articles. Dr. Rosen has disclosed no relevant financial relationships.

N Engl J Med. 2011;364:2405-2416, 2417-2428, 2429-2438.

Source
Thursday, June 23rd, 2011

NIH scientists discuss expanded HIV testing, new prevention tools and a cure

In the 30 years since the first reported cases of a mysterious illness now known as AIDS, researchers have made extraordinary advances in understanding, treating and preventing the disease. Now the challenge, according to experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is to build on those successes to control and, ultimately, end the HIV/AIDS pandemic.

In an article published online today by the Annals of Internal Medicine, Anthony S. Fauci, M.D., NIAID Director, and Carl W. Dieffenbach, Ph.D., Director of the NIAID Division of AIDS, discuss three research and implementation goals they believe are key to successfully achieving the long-term objective of ending the HIV/AIDS pandemic:
  • Efficiently identify greater numbers of HIV-infected people earlier in the course of their disease through expanded voluntary HIV testing programs, and link them to appropriate care and antiretroviral treatment
  • Find innovative approaches to curing HIV/AIDS by eradicating or permanently suppressing the virus in infected people, thereby eliminating the need for lifelong antiretroviral therapy
  • Scale-up implementation of proven HIV prevention strategies, develop additional effective prevention strategies, such as a vaccine, and build on current successes in pre-exposure prophylaxis, microbicides and treatment-as-prevention to achieve a sustainable and comprehensive, combination HIV prevention strategy 
In their paper, the authors explore the challenges and opportunities associated with each of these goals, noting that an integrated strategy combining a variety of effective public health tools is needed to successfully curb HIV/AIDS in the future.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov/.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

 
Contact: Nalini Padmanabhan
padmanabhannm@niaid.nih.gov
301-402-1663
NIH/National Institute of Allergy and Infectious Diseases

Source

Antiviral drugs against Hepatitis C Virus

Published on: 2011-06-23

Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon-alpha (PEG IFN- alpha) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype.

Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials.

Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds.

In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects.

Author: Sidra RehmanUsman AshfaqTariq Javed
Credits/Source: Genetic Vaccines and Therapy 2011, 9:11
 
Source