Bruce R. Bacon, M.D., Stuart C. Gordon, M.D., Eric Lawitz, M.D., Patrick Marcellin, M.D., John M. Vierling, M.D., Stefan Zeuzem, M.D., Fred Poordad, M.D., Zachary D. Goodman, M.D., Ph.D., Heather L. Sings, Ph.D., Navdeep Boparai, M.S., Margaret Burroughs, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Rafael Esteban, M.D. for the HCV RESPOND-2 Investigators
N Engl J Med 2011; 364:1207-1217 March 31, 2011
Background
In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.
Methods
To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.
Results
A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.
Conclusions
The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.)
Results
Baseline Characteristics
A total of 640 patients were evaluated for enrollment in the study; 403 were enrolled and underwent randomization and treatment (Figure S1 in the Supplementary Appendix). The baseline demographic characteristics were balanced among the three treatment groups (Table 1Table 1Baseline Characteristics of the Patients, According to Treatment Group.), with the exception of high viral load (group 2 vs. group 1, P=0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of infection with HCV genotypes 1a and 1b was similar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.
Efficacy
In the primary-analysis population, rates of sustained virologic response were significantly higher among patients receiving boceprevir than among those treated with peginterferon-ribavirin alone (Figure 2Figure 2Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end-of-treatment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 patients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incomplete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).
The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (Figure 2). In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respectively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.
An assessment for amino acid variants associated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibility to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to interferon (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).
In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetectable HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was associated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).
An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response-guided triple therapy (group 2) or 44-week triple therapy (group 3) than with the standard of care (group 1) (Figure 3Figure 3Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.).
Although there was a sustained virologic response in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confidence interval, 0.9 to 2.2). A similarly small difference was seen between these two groups during the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Figure S2 in the Supplementary Appendix). In post hoc exploratory analyses, we observed that this difference appeared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrhosis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Figure S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment-group randomization. In contrast, among patients without cirrhosis at baseline, the percentage with an undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained virologic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine aminotransferase level, and cirrhosis, for which there was a greater odds of a sustained virologic response in group 3 (Figure S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used owing to the variability of biopsy readings.
Multivariable stepwise logistic-regression analysis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low viral load at baseline (odds ratio vs. high load, 2.5; P=0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P=0.04) (Table S1 in the Supplementary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical response (odds ratio, 5.2; P<0.001).
Safety
The study included a stopping rule whereby patients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discontinued all therapy. The low rate of an undetectable HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinuing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Figure S1 in the Supplementary Appendix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2Table 2Adverse Events, According to Treatment Group.).
In the boceprevir groups as compared with the control group, a greater proportion of patients reported serious adverse events and there were more discontinuations and dose modifications owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemoglobin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Adverse events, dose modifications, and study-drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplementary Appendix.
The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with peginterferon-ribavirin therapy (Table S5 in the Supplementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boceprevir groups than in the control group.
Discussion
Our data show that the addition of boceprevir to peginterferon-ribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Furthermore, patients who had previously had a relapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of patients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained virologic response that was similar whether boceprevir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could benefit from shorter treatment. There were no identified groups of patients with a previous treatment failure for whom the standard of care was more efficacious than was triple therapy. We observed high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18 representing a clinically significant improvement over the standard of care.19
Rates of anemia were higher among patients receiving boceprevir-containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Discontinuation for anemia was infrequent (affecting 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red-cell transfusion.
This study included a 4-week lead-in period during which peginterferon-ribavirin was administered, which allowed for the assessment of the patient's interferon responsiveness immediately before the addition of boceprevir. We have previously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We identified 102 patients with a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreatment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness to peginterferon-ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone.
In summary, the results of our phase 3 trial show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients.
The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors' affiliations.
Sponsored by Schering-Plough (now part of Merck).
Methods
Study Oversight
The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering-Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external academic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor concerning the confidentiality of the data. The academic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.
Study Patients
From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibility criteria included demonstrated responsiveness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow-up period]).
Exclusion criteria included hepatitis B or infection with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, and active substance abuse. Liver-biopsy specimens were assessed for Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibrosis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indicates numerous septa without cirrhosis, and 4 indicates cirrhosis.
Study Design
The primary objective was to compare two treatment regimens containing boceprevir in combination with open-label peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon-ribavirin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before randomization.
Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice-response system, to one of three treatment groups, with stratification according to previous response to therapy (nonresponse or relapse) and HCV subgenotype (1a or 1b) as determined by means of sequencing of the HCV 5' noncoding region (Trugene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).
The study design is illustrated in Figure 1Figure 1Study Design.. For purposes of the study doses, peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double-blinded regarding the administration of boceprevir.
During the 4-week lead-in period, all patients received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon-ribavirin plus boceprevir-matched placebo for 44 weeks. Group 2 received a response-guided therapy regimen consisting of boceprevir plus peginterferon-ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an undetectable HCV RNA level at weeks 8 and 12 completed therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an undetectable level at week 12) received peginterferon-ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and peginterferon-ribavirin for 44 weeks.
The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow-up.
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow-up period.
Safety
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening adverse events were managed by means of dose reduction. The recommended guidelines for a two-step dose reduction of peginterferon and for a three-step dose reduction of ribavirin were similar to those previously described (as is summarized in the Supplementary Appendix, available at NEJM.org).7,14-16
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Statistical Analysis
Analyses regarding the primary objective included data from all patients who received at least one dose of any study medication. The key secondary objective was to compare the two boceprevir regimens with the peginterferon-ribavirin regimen in patients who completed the lead-in period and received at least one dose of placebo or boceprevir. Specifically, comparisons for the primary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.
The primary efficacy end point was a sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. Secondary and other efficacy analyses were performed to calculate the proportion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.
The primary statistical comparison was carried out with the use of a two-sided Cochran-Mantel-Haenszel chi-square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an absolute improvement in the rate of sustained virologic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two-sided chi-square test and an alpha value of 0.05.
To control for type I error in the primary analysis, a step-down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison - of group 2 and group 1 - was carried out. A similar step-down approach was prespecified to control for the type I error regarding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.
Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified baseline characteristics. Multivariable logistic-regression analyses involving treatment regimen and prespecified baseline characteristics were performed to evaluate sustained virologic responses. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P=0.05 as the threshold level for variables to be entered into the model and retained in the final model). In addition, we fit a stepwise logistic-regression model of the response (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and baseline characteristics.
Source
April 3, 2011
Boceprevir for Untreated Chronic HCV Genotype 1 Infection
Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Jean-Pierre Bronowicki, M.D., Ph.D. for the SPRINT-2 Investigators
N Engl J Med 2011; 364:1195-1206 March 31, 2011
Background
Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
Methods
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
Results
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.
Conclusions
The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)
The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.
Supported by Schering-Plough (now Merck).
Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon-ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13
Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon-ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1.
Results
Study Patients
A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.
A total of 49 patients discontinued the peginterferon-ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively.
Efficacy
Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups - 67% in group 2 and 68% in group 3 - for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups.
The 4-week lead-in period of peginterferon-ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance-associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group.
The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon-ribavirin for 8 weeks.
The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2).
In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir).
Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period.
Safety
Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.
Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls.
Discussion
SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b-ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials.
As compared with peginterferon alfa-2b-ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population.
Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon-ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population.
This trial featured the use of peginterferon-ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16
The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon-ribavirin than with peginterferon-ribavirin alone among both black and nonblack patients.
The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.
Supported by Schering-Plough (now Merck).
Methods
Study Design
A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon-ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts.
The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses.
Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.
Selection of Patients
Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.
Study Regimens
Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.
All patients received peginterferon-ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon-ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon-ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon-ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon-ribavirin plus oral boceprevir for 44 weeks after the lead-in period.
In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Efficacy Assessment
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.
Safety Assessment
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.
Statistical Analysis
The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.
The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.
Within-cohort comparisons were performed with the use of the two-sided Cochran-Mantel-Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.
Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.
Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.
Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.
Source
N Engl J Med 2011; 364:1195-1206 March 31, 2011
Background
Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
Methods
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
Results
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.
Conclusions
The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)
The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.
Supported by Schering-Plough (now Merck).
Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon-ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13
Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon-ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1.
Results
Study Patients
A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.
A total of 49 patients discontinued the peginterferon-ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively.
Efficacy
Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups - 67% in group 2 and 68% in group 3 - for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups.
The 4-week lead-in period of peginterferon-ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance-associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group.
The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon-ribavirin for 8 weeks.
The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2).
In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir).
Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period.
Safety
Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.
Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls.
Discussion
SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b-ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials.
As compared with peginterferon alfa-2b-ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population.
Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon-ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population.
This trial featured the use of peginterferon-ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16
The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon-ribavirin than with peginterferon-ribavirin alone among both black and nonblack patients.
The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.
Supported by Schering-Plough (now Merck).
Methods
Study Design
A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon-ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts.
The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses.
Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.
Selection of Patients
Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.
Study Regimens
Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.
All patients received peginterferon-ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon-ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon-ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon-ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon-ribavirin plus oral boceprevir for 44 weeks after the lead-in period.
In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Efficacy Assessment
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.
Safety Assessment
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.
Statistical Analysis
The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.
The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.
Within-cohort comparisons were performed with the use of the two-sided Cochran-Mantel-Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.
Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.
Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.
Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.
Source
Could HIV-infected organs save lives?
Public release date: 30-Mar-2011
Contact: Stephanie Desmon
sdesmon1@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions
Johns Hopkins researchers argue for reversing ban on transplanting infected organs and making them available to HIV-infected patients
If Congress reversed its ban on allowing people with HIV to be organ donors after their death, roughly 500 HIV-positive patients with kidney or liver failure each year could get transplants within months, rather than the years they currently wait on the list, new Johns Hopkins research suggests.
"If this legal ban were lifted, we could potentially provide organ transplants to every single HIV-infected transplant candidate on the waiting list," says Dorry L. Segev, M.D., Ph.D., an associate professor of surgery at the Johns Hopkins University School of Medicine and the study's senior author. "Instead of discarding the otherwise healthy organs of HIV-infected people when they die, those organs could be available for HIV-positive candidates."
Not only would HIV-positive transplant candidates get organs sooner if such transplants were legalized, Segev says, but by transplanting those patients and moving them off the waiting list, the time to transplant would be shorter for non-HIV-infected patients.
The ban on organ donation by HIV-positive patients is a relic of the 1980s, when it was still unclear what caused AIDS, at the time a devastating new epidemic sweeping the United States. Congress put the ban into the National Organ Transplant Act of 1984 and it has never been updated, despite the fact that HIV is no longer an immediate death sentence but a chronic disease managed with medication.
The number of HIV-positive patients receiving kidney or liver transplants — with non-HIV-infected organs — is on the rise as doctors become more comfortable with the idea, and patients are having good outcomes, Segev says. In 2009, more than 100 HIV-positive patients got new kidneys and 29 got new livers. HIV-infected patients may encounter accelerated rates of liver and kidney disease due in part to the toxic effects of antiretroviral therapy, the medications that keep HIV at bay.
Segev and his colleagues set out in their study, published early online in the American Journal of Transplantation, to estimate the number of people who die each year in the United States who are good potential organ donors except for that they are HIV-positive. They culled data from two main sources — the Nationwide Inpatient Study, which has information on in-hospital deaths of HIV-infected patients, and the HIV Research Network, a nationally representative registry of people with HIV. The team determined that the number of annual deaths with what are believed to be organs suitable for transplantation was approximately the same as estimated by each data source — an average of 534 each year between 2005 and 2008 in the Nationwide Inpatient Study and an average of 494 each year between 2000 and 2008 in the HIV Research Network.
While no transplants of HIV-infected organs into HIV-infected patients have been done in the United States because of the ban, Segev says doctors in South Africa have started doing this type of transplant with excellent results.
Segev suggests that, in transitioning to a system where HIV-infected donor organs can be transplanted into HIV-infected patients, doctors can call on the lessons and experience of transplanting hepatitis C patients with organs from people with the same disease. This practice, which has not always been the standard, has substantially shortened the waiting list for these recipients without significantly compromising patient or graft survival. The decision of whether or not to use these organs is not a legal one, but one made by the clinician.
Using HIV-infected organs is not without concerns. There are medical and safety issues that need to be addressed. Doctors need to make sure that the harvested organs are healthy enough for transplant and that there is minimal risk of infecting the recipient with a more aggressive strain of the virus. There is also a fear that an HIV-infected organ could accidentally be transplanted into an HIV-negative recipient. Segev says that hepatitis C-infected organs are clearly marked as such and similar protocols can be developed with HIV-infected organs.
"The same processes that are in place to protect people from getting an organ with hepatitis C accidentally could be put in place for HIV-infected organs," Segev says. "When you consider the alternative — a high risk of dying on the waiting list — then these small challenges are overshadowed by the large potential benefit."
Segev says eliminating the prohibition on HIV-infected organ donation would have immediate results. At first, he predicts, there would be more HIV-infected organs than people on the waiting list. Then, as doctors realized that their HIV-infected patients would no longer have to wait five-to-seven years for a transplant, Segev says he thinks more and more HIV-infected patients would sign up for the shortened list for an HIV-infected organ.
"The whole equation for seeking a transplant for someone with HIV and kidney or liver failure would change if this source of organs became available," he says. "We want the decisions taken out of the hands of Congress and put into the hands of clinicians."
###
This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases.
Other Johns Hopkins researchers contributing to this study include Brian J. Boyarsky, B.A.; Erin C. Hall, M.D., M.P.H.; Andrew L. Singer, M.D., Ph.D.; Robert A. Montgomery, M.D., D.Phil.; and Kelly A. Gebo, M.D., M.P.H.
For more information: http://www.hopkinsmedicine.org/transplant/About/Segev.html
Source
Contact: Stephanie Desmon
sdesmon1@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions
Johns Hopkins researchers argue for reversing ban on transplanting infected organs and making them available to HIV-infected patients
If Congress reversed its ban on allowing people with HIV to be organ donors after their death, roughly 500 HIV-positive patients with kidney or liver failure each year could get transplants within months, rather than the years they currently wait on the list, new Johns Hopkins research suggests.
"If this legal ban were lifted, we could potentially provide organ transplants to every single HIV-infected transplant candidate on the waiting list," says Dorry L. Segev, M.D., Ph.D., an associate professor of surgery at the Johns Hopkins University School of Medicine and the study's senior author. "Instead of discarding the otherwise healthy organs of HIV-infected people when they die, those organs could be available for HIV-positive candidates."
Not only would HIV-positive transplant candidates get organs sooner if such transplants were legalized, Segev says, but by transplanting those patients and moving them off the waiting list, the time to transplant would be shorter for non-HIV-infected patients.
The ban on organ donation by HIV-positive patients is a relic of the 1980s, when it was still unclear what caused AIDS, at the time a devastating new epidemic sweeping the United States. Congress put the ban into the National Organ Transplant Act of 1984 and it has never been updated, despite the fact that HIV is no longer an immediate death sentence but a chronic disease managed with medication.
The number of HIV-positive patients receiving kidney or liver transplants — with non-HIV-infected organs — is on the rise as doctors become more comfortable with the idea, and patients are having good outcomes, Segev says. In 2009, more than 100 HIV-positive patients got new kidneys and 29 got new livers. HIV-infected patients may encounter accelerated rates of liver and kidney disease due in part to the toxic effects of antiretroviral therapy, the medications that keep HIV at bay.
Segev and his colleagues set out in their study, published early online in the American Journal of Transplantation, to estimate the number of people who die each year in the United States who are good potential organ donors except for that they are HIV-positive. They culled data from two main sources — the Nationwide Inpatient Study, which has information on in-hospital deaths of HIV-infected patients, and the HIV Research Network, a nationally representative registry of people with HIV. The team determined that the number of annual deaths with what are believed to be organs suitable for transplantation was approximately the same as estimated by each data source — an average of 534 each year between 2005 and 2008 in the Nationwide Inpatient Study and an average of 494 each year between 2000 and 2008 in the HIV Research Network.
While no transplants of HIV-infected organs into HIV-infected patients have been done in the United States because of the ban, Segev says doctors in South Africa have started doing this type of transplant with excellent results.
Segev suggests that, in transitioning to a system where HIV-infected donor organs can be transplanted into HIV-infected patients, doctors can call on the lessons and experience of transplanting hepatitis C patients with organs from people with the same disease. This practice, which has not always been the standard, has substantially shortened the waiting list for these recipients without significantly compromising patient or graft survival. The decision of whether or not to use these organs is not a legal one, but one made by the clinician.
Using HIV-infected organs is not without concerns. There are medical and safety issues that need to be addressed. Doctors need to make sure that the harvested organs are healthy enough for transplant and that there is minimal risk of infecting the recipient with a more aggressive strain of the virus. There is also a fear that an HIV-infected organ could accidentally be transplanted into an HIV-negative recipient. Segev says that hepatitis C-infected organs are clearly marked as such and similar protocols can be developed with HIV-infected organs.
"The same processes that are in place to protect people from getting an organ with hepatitis C accidentally could be put in place for HIV-infected organs," Segev says. "When you consider the alternative — a high risk of dying on the waiting list — then these small challenges are overshadowed by the large potential benefit."
Segev says eliminating the prohibition on HIV-infected organ donation would have immediate results. At first, he predicts, there would be more HIV-infected organs than people on the waiting list. Then, as doctors realized that their HIV-infected patients would no longer have to wait five-to-seven years for a transplant, Segev says he thinks more and more HIV-infected patients would sign up for the shortened list for an HIV-infected organ.
"The whole equation for seeking a transplant for someone with HIV and kidney or liver failure would change if this source of organs became available," he says. "We want the decisions taken out of the hands of Congress and put into the hands of clinicians."
###
This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases.
Other Johns Hopkins researchers contributing to this study include Brian J. Boyarsky, B.A.; Erin C. Hall, M.D., M.P.H.; Andrew L. Singer, M.D., Ph.D.; Robert A. Montgomery, M.D., D.Phil.; and Kelly A. Gebo, M.D., M.P.H.
For more information: http://www.hopkinsmedicine.org/transplant/About/Segev.html
Source
OraQuick HCV Rapid Test Now Approved for Use With Fingerstick Whole Blood Samples
Infectious Disease Special Edition
ISSUE: MARCH 2011 VOLUME: 1
OraSure Technologies, Inc. has received FDA approval for its OraQuick HCV Rapid Antibody Test, which detects HCV antibodies with a fingerstick whole blood sample.
The fingerstick whole blood claim is the second application to be approved by the FDA for the OraQuick HCV test. The first product, approved in June 2010, required venous whole blood specimens.
The OraQuick HCV Rapid Antibody Test is the first FDA-approved rapid, point-of-care test to detect antibodies to hepatitis C virus. This test eliminates the need to draw blood and provides results in 20 minutes, which may allow healthcare providers to identify more individuals infected with hepatitis C.
OraSure is partnering with Merck & Co., through its predecessor Schering Plough Corp., to collaborate on the development and promotion of the OraQuick HCV test.
For more information, visit http://www.orasure.com/.
—Based on a press release from OraSure Technologies, Inc.
Source
ISSUE: MARCH 2011 VOLUME: 1
OraSure Technologies, Inc. has received FDA approval for its OraQuick HCV Rapid Antibody Test, which detects HCV antibodies with a fingerstick whole blood sample.
The fingerstick whole blood claim is the second application to be approved by the FDA for the OraQuick HCV test. The first product, approved in June 2010, required venous whole blood specimens.
The OraQuick HCV Rapid Antibody Test is the first FDA-approved rapid, point-of-care test to detect antibodies to hepatitis C virus. This test eliminates the need to draw blood and provides results in 20 minutes, which may allow healthcare providers to identify more individuals infected with hepatitis C.
OraSure is partnering with Merck & Co., through its predecessor Schering Plough Corp., to collaborate on the development and promotion of the OraQuick HCV test.
For more information, visit http://www.orasure.com/.
—Based on a press release from OraSure Technologies, Inc.
Source
Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes
PRINCETON, N.J., March 30, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that screening has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.
"We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The ATOMIC trial is designed to explore 12 and 24 week durations of PSI-7977. The potency, high barrier to resistance, and consistent antiviral activity across genotypes provided the data to support an interferon free dosing period in this trial, as well as enabling us to enroll multiple genotypes in this trial."
About the Phase 2b ATOMIC Trial
This Phase 2b trial is planned to enroll approximately 300 patients with chronic HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the safety and tolerability of PSI-7977 in combination with peginterferon and ribavirin over 12 or 24 weeks. The trial will be conducted in the U.S. Patients will be randomized (1:2:3) into the following arms:
* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks;
* PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks;
* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks, followed by either PSI-7977 400mg QD monotherapy for 12 weeks or PSI-7977 400mg QD plus ribavirin for 12 weeks.
HCV GT1 patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. An additional 25 treatment-naïve patients with HCV genotype 4, 5, 6 or indeterminate genotype, will receive PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks.
Additional details on this and all Pharmasset trials can be found at http://www.clinicaltrials.gov/
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates. Mericitabine (RG7128, MCB), a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys® plus Copegus® and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys® and Copegus®, all conducted through a strategic collaboration with Roche. PSI-7977 is our unpartnered uracil nucleotide analog currently dosing in three Phase 2 studies in patients with HCV genotypes 1 through 6, including studies with abbreviated duration or no interferon. PSI-938 is our unpartnered guanosine nucleotide analog which recently completed a 14-day monotherapy and combination study with PSI-7977. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 613-4181
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 and our Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
SOURCE Pharmasset, Inc.
Source
"We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The ATOMIC trial is designed to explore 12 and 24 week durations of PSI-7977. The potency, high barrier to resistance, and consistent antiviral activity across genotypes provided the data to support an interferon free dosing period in this trial, as well as enabling us to enroll multiple genotypes in this trial."
About the Phase 2b ATOMIC Trial
This Phase 2b trial is planned to enroll approximately 300 patients with chronic HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the safety and tolerability of PSI-7977 in combination with peginterferon and ribavirin over 12 or 24 weeks. The trial will be conducted in the U.S. Patients will be randomized (1:2:3) into the following arms:
* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks;
* PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks;
* PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks, followed by either PSI-7977 400mg QD monotherapy for 12 weeks or PSI-7977 400mg QD plus ribavirin for 12 weeks.
HCV GT1 patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. An additional 25 treatment-naïve patients with HCV genotype 4, 5, 6 or indeterminate genotype, will receive PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks.
Additional details on this and all Pharmasset trials can be found at http://www.clinicaltrials.gov/
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates. Mericitabine (RG7128, MCB), a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys® plus Copegus® and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys® and Copegus®, all conducted through a strategic collaboration with Roche. PSI-7977 is our unpartnered uracil nucleotide analog currently dosing in three Phase 2 studies in patients with HCV genotypes 1 through 6, including studies with abbreviated duration or no interferon. PSI-938 is our unpartnered guanosine nucleotide analog which recently completed a 14-day monotherapy and combination study with PSI-7977. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 613-4181
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 and our Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
SOURCE Pharmasset, Inc.
Source
Presidio Pharmaceuticals, Inc. Announces Positive Results in a Phase 1b Clinical Trial of PPI-461, a Novel, Potent Broadly-Active Hepatitis C Virus (HCV) Inhibitor
SAN FRANCISCO----Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C. "These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality"
The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.
The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.
Pharmacokinetic (PK) analyses of patients' PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.
Virologic data from the first two dosing groups indicate rapid and marked reductions in patients' serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).
Efficacy data for individual patients receiving active PPI-461 treatment in the first two dosing cohorts in the Phase 1b trial are presented in Table 1:
"These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer.
The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.
About Presidio's HCV NS5A Inhibitors
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).
PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio's NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.
About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: http://www.presidiopharma.com/.
Contacts
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD,
415-655-7561
omar@presidiopharma.com
Source
The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.
The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.
Pharmacokinetic (PK) analyses of patients' PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.
Virologic data from the first two dosing groups indicate rapid and marked reductions in patients' serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).
Efficacy data for individual patients receiving active PPI-461 treatment in the first two dosing cohorts in the Phase 1b trial are presented in Table 1:
The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.
About Presidio's HCV NS5A Inhibitors
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).
PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio's NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.
About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: http://www.presidiopharma.com/.
Contacts
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD,
415-655-7561
omar@presidiopharma.com
Source
Achillion Announces Positive RVR Results With ACH-1625 to Treat Chronic Hepatitis C
Once-Daily Dose Achieves 75 - 81% RVR in a Well Tolerated Combination Regimen
NEW HAVEN, Conn., March 30, 2011 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced top-line results from its on-going Phase 2a clinical trial of ACH-1625 dosed once daily (QD) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin), a current standard of care (SOC) in patients with chronic hepatitis C (HCV) infection. The analysis demonstrated that 75-81% of patients receiving ACH-1625 achieved rapid virologic response (RVR) with a promising safety and tolerability profile. ACH-1625 is an inhibitor of HCV NS3 protease that was discovered by and is being developed by Achillion.
Study Design
In this first of a two segment Phase 2a trial, a total of 64 patients were enrolled and randomized across three doses of ACH-1625 given once daily (200mg, 400mg or 800mg) or placebo with peginterferon alfa-2a and ribavirin, and were dosed for 4 weeks of therapy. Patients then continue on SOC for up to an additional 44 weeks. Subjects were randomized and stratified by HCV genotype and IL28B genotype.
Top-line Results
The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient's diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:
Mean maximum HCV RNA
decline through Week 4 (log10) 4.90 4.63 4.96 2.25 Safety results from a planned safety analysis included 56 patients from this segment of the trial and indicated that adverse events (AEs) were similar to those observed in the previously reported Phase 1a and 1b trials of ACH-1625. Over 4 weeks of co-administration of ACH-1625 with SOC, there were no discontinuations due to adverse events and there were no serious adverse events (SAEs) reported. Most reported AEs in patients receiving ACH-1625 were classified as mild to moderate and were transient. The most common AEs were consistent with peginterferon alfa-2a and ribavirin.
"These data reflect a positive outcome with high RVR, irrespective of IL28B status, which places ACH-1625 among the most potent protease inhibitors in development," commented Elizabeth A. Olek, M.D., Vice President and Chief Medical Officer of Achillion. "We look forward to selecting two of these doses and beginning the second segment of the trial, dosing ACH-1625 with SOC over 12 weeks, and anticipate reporting cEVR data by the end of this year." "We are quite pleased with the continued robust efficacy results and good safety profile with once-daily doses of ACH-1625," said Michael D. Kishbauch, Achillion's President and Chief Executive Officer. "ACH-1625 continues to demonstrate best-in-class features, including once-daily dosing, robust antiviral activity, coupled with safety and tolerability for patients. These attributes distinguish our drug and suggest it could offer improvements over other next-generation protease inhibitors that will reach the market mid-decade."
The preliminary safety profile of ACH-1625 continues to support future plans to combine this protease inhibitor with other directly acting antiviral agents. Achillion expects to initiate during 2012 a clinical trial evaluating ACH-1625 in combination with ACH-2928, an internally discovered and developed NS5A inhibitor.
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 Phase 1a clinical studies, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg per day for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no SAEs, and no clinically significant changes in vital signs, electrocardiograms or laboratory evaluations. In Phase 1b clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.63 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of at least 1log10 from baseline through day 12, the last day of viral load measurement in the study.
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; 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 are described 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.
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.
ACHN-G
CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
gschulman@achillion.com
Source
NEW HAVEN, Conn., March 30, 2011 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced top-line results from its on-going Phase 2a clinical trial of ACH-1625 dosed once daily (QD) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin), a current standard of care (SOC) in patients with chronic hepatitis C (HCV) infection. The analysis demonstrated that 75-81% of patients receiving ACH-1625 achieved rapid virologic response (RVR) with a promising safety and tolerability profile. ACH-1625 is an inhibitor of HCV NS3 protease that was discovered by and is being developed by Achillion.
Study Design
In this first of a two segment Phase 2a trial, a total of 64 patients were enrolled and randomized across three doses of ACH-1625 given once daily (200mg, 400mg or 800mg) or placebo with peginterferon alfa-2a and ribavirin, and were dosed for 4 weeks of therapy. Patients then continue on SOC for up to an additional 44 weeks. Subjects were randomized and stratified by HCV genotype and IL28B genotype.
Top-line Results
The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient's diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:
Mean maximum HCV RNA
decline through Week 4 (log10) 4.90 4.63 4.96 2.25 Safety results from a planned safety analysis included 56 patients from this segment of the trial and indicated that adverse events (AEs) were similar to those observed in the previously reported Phase 1a and 1b trials of ACH-1625. Over 4 weeks of co-administration of ACH-1625 with SOC, there were no discontinuations due to adverse events and there were no serious adverse events (SAEs) reported. Most reported AEs in patients receiving ACH-1625 were classified as mild to moderate and were transient. The most common AEs were consistent with peginterferon alfa-2a and ribavirin.
"These data reflect a positive outcome with high RVR, irrespective of IL28B status, which places ACH-1625 among the most potent protease inhibitors in development," commented Elizabeth A. Olek, M.D., Vice President and Chief Medical Officer of Achillion. "We look forward to selecting two of these doses and beginning the second segment of the trial, dosing ACH-1625 with SOC over 12 weeks, and anticipate reporting cEVR data by the end of this year." "We are quite pleased with the continued robust efficacy results and good safety profile with once-daily doses of ACH-1625," said Michael D. Kishbauch, Achillion's President and Chief Executive Officer. "ACH-1625 continues to demonstrate best-in-class features, including once-daily dosing, robust antiviral activity, coupled with safety and tolerability for patients. These attributes distinguish our drug and suggest it could offer improvements over other next-generation protease inhibitors that will reach the market mid-decade."
The preliminary safety profile of ACH-1625 continues to support future plans to combine this protease inhibitor with other directly acting antiviral agents. Achillion expects to initiate during 2012 a clinical trial evaluating ACH-1625 in combination with ACH-2928, an internally discovered and developed NS5A inhibitor.
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 Phase 1a clinical studies, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg per day for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no SAEs, and no clinically significant changes in vital signs, electrocardiograms or laboratory evaluations. In Phase 1b clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.63 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of at least 1log10 from baseline through day 12, the last day of viral load measurement in the study.
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; 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 are described 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.
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.
ACHN-G
CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
gschulman@achillion.com
Source
Tibotec Advances Global Clinical Research Program for TMC435 in HCV; Will Present Four Abstracts Evaluating Safety and Efficacy at EASL
-Company Recently Launched Phase III Studies of TMC435 in Treatment-Naive HCV Patients in 12 Countries-
CORK, Ireland, March 29, 2011 /PRNewswire/ -- Tibotec Pharmaceuticals announced today that four abstracts reporting research findings with TMC435, the company's investigational hepatitis C protease inhibitor, have been accepted for presentation at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany, March 30 to April 3, 2011.
The four abstracts for TMC435 support Tibotec's continued efforts to advance its research and development program for the treatment of HCV. TMC435 highlights at the meeting include one oral presentation and one late-breaker poster presentation:
* Analysis of the predictive nature of IL28B genotype and pretreatment serum IP-10 in treatment-naive HCV patients from phase IIb PILLAR study on TMC435 administered with pegIFN/ribavirin
* Results from interim 24 week data of the international phase IIb randomized, double-blind, placebo-controlled ASPIRE study on efficacy, tolerability, safety, and pharmacokinetics of TMC435 administered with pegIFN/ribavirin in treatment-experienced HCV patients
"Tibotec is committed to developing innovative new treatment options that may offer better treatment outcomes and that may decrease the duration of treatment for patients with chronic hepatitis C infection," said Brian Woodfall M.D., Vice President of Global Clinical Development at Tibotec. "The company's presence at this year's EASL meeting and the recent launch of the phase 3 clinical trial program for TMC435 reinforce the value of this investigational agent in our growing HCV pipeline."
The titles of the abstracts and times for Tibotec's presentations on TMC435 appear below - full abstracts can also be accessed at http://www.easl.eu/.
Oral Presentation:
* "Impact of IL28B genotype and pretreatment serum IP-10 in treatment-naive genotype-1 HCV patients treated with TMC435 in combination with peginterferon alpha-2a and ribavirin in PILLAR study" - Thursday, March 31, 2011 from 17:00 to 19:00
Poster Presentations:
* Late-breaker "The ASPIRE trial: TMC435 in treatment-experienced patients with genotype-1 HCV infection who have failed previous PEG/RBV treatment" - Thursday, March 31, 2011 to Saturday, April 2, 2011
* "Pharmacokinetics of TMC435 in subjects with moderate hepatic impairment" - Thursday, March 31, 2011 from 09:00 to 18:00
* "Treatment outcome and resistance analysis in HCV genotype-1 patients previously exposed to TMC435 monotherapy and re-treated with TMC435 in combination with pegIFNalpha-2a/ribavirin" - Saturday, April 2, 2011 from 09:00 to 18:00
About HCV
HCV is a blood-borne infectious disease that affects the liver. With an estimated 170 million people infected worldwide and three to four million people newly infected each year, HCV puts a significant burden on patients and society. Chronic infection with HCV can lead to liver cancer and other serious and fatal liver diseases, and is the most common cause of liver transplant worldwide. The current standard of care for HCV, pegylated interferon combined with ribavirin, causes serious side effects and only cures 40 to 50 percent of genotype 1 patients. The development of new therapies, particularly direct antivirals with different modes of action, may allow HCV patients to undergo a shorter and more effective treatment regimen.
About Tibotec Pharmaceuticals
Tibotec Pharmaceuticals is a global pharmaceutical and research development company and one of the companies that compose the Janssen Pharmaceutical Companies of Johnson & Johnson. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS and hepatitis C drugs, and anti-infectives for diseases of high unmet medical need.
Source
CORK, Ireland, March 29, 2011 /PRNewswire/ -- Tibotec Pharmaceuticals announced today that four abstracts reporting research findings with TMC435, the company's investigational hepatitis C protease inhibitor, have been accepted for presentation at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany, March 30 to April 3, 2011.
The four abstracts for TMC435 support Tibotec's continued efforts to advance its research and development program for the treatment of HCV. TMC435 highlights at the meeting include one oral presentation and one late-breaker poster presentation:
* Analysis of the predictive nature of IL28B genotype and pretreatment serum IP-10 in treatment-naive HCV patients from phase IIb PILLAR study on TMC435 administered with pegIFN/ribavirin
* Results from interim 24 week data of the international phase IIb randomized, double-blind, placebo-controlled ASPIRE study on efficacy, tolerability, safety, and pharmacokinetics of TMC435 administered with pegIFN/ribavirin in treatment-experienced HCV patients
"Tibotec is committed to developing innovative new treatment options that may offer better treatment outcomes and that may decrease the duration of treatment for patients with chronic hepatitis C infection," said Brian Woodfall M.D., Vice President of Global Clinical Development at Tibotec. "The company's presence at this year's EASL meeting and the recent launch of the phase 3 clinical trial program for TMC435 reinforce the value of this investigational agent in our growing HCV pipeline."
The titles of the abstracts and times for Tibotec's presentations on TMC435 appear below - full abstracts can also be accessed at http://www.easl.eu/.
Oral Presentation:
* "Impact of IL28B genotype and pretreatment serum IP-10 in treatment-naive genotype-1 HCV patients treated with TMC435 in combination with peginterferon alpha-2a and ribavirin in PILLAR study" - Thursday, March 31, 2011 from 17:00 to 19:00
Poster Presentations:
* Late-breaker "The ASPIRE trial: TMC435 in treatment-experienced patients with genotype-1 HCV infection who have failed previous PEG/RBV treatment" - Thursday, March 31, 2011 to Saturday, April 2, 2011
* "Pharmacokinetics of TMC435 in subjects with moderate hepatic impairment" - Thursday, March 31, 2011 from 09:00 to 18:00
* "Treatment outcome and resistance analysis in HCV genotype-1 patients previously exposed to TMC435 monotherapy and re-treated with TMC435 in combination with pegIFNalpha-2a/ribavirin" - Saturday, April 2, 2011 from 09:00 to 18:00
About HCV
HCV is a blood-borne infectious disease that affects the liver. With an estimated 170 million people infected worldwide and three to four million people newly infected each year, HCV puts a significant burden on patients and society. Chronic infection with HCV can lead to liver cancer and other serious and fatal liver diseases, and is the most common cause of liver transplant worldwide. The current standard of care for HCV, pegylated interferon combined with ribavirin, causes serious side effects and only cures 40 to 50 percent of genotype 1 patients. The development of new therapies, particularly direct antivirals with different modes of action, may allow HCV patients to undergo a shorter and more effective treatment regimen.
About Tibotec Pharmaceuticals
Tibotec Pharmaceuticals is a global pharmaceutical and research development company and one of the companies that compose the Janssen Pharmaceutical Companies of Johnson & Johnson. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS and hepatitis C drugs, and anti-infectives for diseases of high unmet medical need.
Source
March 19, 2011
Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits
Digestive and Liver Disease
Articles in Press
Rolf Teschkea, Samuel X. Qiub, Vincent Lebotc
Received 2 December 2010; accepted 25 January 2011. published online 07 March 2011.
Corrected Proof
Abstract
Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.
Keywords: Drug induced liver injury, Herbal hepatotoxicity, Herbs induced liver injury, Kava, Kava hepatotoxicity, Piper methysticum
a Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Germany
b Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China
c CIRAD, Port-Vila, Vanuatu
Corresponding author at: Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany. Tel.: +49 6181 2964200; fax: +49 6181 2964211.
PII: S1590-8658(11)00048-X
doi:10.1016/j.dld.2011.01.018
© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved.
Source
Articles in Press
Rolf Teschkea, Samuel X. Qiub, Vincent Lebotc
Received 2 December 2010; accepted 25 January 2011. published online 07 March 2011.
Corrected Proof
Abstract
Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.
Keywords: Drug induced liver injury, Herbal hepatotoxicity, Herbs induced liver injury, Kava, Kava hepatotoxicity, Piper methysticum
a Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Germany
b Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China
c CIRAD, Port-Vila, Vanuatu
Corresponding author at: Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany. Tel.: +49 6181 2964200; fax: +49 6181 2964211.
PII: S1590-8658(11)00048-X
doi:10.1016/j.dld.2011.01.018
© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Inc All rights reserved.
Source
Effects of silybum marianum on patients with chronic hepatitis C
Journal of Research in Medical Sciences, Vol 16, No 3 (2011)
Hamid Kalantari, Zahra Shahshahan, Mehdi Hejazi, Taghi Ghafghazi, Vahid Sebghatolahi
Abstract
• BACKGROUND: Silymarin derived from silybum marianum (milk thistle), a flowering member of the daisy family, may benefit liver function in people infected with the hepatitis C virus. The aims of this pilot study were to assess the efficacy and safety of silymarin on serum hepatitis C virus (HCV) RNA, serum aminotransferases (ALT, AST) levels, liver fibrosis and well-being in patients with chronic hepatitis C (CHC).
• METHODS: This prospective self-controlled trial study was conducted from March to September 2006 at Department of Gastroenterology, Isfahan University of Medical Sciences, Isfahan, Iran. 55 patients with HCV (10 female and 45 male) with a mean age of 31.8 ± 6.4 years (10-67 years) were participated in the study. Patients received 24 weeks of silymarin (630 mg/day). Baseline virological biochemical, liver fibrosis (by a serum fibrosis markers, including YKL–40 and Hyaluronic acid), and SF-36 questionnaire were performed with biochemical tests repeated at the end of the treatment period.
• RESULTS: There was statistically difference in mean of ALT (108.7 ± 86.6 vs 70.3 ± 57.7) before and after the treatment (p < 0.001). The means of AST were 99.4 ± 139.7 and 59.7 ± 64.32 before and after the treatment with statistically differences (p = 0.004). After the treatment, nine patients were found with negative HCV-RNA (p = 0.004) and statistically significant improvement in results of liver fibrosis markers were found only in fibrosis group (p = 0.015). Quality of life was improved significantly (p < 0.001).
• CONCLUSIONS: This study indicated that in patients with CHC performing silymarin (650 mg/day) for 6 months, improved serum HCV-RNA titer, serum aminotransferases (ALT, AST), hepatic fibrosis and patient’s quality of life. More future studies are warranted.
• KEYWORDS: Hepatitis C Virus (HCV), Quality of life, Serum Aminotransferases.
Source
Hamid Kalantari, Zahra Shahshahan, Mehdi Hejazi, Taghi Ghafghazi, Vahid Sebghatolahi
Abstract
• BACKGROUND: Silymarin derived from silybum marianum (milk thistle), a flowering member of the daisy family, may benefit liver function in people infected with the hepatitis C virus. The aims of this pilot study were to assess the efficacy and safety of silymarin on serum hepatitis C virus (HCV) RNA, serum aminotransferases (ALT, AST) levels, liver fibrosis and well-being in patients with chronic hepatitis C (CHC).
• METHODS: This prospective self-controlled trial study was conducted from March to September 2006 at Department of Gastroenterology, Isfahan University of Medical Sciences, Isfahan, Iran. 55 patients with HCV (10 female and 45 male) with a mean age of 31.8 ± 6.4 years (10-67 years) were participated in the study. Patients received 24 weeks of silymarin (630 mg/day). Baseline virological biochemical, liver fibrosis (by a serum fibrosis markers, including YKL–40 and Hyaluronic acid), and SF-36 questionnaire were performed with biochemical tests repeated at the end of the treatment period.
• RESULTS: There was statistically difference in mean of ALT (108.7 ± 86.6 vs 70.3 ± 57.7) before and after the treatment (p < 0.001). The means of AST were 99.4 ± 139.7 and 59.7 ± 64.32 before and after the treatment with statistically differences (p = 0.004). After the treatment, nine patients were found with negative HCV-RNA (p = 0.004) and statistically significant improvement in results of liver fibrosis markers were found only in fibrosis group (p = 0.015). Quality of life was improved significantly (p < 0.001).
• CONCLUSIONS: This study indicated that in patients with CHC performing silymarin (650 mg/day) for 6 months, improved serum HCV-RNA titer, serum aminotransferases (ALT, AST), hepatic fibrosis and patient’s quality of life. More future studies are warranted.
• KEYWORDS: Hepatitis C Virus (HCV), Quality of life, Serum Aminotransferases.
Source
Low-Dose Peginterferon Alfa-2a Is Safe and Produces a Sustained Virologic Response in Patients With Chronic Hepatitis C and End-Stage Renal Disease
Clinical Gastroenterology and Hepatology
Volume 9, Issue 3 , Pages 242-248, March 2011
Markus Peck–Radosavljevic, John Boletis, Fatih Besisik, Maria Lúcia Ferraz, Laurent Alric, Didier Samuel, Diethelm Messinger, Andreas Tietz, Hugo Cheinquer
published online 09 November 2010.
Abstract
Background & Aims
Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis.
Methods
We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 μg/wk for 48 weeks.
Results
The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 μg/wk group and 34.9% (15/43) in the 90 μg/wk group (odds ratio, 1.22; 95% confidence interval, 0.49–3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 μg/wk group and 87.5% (14/16) of those in the 90 μg/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment.
Conclusions
Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%–40% of patients with chronic hepatitis C and ESRD on hemodialysis.
Keywords: Chronic Hepatitis C, End-Stage Renal Disease, Hemodialysis, Hepatitis C Virus, Peginterferon, Sustained Virologic Response
Source
Volume 9, Issue 3 , Pages 242-248, March 2011
Markus Peck–Radosavljevic, John Boletis, Fatih Besisik, Maria Lúcia Ferraz, Laurent Alric, Didier Samuel, Diethelm Messinger, Andreas Tietz, Hugo Cheinquer
published online 09 November 2010.
Abstract
Background & Aims
Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis.
Methods
We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 μg/wk for 48 weeks.
Results
The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 μg/wk group and 34.9% (15/43) in the 90 μg/wk group (odds ratio, 1.22; 95% confidence interval, 0.49–3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 μg/wk group and 87.5% (14/16) of those in the 90 μg/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment.
Conclusions
Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%–40% of patients with chronic hepatitis C and ESRD on hemodialysis.
Keywords: Chronic Hepatitis C, End-Stage Renal Disease, Hemodialysis, Hepatitis C Virus, Peginterferon, Sustained Virologic Response
Source
HIV Treatment Gap Widening
Jim Kling
March 18, 2011 — There is a growing gap between the number of individuals living with HIV and the number of healthcare providers required to meet their needs, according to a new report from the Institute of Medicine entitled "HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care." The report was published online March 17 by the Institute of Medicine's Committee on HIV Screening and Access to Care.
There are believed to be 1.1 million people living with HIV in the United States, and an estimated 21% of them are not aware that they are infected. About 56,000 individuals contract new infections each year. Individuals are also living longer with HIV, further increasing demand for services. However, there are currently more providers retiring from the HIV/AIDS field than there are new providers entering the field.
In 2006, the Centers for Disease Control and Prevention recommended routine HIV testing for individuals between the ages of 13 and 64 years. After those recommendations were issued, state health departments and other organizations received additional financial support for screening, but there is some debate as to whether the support is sufficient and whether the programs will be sustainable once outside funding ceases.
Expanded screening is also resulting in the identification of more individuals with HIV, which in turn will lead to a greater demand for service providers to meet their needs.
There are few data on patterns of care for patients with HIV/AIDS, but the committee concluded that most medical care for HIV-positive individuals is provided by primary care physicians, infectious disease specialists, advanced practice registered nurses, and physician assistants. Other needed providers include registered nurses, dentists, pharmacists, and social workers.
HIV-positive patients are well served by primary care providers who can address their other health needs, but there is a lack of adequate training and experience in HIV care among this group. This is especially true in outpatient clinics, which currently provide the majority of current HIV care.
The committee recommends that medical schools and residency training incorporate exposure to outpatient HIV care, and that continuing medical education programs also be developed to address the needs for the growing population of HIV-positive individuals.
In addition to the overall number of providers, it is important to have an adequate racial, ethnic, and cultural diversity among providers because many HIV-positive individuals are racial/ethnic minorities.
Another strategy in addition to increasing providers is to maximize the capacity of the current healthcare system to absorb increased demand. One approach is to implement delivery system strategies such as task shifting, comanagement, and care coordination models.
"Pathway" strategies can expose more trainees to HIV care, and financial and other incentives can be implemented to encourage more providers to enter the field. The committee also highlighted the current Ryan White model of care, in which patients receive a variety of medical and nonmedical services, and which incorporates task shifting. The Institute of Medicine recommends that this sort of integrated delivery system serve as a model for future care systems.
No matter what approach is used, it is imperative that there be an increase in HIV/AIDS care capacity. Each new detection of an HIV infection creates the need to counsel, refer, treat, and monitor an additional patient, at an average annual cost of $19,912.
If service is interrupted, patients suffer and become less productive, and the likelihood of new transmissions rises.
The report is the third and final in a series examining policy and capacity issues related to carrying out the National HIV/AIDS Strategy for the United States, which is designed to reduce the number of new HIV infections and improve access to care. Previous reports included "HIV Screening and Access to Care: Exploring Barriers and Facilitators to Expanded HIV Testing and HIV Screening" and "Access to Care: Exploring the Impact of Policies on Access to and Provision of HIV Care."
The study was supported by the National Academy of Sciences and the White House Office of National AIDS Policy. The report topic was approved by the Governing Board of the National Research Council. The members of the committee were drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The authors have disclosed no relevant financial relationships.
Institute of Medicine. Published online March 17, 2011.
Source
March 18, 2011 — There is a growing gap between the number of individuals living with HIV and the number of healthcare providers required to meet their needs, according to a new report from the Institute of Medicine entitled "HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care." The report was published online March 17 by the Institute of Medicine's Committee on HIV Screening and Access to Care.
There are believed to be 1.1 million people living with HIV in the United States, and an estimated 21% of them are not aware that they are infected. About 56,000 individuals contract new infections each year. Individuals are also living longer with HIV, further increasing demand for services. However, there are currently more providers retiring from the HIV/AIDS field than there are new providers entering the field.
In 2006, the Centers for Disease Control and Prevention recommended routine HIV testing for individuals between the ages of 13 and 64 years. After those recommendations were issued, state health departments and other organizations received additional financial support for screening, but there is some debate as to whether the support is sufficient and whether the programs will be sustainable once outside funding ceases.
Expanded screening is also resulting in the identification of more individuals with HIV, which in turn will lead to a greater demand for service providers to meet their needs.
There are few data on patterns of care for patients with HIV/AIDS, but the committee concluded that most medical care for HIV-positive individuals is provided by primary care physicians, infectious disease specialists, advanced practice registered nurses, and physician assistants. Other needed providers include registered nurses, dentists, pharmacists, and social workers.
HIV-positive patients are well served by primary care providers who can address their other health needs, but there is a lack of adequate training and experience in HIV care among this group. This is especially true in outpatient clinics, which currently provide the majority of current HIV care.
The committee recommends that medical schools and residency training incorporate exposure to outpatient HIV care, and that continuing medical education programs also be developed to address the needs for the growing population of HIV-positive individuals.
In addition to the overall number of providers, it is important to have an adequate racial, ethnic, and cultural diversity among providers because many HIV-positive individuals are racial/ethnic minorities.
Another strategy in addition to increasing providers is to maximize the capacity of the current healthcare system to absorb increased demand. One approach is to implement delivery system strategies such as task shifting, comanagement, and care coordination models.
"Pathway" strategies can expose more trainees to HIV care, and financial and other incentives can be implemented to encourage more providers to enter the field. The committee also highlighted the current Ryan White model of care, in which patients receive a variety of medical and nonmedical services, and which incorporates task shifting. The Institute of Medicine recommends that this sort of integrated delivery system serve as a model for future care systems.
No matter what approach is used, it is imperative that there be an increase in HIV/AIDS care capacity. Each new detection of an HIV infection creates the need to counsel, refer, treat, and monitor an additional patient, at an average annual cost of $19,912.
If service is interrupted, patients suffer and become less productive, and the likelihood of new transmissions rises.
The report is the third and final in a series examining policy and capacity issues related to carrying out the National HIV/AIDS Strategy for the United States, which is designed to reduce the number of new HIV infections and improve access to care. Previous reports included "HIV Screening and Access to Care: Exploring Barriers and Facilitators to Expanded HIV Testing and HIV Screening" and "Access to Care: Exploring the Impact of Policies on Access to and Provision of HIV Care."
The study was supported by the National Academy of Sciences and the White House Office of National AIDS Policy. The report topic was approved by the Governing Board of the National Research Council. The members of the committee were drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The authors have disclosed no relevant financial relationships.
Institute of Medicine. Published online March 17, 2011.
Source
Report Highlights Shortage of HIV Care Providers in U.S.
Gap widening between number infected and those trained to treat these patients, experts say
Posted: March 18, 2011
FRIDAY, March 18 (HealthDay News) -- The U.S. medical system is ill-prepared to cope with the number of Americans now infected with HIV, a new report suggests.
Specifically, too few health care providers are adequately trained and experienced in providing the care these patients need, the report authors indicate.
The observation is outlined in the third and final report of a series focused on the state of HIV health care in the United States that was put together by the Institute of Medicine (IOM), an independent, nonprofit organization.
"There will be numerous challenges as the nation begins implementing the [Obama administration's] new National HIV/AIDS Strategy," Paul Cleary, dean of the Yale School of Public Health in New Haven, Conn., said in a news release from the National Academy of Sciences.
Cleary, chair of the committee that wrote the series, said that the reports set out to articulate "many practical suggestions from the research literature and experts about how to address and overcome the obstacles to a more effective and efficient HIV/AIDS strategy."
Given the widening gap between HIV-care supply and demand, the report emphasizes the need for health-care provider flexibility, in order to overcome the constraints under which many providers labor.
For example, the report authors say that collaboration across facilities should be encouraged, in order to better allocate and share sparse resources among multiple providers. However, at times such task-sharing may run afoul of state regulations, which can limit the ability of providers to share caseload responsibilities.
Released online March 17, the report -- entitled HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care -- also highlights the need for more training to provide caregivers with greater exposure to the demands of HIV care.
Two earlier reports in the series examined barriers to expanded HIV testing and the impact of policies on access and provision of care. The aim of the series is to facilitate the goals of the new National HIV/AIDS Strategy, which the White House has described as a roadmap for policy makers and the public.
That strategy aims to bring about a drop in the rate of HIV infection while at the same boosting access to care among those already infected.
The report series as a whole has highlighted a range of problems and issues that need addressing, according to the news release. Those include the lack of a clear federal policy regarding HIV testing, statewide differences regarding how testing is implemented, obstacles to the provision of rapid HIV testing and discrimination against HIV-positive individuals. Current prison practices are also a concern, the authors say.
The series was sponsored by the White House Office of National AIDS Policy.
More information
For more on HIV care, visit the New York State Department of Health AIDS Institute.
Source
Posted: March 18, 2011
FRIDAY, March 18 (HealthDay News) -- The U.S. medical system is ill-prepared to cope with the number of Americans now infected with HIV, a new report suggests.
Specifically, too few health care providers are adequately trained and experienced in providing the care these patients need, the report authors indicate.
The observation is outlined in the third and final report of a series focused on the state of HIV health care in the United States that was put together by the Institute of Medicine (IOM), an independent, nonprofit organization.
"There will be numerous challenges as the nation begins implementing the [Obama administration's] new National HIV/AIDS Strategy," Paul Cleary, dean of the Yale School of Public Health in New Haven, Conn., said in a news release from the National Academy of Sciences.
Cleary, chair of the committee that wrote the series, said that the reports set out to articulate "many practical suggestions from the research literature and experts about how to address and overcome the obstacles to a more effective and efficient HIV/AIDS strategy."
Given the widening gap between HIV-care supply and demand, the report emphasizes the need for health-care provider flexibility, in order to overcome the constraints under which many providers labor.
For example, the report authors say that collaboration across facilities should be encouraged, in order to better allocate and share sparse resources among multiple providers. However, at times such task-sharing may run afoul of state regulations, which can limit the ability of providers to share caseload responsibilities.
Released online March 17, the report -- entitled HIV Screening and Access to Care: Health Care System Capacity for Increased HIV Testing and Provision of Care -- also highlights the need for more training to provide caregivers with greater exposure to the demands of HIV care.
Two earlier reports in the series examined barriers to expanded HIV testing and the impact of policies on access and provision of care. The aim of the series is to facilitate the goals of the new National HIV/AIDS Strategy, which the White House has described as a roadmap for policy makers and the public.
That strategy aims to bring about a drop in the rate of HIV infection while at the same boosting access to care among those already infected.
The report series as a whole has highlighted a range of problems and issues that need addressing, according to the news release. Those include the lack of a clear federal policy regarding HIV testing, statewide differences regarding how testing is implemented, obstacles to the provision of rapid HIV testing and discrimination against HIV-positive individuals. Current prison practices are also a concern, the authors say.
The series was sponsored by the White House Office of National AIDS Policy.
More information
For more on HIV care, visit the New York State Department of Health AIDS Institute.
Source
Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes
European Journal of Internal Medicine
Volume 22, Issue 2 , Pages 187-190, April 2011
Heba S. Selim, Hadia A. Abou-Donia, Hossam A. Taha, Gasser I. El Azab, Ahmed F. Bakry
Received 16 August 2010; received in revised form 28 October 2010; accepted 1 December 2010. published online 18 January 2011
Abstract
Background
Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare.
Methods
Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique.
Results
In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p<0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection.
Conclusion
Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.
Keywords: Hepatitis C, Flare of liver enzyme, Elevated aminotransferases, Occult hepatitis B
Source
Volume 22, Issue 2 , Pages 187-190, April 2011
Heba S. Selim, Hadia A. Abou-Donia, Hossam A. Taha, Gasser I. El Azab, Ahmed F. Bakry
Received 16 August 2010; received in revised form 28 October 2010; accepted 1 December 2010. published online 18 January 2011
Abstract
Background
Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare.
Methods
Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique.
Results
In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p<0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection.
Conclusion
Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.
Keywords: Hepatitis C, Flare of liver enzyme, Elevated aminotransferases, Occult hepatitis B
Source
Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients
HIV Medicine
Early View (Articles online in advance of print)
P Trimoulet 1,†, C Belzunce 2,†, M Faure 1, L Wittkop 3, S Reigadas 1, M Dupon 2, J-M Ragnaud 2, H Fleury 1, D Neau 2
Article first published online: 16 MAR 2011
DOI: 10.1111/j.1468-1293.2011.00913.x
© 2011 British HIV Association
Author Information
1 Virology Laboratory, Bordeaux University Hospital, Bordeaux, France
2 Department of Tropical and Infectious Diseases, Bordeaux University Hospital, Bordeaux, France
3 INSERM U897 Center of Epidemiology and Biostatistics, ISPED Bordeaux School of Public Health, University of Bordeaux 2, Bordeaux, France
* Correspondence: Dr Pascale Trimoulet, Laboratoire de Virologie, Hôpital Pellegrin Tripode, Place Amélie Raba-Léon, EA 2968, Bordeaux University Hospital, Bordeaux Cedex 33076, France. Tel: +33 5 56 79 55 10; fax: +33 5 56 79 56 73; e-mail: pascale.trimoulet@chu-bordeaux.fr
†† The first two authors contributed equally to the study
Abstract
Keywords: HCV protease inhibitor resistance; HCV protease; HIV/HCV-coinfected patients
Objectives
Data on the natural selection of isolates harbouring mutations within the NS3 protease, conferring resistance to hepatitis C virus (HCV) protease inhibitors (PIs), are limited for HIV/HCV-coinfected patients. The aim of this study was to describe the natural prevalence of mutations conferring resistance to HCV PIs in HIV/HCV-coinfected patients compared with HCV-monoinfected patients.
Methods
The natural prevalences of HCV PI resistance mutations in 120 sequences from HIV/HCV-coinfected patients (58 genotype 1a, 18 genotype 1b and 44 genotype 4) and 501 sequences from HCV-monoinfected patients (476 genotype 1 and 25 genotype 4), retrieved from GenBank as a control group, were compared.
Results
Of 76 sequences from HIV/HCV genotype 1-coinfected patients, six (7.9%) showed amino acid substitutions associated with HCV PI resistance (V36L, n=1; V36M, n=2; T54S, n=2; R155K, n=1). In 31 of 476 (6.5%) HCV genotype 1 sequences retrieved from the GenBank database, HCV PI resistance mutations were found. The difference was not statistically significant (P=0.6). All of the sequences from HIV/HCV genotype 4-coinfected patients and those retrieved from the GenBank database had amino acid changes at position 36 (V36L).
Conclusion
Our study suggests that the natural prevalence of strains resistant to HCV PIs does not differ between HCV-monoinfected and HIV/HCV-coinfected patients. Further studies on larger cohorts are needed to confirm these findings and to evaluate the impact of these mutations in clinical practice.
Source
Early View (Articles online in advance of print)
P Trimoulet 1,†, C Belzunce 2,†, M Faure 1, L Wittkop 3, S Reigadas 1, M Dupon 2, J-M Ragnaud 2, H Fleury 1, D Neau 2
Article first published online: 16 MAR 2011
DOI: 10.1111/j.1468-1293.2011.00913.x
© 2011 British HIV Association
Author Information
1 Virology Laboratory, Bordeaux University Hospital, Bordeaux, France
2 Department of Tropical and Infectious Diseases, Bordeaux University Hospital, Bordeaux, France
3 INSERM U897 Center of Epidemiology and Biostatistics, ISPED Bordeaux School of Public Health, University of Bordeaux 2, Bordeaux, France
* Correspondence: Dr Pascale Trimoulet, Laboratoire de Virologie, Hôpital Pellegrin Tripode, Place Amélie Raba-Léon, EA 2968, Bordeaux University Hospital, Bordeaux Cedex 33076, France. Tel: +33 5 56 79 55 10; fax: +33 5 56 79 56 73; e-mail: pascale.trimoulet@chu-bordeaux.fr
†† The first two authors contributed equally to the study
Abstract
Keywords: HCV protease inhibitor resistance; HCV protease; HIV/HCV-coinfected patients
Objectives
Data on the natural selection of isolates harbouring mutations within the NS3 protease, conferring resistance to hepatitis C virus (HCV) protease inhibitors (PIs), are limited for HIV/HCV-coinfected patients. The aim of this study was to describe the natural prevalence of mutations conferring resistance to HCV PIs in HIV/HCV-coinfected patients compared with HCV-monoinfected patients.
Methods
The natural prevalences of HCV PI resistance mutations in 120 sequences from HIV/HCV-coinfected patients (58 genotype 1a, 18 genotype 1b and 44 genotype 4) and 501 sequences from HCV-monoinfected patients (476 genotype 1 and 25 genotype 4), retrieved from GenBank as a control group, were compared.
Results
Of 76 sequences from HIV/HCV genotype 1-coinfected patients, six (7.9%) showed amino acid substitutions associated with HCV PI resistance (V36L, n=1; V36M, n=2; T54S, n=2; R155K, n=1). In 31 of 476 (6.5%) HCV genotype 1 sequences retrieved from the GenBank database, HCV PI resistance mutations were found. The difference was not statistically significant (P=0.6). All of the sequences from HIV/HCV genotype 4-coinfected patients and those retrieved from the GenBank database had amino acid changes at position 36 (V36L).
Conclusion
Our study suggests that the natural prevalence of strains resistant to HCV PIs does not differ between HCV-monoinfected and HIV/HCV-coinfected patients. Further studies on larger cohorts are needed to confirm these findings and to evaluate the impact of these mutations in clinical practice.
Source
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