54th Annual Meeting of
The American Association for
the Study of Liver Diseases
October 24, 28- 2003
Boston, Massachusetts
Page Nine
Dosing
Fibrosis and Cirrhosis
Immune Responses
Adherence
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Ribavirin Dosage Significantly Affects Virological Response Rates in HCV
Patients Treated with Interferon/Ribavirin
The influence of absolute dose and dose in mg per kg body weight of
ribavirin on sustained virologic response (SVR) in interferon-based
combination treatment of chronic hepatitis C as well as the influence of
dose reduction is still controversial. In this study, investigators address this problem by reanalyzing data of 343 previously untreated patients with chronic hepatitis C from a multicenter trial who were treated with Pegasys (interferon alfa-2a) plus ribavirin and amantadine or interferon alfa-2a plus ribavirin (Berg et al, Hepatology 2003, 37, 1359-1367) and completed therapy.
The researchers used a multivariate approach to account for correlations of
the dose of ribavirin with body weight and body mass index (BMI) and known
predictor variables from this data set which are low baseline HCV RNA, high
platelet counts, high pretreatment ALT, and low γ glutamyl transpeptidase (GGT)
as well as HCV genotype non-1. Because per protocol, dosage of ribavirin was weight-adjusted (1000 mg for body weight below 75 kg and 1200 mg for body weight 75 kg or more) and body weight was positively correlated with GGT and negatively correlated with platelet counts, respectively, the investigators used a stratification with respect to genotype (GT 1 vs. non-1), GGT, and platelet counts in the analysis of ribavirin dose.
When comparing body weight, BMI, the absolute intention to treat (ITT)
ribavirin dose as well as the ITT dose of ribavirin measured in mg per kg
body weight and the respective ribavirin doses at the end of treatment (EOT),
a significant association with SVR was found for the EOT ribavirin dosage
(mg per kg body weight) and BMI (p=1.8% and p=3.0%, respectively).
For predicting SVR, a weight-based ribavirin dosage threshold of 13.75 mg/kg
was calculated using receiver operating characteristics (ROC) curves. The
SVR rate was 66% (112/169) in patients with a ribarivin dose of more than
13.75 mg/kg as compared with 46% (79/172) in patients receiving equal or
less than 13.75 mg/kg ribavirin at EOT. In conclusion, the analysis of ribavirin dosage motivates new considerations of weight-adjustments of the ribavirin dosage to further increase SVR in HCV-infected patients treated with combination therapy. 10/27/03
Reference
Weight-based Dosing of PEG-Intron or Double the Dose Plus Ribavirin for
Naïve Patients and Double Dose PEG-Intron Plus Ribavirin for Nonresponders
and Relapsers Pegylated interferon (Peg) plus ribavirin (RBV) is the mainstay of chronic hepatitis C treatment. However, an upper limit in terms of safety and efficacy for dosing with Peg has not been evaluated. In the current study, researchers studied a group of naïve patients using either conventional weight-based dosing of PEG-Intron (Peg); (1.5 μg/kg) or double the dose (3.0 μg/kg) plus RBV 13+ 2mg/kg/day for 48 weeks. Genotype 1 patients were randomized 1:1 and to receive medication accordingly in unblinded fashion, with intent to enroll a total of 1,100 naïve patients N, an additional 300 previous NR or R to any type of interferon + RBV in a non randomized arm, using only the 3.0 μg/kg Peg dose. Values for HCV RNA at week 12 were compared to those obtained at baseline. Study Results To date, 573 patients 306 N, 193 NR, 74 R have enrolled in the study. 175 patients 106 N, 48 NR, 21 R have reached week 12. HCV RNA results at week 12 are shown in the table below. Treatment was well tolerated in most patients. Dose reductions were required in 20% of N 1.5μg/kg Peg and 29% of N 3.0μg/kg Peg patients. Side effects were equivalent between the two groups as shown in the table below. Serious adverse events (SAE’s) were less than 5% and equally observed in both arms of the N patients. None were directly attributed to study drug. There were 25 patients in the wk 12 analysis that discontinued therapy. The reasons these patients were discontinued after reaching wk 12 were side effects (36%), + HCV RNA (32%). It is interesting to note that 40% of the patients that were discontinued had > 2 log drop or negative HCV-RNA at week 12 and a positive HCV RNA was not a reason for their discontinuation. Conclusions 3.0μg/kg Peg dosing does not appear to improve 12 wk viral response, but we await 24 wk results and sustained viral response rates. Of interest, increased side effects as a result of doubling the interferon dose were not observed. More data are needed to verify the long-term efficacy and safety of this dosing regimen for patients with chronic hepatitis C. Table 1
10/27/03
Reference
In Nonresponders at Week 48, High Dose PEG-Intron (3.0
mcg/kg/wk) Plus Ribavirin Produces Similar Viral Clearance Rate as Standard
Dose (1.5 mcg/kg/wk): The Renew Trial Ten percent of interferon/ribavirin nonresponders treated with conventional doses of peginterferon + ribavirin have a sustained virological response. The current trial was designed to see if better results could be achieved by retreating with higher doses of PEG-Intron (peginterferon alfa-2b /PEG2b) + weight-based ribavirin. The objectives were to compare the efficacy, safety and tolerability of three different doses of PEG2b + weight-based ribavirin among interferon/ribavirin nonresponders. Patients were randomized to 1 yr of treatment with PEG2b 0.5, 1.5 or 3.0 mcg/kg/wk, plus ribavirin 12-15 mg/kg/day. Treatment assignment was stratified for sex, race, HCV genotype and histologic fibrosis. Treatment was stopped at 24 wk if PCR(+). Doses were reduced by 33% for toxicity; growth factors were not allowed. Study ResultsPatients: Enrollment took place between February 2001 and November 2002, with 963 patients recruited from 100 centers; data forms have been received on 794 thus far. Enrollment was stopped in the low-dose group after FDA approval of higher doses of PEG2b. The study population is 31% female, 16% African-American, 93% genotype 1, and 63% F2/3/4. Efficacy: On-treatment virological response rates were dose-related at 24 wk but less so at 48 wk (see Table below). This was partly due to a higher rate of discontinuation after a satisfactory response at 24 wk on the higher dose. On-treatment response rates were lower among African-Americans and patients with more advanced fibrosis. Tolerability: The rate of dose reduction was 33% on PEG2b 1.5 mcg/kg/wk, vs. 45% on 3.0. Rates of discontinuation were the same for PEG2b 1.5 and 3.0 mcg/kg/wk: 25% vs. 24% overall, and 13% vs. 14% for adverse events. The frequencies of subjective adverse events were similar between the two groups. Some degree of neutropenia was observed in 27% on 1.5 mcg/kg/wk, vs. 32% on 3.0; however, only 14 patients in the study discontinued treatment for neutropenia overall. Conclusions
11/17/03
Reference
Patients with Chronic Hepatitis C and Normal ALT Levels Show Impaired
Quality of Life But Significantly Lower Liver Inflammation and Fibrosis
Progression Compared to Patients with Elevated ALT
A
significant proportion of the patients chronically infected with the
hepatitis C virus (HCV) have persistently normal serum ALT levels. Previous
studies suggested a lower risk for these patients to progress to liver
cirrhosis and its sequelae. Comprehensive data on the quality of life in
these patients are currently not available. In the present study, 45 patients with chronic hepatitis C and persistently normal aminotransferases, defined by normal serum ALT levels on at least three occasions during a 6 months period, 70 patients with chronic hepatitis C and elevated aminotransferases and 50 healthy subjects without any evidence of a chronic disease were enrolled. Patients with chronic hepatitis C and persistently normal ALT levels and healthy subjects were matched regarding age and gender. For patients with chronic hepatitis C several biochemical (e. g. ALT, AST, ferritine) and virological tests (e. g. HCV RNA serum concentration, HCV genotype) were performed. In 27/45 patients with persistently normal ALT levels and in 68/70 patients with elevated ALT levels liver inflammation and fibrosis were histologically evaluated by the HAI scoring system. Emotional and psychological states were measured by a German adapted and validated “Profile of Mood States scale,” which measures 4 factor scores for depression, fatigue, vigor, and anger.
Furthermore,
quality of life was assessed by the “Everyday Life” questionnaire (EDLQ), a
German validated questionnaire related to the SF-36 Health Survey.
Statistical significance was assessed by Fisher exact test and Mann-Whitney
U test. Study Results In patients with chronic hepatitis C and persistently normal ALT levels duration of infection was significantly longer than in patients with chronic hepatitis C and elevated ALT levels (176.9 vs. 131.2 months; p=.016). However, the portion of male patients (36% vs. 66%; p=.001) and the number of patients with hepatitis B infection in the past (27 vs. 51%; p=.01) were significantly lower in the group of patients with persistently normal ALT levels. Liver histology showed significantly less inflammation (3.88 vs. 4.89; p<.02) in patients with persistently normal ALT levels compared with those with elevated ALT levels. Calculation of the liver fibrosis progression rate per year as the ratio between the liver fibrosis stage and the estimated duration of infection in years revealed a significant lower fibrosis progression rate for patients with persistently normal ALT levels (0.2 vs. 0.5; p=.002). However, current stage of liver fibrosis was similar in both groups. I In patients with persistently normal ALT levels the “Profile of Mood States scale” showed a reduction in quality of life in all 4 items compared with the matched control group with significant differences for depression (p=.006) and anger (p=.007). In the EDLQ significant differences were also found for the items body (p=.04), relationship to partner (p=.01), self-confidence (p=.04), and zest for life (p=.01) between patients with chronic hepatitis C and persistently normal ALT levels and healthy subjects. No significant differences were observed for any item in POMS or EDLQ between patients with chronic hepatitis C and persistently normal ALT levels and patients with elevated ALT levels and chronic hepatitis C. Conclusions
Patients with chronic
hepatitis C and persistently normal ALT levels show significantly lower
liver inflammation and fibrosis progression rate per year compared with
patients with elevated ALT levels. Quality of life assessments show a
significant impairment of health-related quality of life in patients with
chronic hepatitis C compared with healthy controls, however, no differences
between chronically HCV-infected patients with persistently normal or
elevated aminotransferase levels.
Reference
Race, Insulin Resistance, Visceral Adiposity and Hepatic
Steatosis in Genotype 1 HCV Patients Additionally, recent data suggest an association between body mass index (BMI) and the degree of hepatic steatosis and fibrosis in HCV infection. Insulin resistance (IR) is a key factor in the pathogenesis of NASH and may play a similar role in the steatosis seen in chronic hepatitis C The objectives of the current study were to compare the prevalence and severity of hepatic steatosis, visceral adiposity, IR and their relation to disease severity in African Americans (AA) vs Caucasians (CA) with genotype 1 HCV infection being considered for anti-viral therapy. Virahep-C is a prospective study of response rates to peginterferon and ribavirin in treatment-naïve AA vs CA patients with genotype 1 HCV infection. All patients underwent liver biopsy within 18 months of enrollment. Biopsies were read blindly by a central pathologist and scored for inflammation and fibrosis using the histologic activity index [HAI] and for steatosis (0-4+) and features of steatohepatitis (zone 3 ballooning, zone 3 perisinusoidal fibrosis and Mallory bodies). Waist circumference and waist-hip ratio were measured as determinants of visceral adiposity. IR was determined using fasting glucose and insulin levels based upon the HOMA method. Results: To date, 177 patients have been enrolled and 166 have complete liver biopsy information (75 AA and 91 CA). Steatosis was present in 66 patients (40%) with similar rates among AA (39%) and CA (41% CA). Grades of steatosis were also similar between AA and CA: 1+ (38% vs 41%), 2+ (45% vs 27%), 3+ (14% vs 27%) and 4+ (3% vs 5%) (p = ns). Patients with steatosis had significantly higher values for HOMA index (4.0 vs 2.4, <0.01), total HAI score (10.3 vs 8.7, p<0.0001), HAI inflammation score (8.5 vs 7.1, <0.0001), waist circumference (40.2 in vs 36.5 inches, p<0.0001) and BMI (30.6 vs 26.7, p<0.0001). There were no significant differences in amount of alcohol consumption between patients with and without steatosis. Spearman’s non-parametric correlations were performed to assess associations between the ordinal variables (scores for fat , steatohepatitis [ballooning degeneration + perisinusoidal fibrosis + Mallory bodies], total HAI, inflammation and fibrosis) and one continuous variable (HOMA index). Waist circumference, waist-hip ratio, BMI, HOMA index, total HAI, HAI inflammation and HAI fibrosis all correlated with both the fat score and steatohepatitis score (p<0.01). Median HOMA index levels were significantly greater among AA than CA (3.1 vs 2.7, p<0.05), but step-wise logistic regression showed that race was not an independent predictor of steatosis after controlling for ALT, AST, waist circumference, waist-hip ratio, BMI and HOMA index. ConclusionsIn patients with chronic hepatitis C and genotype 1, steatosis and steatohepatitis correlate strongly with the presence of insulin resistance and visceral adiposity. Race is not an independent predictor of steatosis after controlling for other factors. 10/29/03
Reference
PEG-Intron Plus Ribavirin Improves Histology and Fibrosis in Nonresponders to Conventional Interferon and Ribavirin Virologic non-responders to the combination of standard Interferon alfa-2b and Ribavirin could respond histologically to re-treatment by a combination of Pegylated Interferon Alfa-2b and Ribavirin. The aim of the present study was to determine whether histological improvement correlates with different dosages of PEG-Intron (Pegylated Interferon alfa-2b (Peg IFN) and Ribavirin; and to identify which component of the Histological Activity Index (HAI) changes the most with a variation in the Peg IFN and Ribavirin dosage. 93 patients who were virologic non-responders to Rebetron were included in this study. The mean age was 48.5 ± 7.33 years. 134 patients (69.4%) were males. 130 patients (67.4%) were Caucasian, 29 (15%) Hispanic and 34 (17.6%) other. 78.2% have genotype 1. 59 patients finished 48 weeks of treatment and had a pre and post treatment biopsy. A single pathologist blinded to clinical findings and pre/post biopsy status scored biopsies using the modified Knodell scoring system. Of the 59, 28 (47.5%) patients were randomized to study arm 1 and received 1.5 mcg/kg/week of Peg IFN alfa-2b and 800 mg qd of Ribavirin, while 31 (52.5%) patients were randomized to study arm 2 and received 1.0 mcg/kg/week of Peg IFN alfa-2b and 1000-1200 mg qd of Ribavirin. Study ResultsRegardless of study arm, and even though there was no difference in the sustained viral response (SVR) between both groups, there was an overall improvement in HAI from 6.10 ± 2.04 to 2.14 ± 1.37 (P < 0.01) and in fibrosis from 2.51 ± 1.18 to 2.14 ± 1.37 (P < 0.01). However, patients in study arm 1 had significant improvement in HAI. This improvement was attributed to the significant decrease in lobular activity (see table below). Conclusions 1) The combination of PEG-Intron and ribavirin improves Histological Activity Index (HAI) and fibrosis in patients with chronic hepatitis C who failed to respond virologically to standard interferon and ribavirin; 2) This improvement is significant in patients receiving a high dose of PEG-Intron and a low dose of ribavirin; and 3) The histological improvement is mainly due to decrease in lobular activity.
11/07/03
Reference
Treatment with Pirfenidone for One Year Produces a
Significant Reduction in Necroinflammation and Steatosis in Patients with
Liver Cirrhosis Pirfenidone (PFD) is an orally bioavailable pyridone derivative that affects a variety of cytokines, including inhibition of TGF-beta, TNF-alpha, PDGF, and EGF. PFD has been shown in clinical studies to improve physiologic parameters in patients with pulmonary fibrosis.
This Mexican
research group has previously shown that PFD decreased hepatic fibrosis in
two different rat models of cirrhosis (J of Hepatology 37: 797-805,
2002). The objective of this pilot clinical study was to evaluate the safety
and preliminary activity of PFD in patients with cirrhosis of varying
etiologies. All patients had histologic and/or clinical evidence of cirrhosis. PFD was given orally at a dose of 400 mg TID for 12 months. Physical examination and labs including ALT, AST, bilirubin, albumin and prothrombin time, and platelet count were assessed at baseline and on monthly basis. HCV RNA levels were
measured in patients with chronic hepatitis C (Cobas Amplicor HCV Monitor
v2.0). Liver biopsies were obtained at baseline and after 12 months of
treatment and were read independently by two hepatopathologists who were
blinded to the biopsy sequence. Modified Histological Activity (HAI) Index
of Knodell and Ishak fibrosis stage were used to assess changes in
necroinflammatory scores and fibrosis stage, respectively. Change in
steatosis was also assessed. Study Results A total of 26 patients with cirrhosis due to hepatitis C (15), ethanol (8), amyloidosis (1), autoimmune disease (1) and Budd-Chiari syndrome (1) were included. The mean age was 57 years (range, 29-75) with 13 males. Liver biopsies at end of therapy showed a 2-point or greater reduction in the HAI necroinflammatory score in 41% of the patients.
Steatosis
decreased in 33% of the patients, was unchanged in 42% and worsened in 25%.
While there was no significant reduction in the Ishak fibrosis stage,
improvement in interstitial fibrosis was noted. Evidence of cell
regeneration was seen in some patients. HCV RNA levels were measured in 15 patients with chronic hepatitis C. At 6 months, 9 patients had a decrease in viral load, 2 patients remained unchanged and 4 patients displayed an increase in viral load compared to baseline. No patient had a sustained virologic response. 4 out of 15 (27%) HCV patients had normalization of ALT, 7 out of 15 (47%) had decreased ALT values, 1 did not change (7%) and 3 patients showed a modest increase in ALT (20%).
PFD was well
tolerated with the predominant drug-related adverse events being nausea,
photosensitivity rash, and itching occurring in 15% of the patients and
which improved after 2 to 3 months of therapy. Conclusions In this pilot study, treatment of cirrhotic patients with pirfenidone for one year was well tolerated. A significant reduction in necro-inflammation (≥ 2-point reduction in HAI grade) and steatosis was observed in a substantial proportion of patients. A subset of patients with chronic HCV infection showed on-treatment reduction in HCV RNA levels. Longer treatment duration or a less cirrhotic patient population may be needed to demonstrate effects on fibrosis. These data support conducting clinical studies to evaluate a potential role of PFD in the treatment of steatosis, or in combination therapy for chronic hepatitis C. This work was supported by Grants of Marnac, Inc and InterMune, Inc. 11/19/03
Reference
HCV-specific Immune Responses at Baseline Do Not
Predict a Favorable Retreatment Outcome in Patients with Advanced Disease
The HALT-C study is a randomized, controlled clinical trial of patients with chronic hepatitis C and advanced liver fibrosis who previously failed interferon therapy. Subjects in the lead-in phase of the study were treated with Pegasys (peg-interferon alfa 2a) and ribavirin for 20 weeks; those with undetectable HCV RNA at that time point were considered to be week 20 (W20) on-treatment responders and completed 48 weeks of therapy and an additional 24 weeks of follow-up.
The
researchers hypothesized that vigorous immune responses at baseline would
favor virologic response to therapy and higher rates of sustained virologic
response (SVR). HCV-specific lympho-proliferative (LP) responses, neutralizing antibody (NA) responses, HCV quasi-species (QS) genetic diversity and complexity, intrahepatic cytolytic T cell (CTL) function, as well as quantification of intrahepatic viral genomes and replicative RNA were analyzed in specimens obtained prior to initiation of treatment (baseline). CD4+ and CD8+ T cell responses to HCV antigens were tested using LP and CTL assays, respectively. Presence of NA were measured using VSV pseudotyped viruses expressing HCV chimeric envelope glycoproteins E1 or E2.
HCV QS were
evaluated using clonal frequency analysis of the HCV E2 HVR1 gene. Serum HCV
RNA and intrahepatic viral genomes were quantified using the Roche Amplicor
Monitor assay v. 2.0, while negative strand HCV RNA was quantified by in
situ hybridization. Study Results The W20 response rate was 37% and the SVR rate was 18% in this cohort. The rates of HCV-specific LP, NA and CTL responses were 23%, 20% and 22%. Surprisingly, LP and NA responses were found less commonly at baseline in those who developed SVR. Specifically, positive LP responses to any HCV antigen (SI>3.0) were infrequently found in subjects who became SVRs (10.3%) compared to those classified as nonresponders or relapsers at Week 60 (W60) (28.6%, p=0.046). Similarly, subjects with baseline serum NA responses to either E1 and/or E2 (at 1:50 or 1:20) were less likely to achieve W20 virologic response (p=0.057) or SVR (p=0.023). Moreover, subjects with SVR displayed lower levels of HCV complexity (4.0) and diversity at baseline, implying decreased immune pressure on viral evolution, compared to those who were non-responder. No differences in baseline intrahepatic CTL activity, HCV RNA level, or replication were noted between those who developed W20 response or SVR compared to non-responders.
Factors more
strongly associated with response were non-genotype 1, non-African American
race, absence of previous ribavirin use, and absence of cirrhosis. Conclusions Patients with chronic HCV infection and advanced liver fibrosis who are refractory to treatment infrequently exhibit HCV-specific immune responses. However, subjects with immune responses detected prior to retreatment with peg-interferon-alfa 2a and ribavirin are less likely to achieve on-treatment virologic response or sustained eradication of HCV infection. Thus, the presence of HCV-specific responses per se does not necessarily portend a favorable re-treatment outcome in subjects with advanced disease. 11/21/03
Reference
Viral Diversity and Immune Responses to HCV Do Not
Correlate with Liver Injury at a Single Time Point The relationship of host immune and viral factors to the outcome of liver disease due to hepatitis C virus (HCV) is poorly understood. Previous studies have generally focused on individual components of the immune response to HCV, often in relatively small numbers of patients.
Researchers
in the HALT-C trial characterized these relationships in baseline data
obtained from 300 subjects with advanced liver fibrosis (Ishak > 3) upon
entry into the study. The goal of the study was to examine multiple factors in individual patients. Data are available from 197, 329, 220, and 75 patients enrolled in the CTL, LP, NA and QS studies, respectively. CTL, LP, NA and QS profiles were correlated with baseline clinical characteristics including ALT, Ishak score (inflammation and fibrosis), steatosis, use of alcohol, iron, BMI, race, age, sex, previous treatment with ribavirin, serum HCV RNA level, and genotype. Study Results HCV-specific LP, NA and CTL responses were detected in 23%, 20% and 22% of subjects tested, respectively. Patients with positive CTL responses at baseline had significantly higher ALT values than patients without CTL responses (126+92 vs. 96+62, respectively, p=.019) but there was no relationship of CTL response to baseline inflammation, fibrosis or serum HCV RNA in this large cohort.
Patients
with positive LP responses were less likely to have cirrhosis (p=.026) and
there was a trend toward lower HCV RNA levels (p=.09). As with CTL, no
relationship to baseline inflammation or fibrosis score was found. Baseline
NA and QS results did not correlate significantly with any baseline clinical
parameters. Conclusions In this selected population of patients with chronic hepatitis C, immune responses to HCV and viral diversity showed little relationship to histologic findings at a single time point. However, the association between HCV-specific intrahepatic CTL responses and higher serum ALT supports a model of immune-mediated liver injury. Further studies will determine the role of these immune responses in the progression of liver disease over time in this cohort. 11/21/03
Reference
HCV-specific Immune Responses at Baseline Do Not Predict
a Favorable Retreatment Outcome in Patients with Advanced Disease The HALT-C study is a randomized, controlled clinical trial of patients with chronic hepatitis C and advanced liver fibrosis who previously failed interferon therapy. Subjects in the lead-in phase of the study were treated with Pegasys (peg-interferon alfa 2a) and ribavirin for 20 weeks; those with undetectable HCV RNA at that time point were considered to be week 20 (W20) on-treatment responders and completed 48 weeks of therapy and an additional 24 weeks of follow-up.
The
researchers hypothesized that vigorous immune responses at baseline would
favor virologic response to therapy and higher rates of sustained virologic
response (SVR). HCV-specific lympho-proliferative (LP) responses, neutralizing antibody (NA) responses, HCV quasi-species (QS) genetic diversity and complexity, intrahepatic cytolytic T cell (CTL) function, as well as quantification of intrahepatic viral genomes and replicative RNA were analyzed in specimens obtained prior to initiation of treatment (baseline). CD4+ and CD8+ T cell responses to HCV antigens were tested using LP and CTL assays, respectively. Presence of NA were measured using VSV pseudotyped viruses expressing HCV chimeric envelope glycoproteins E1 or E2.
HCV QS were
evaluated using clonal frequency analysis of the HCV E2 HVR1 gene. Serum HCV
RNA and intrahepatic viral genomes were quantified using the Roche Amplicor
Monitor assay v. 2.0, while negative strand HCV RNA was quantified by in
situ hybridization. Study Results The W20 response rate was 37% and the SVR rate was 18% in this cohort. The rates of HCV-specific LP, NA and CTL responses were 23%, 20% and 22%. Surprisingly, LP and NA responses were found less commonly at baseline in those who developed SVR. Specifically, positive LP responses to any HCV antigen (SI>3.0) were infrequently found in subjects who became SVRs (10.3%) compared to those classified as nonresponders or relapsers at Week 60 (W60) (28.6%, p=0.046). Similarly, subjects with baseline serum NA responses to either E1 and/or E2 (at 1:50 or 1:20) were less likely to achieve W20 virologic response (p=0.057) or SVR (p=0.023). Moreover, subjects with SVR displayed lower levels of HCV complexity (4.0) and diversity at baseline, implying decreased immune pressure on viral evolution, compared to those who were non-responder. No differences in baseline intrahepatic CTL activity, HCV RNA level, or replication were noted between those who developed W20 response or SVR compared to non-responders.
Factors more
strongly associated with response were non-genotype 1, non-African American
race, absence of previous ribavirin use, and absence of cirrhosis. Conclusions Patients with chronic HCV infection and advanced liver fibrosis who are refractory to treatment infrequently exhibit HCV-specific immune responses. However, subjects with immune responses detected prior to retreatment with peg-interferon-alfa 2a and ribavirin are less likely to achieve on-treatment virologic response or sustained eradication of HCV infection. Thus, the presence of HCV-specific responses per se does not necessarily portend a favorable re-treatment outcome in subjects with advanced disease. 11/21/03
Reference
As HAART Therapy Prolongs Survival, More HIV-HCV Coinfected
Individuals May Experience Morbidity and Death from Progressive Liver
Disease Since the introduction of HAART, hepatitis C (HCV) has emerged as the leading cause of non-AIDS mortality. The natural history of co-infection remains controversial with varying estimates of liver-related mortality. Improved HAART-related survival and the rapid progression of HCV in HIV co-infection may account for increasing liver deaths. The aim of the current study was to predict the natural history of hepatic fibrosis in co-infection and to examine the effect of risk factors and HIV survival. AIDS-related mortality was based on a Weibull proportional hazards survival model developed from 12,574 HIV-infected patients starting HAART (Egger Lancet 2002). Weibull model covariates included age <50, injection drug use (IDU), CDC stage A/B versus C, CD4 counts (<50, 50-100, 100-199, 200-349, >350) and HIV RNA<100,000. For hepatitis C, the likelihood of developing Metavir fibrosis stages F1, F2, F3 or F4 over time applied Cox proportional hazards models derived from liver biopsies in 2313 untreated mono-infected patients with age, gender, alcohol consumption (>50 gm/day), injection drug use, and Metavir inflammation A2 or A3 as covariates. Based on a meta-analysis (Graham Clin Infect Dis 2001), these fibrosis progression rates were modified to reflect the 2.07 relative risk of progression to cirrhosis and 6.14 relative risk of compensated cirrhosis progression to decompensated cirrhosis with HIV co-infection versus mono-infection. These Weibull and Cox models and recent UNOS, SEER and NIH data were used to modify a previously published computer cohort simulation (Wong JAMA 1998) to develop a fibrosis-based Markov model of co-infection to project future health outcomes. Study ResultsWhen compared to Puoti (JAIDS 2000), the model predicted 14% of deaths due to liver disease compared to the reported 12±4%. For Soto (J Hep 1997), the model predicted a 9% incidence of cirrhosis versus the observed 12±6%. For Grueb (Lancet 2000), the model predicted 11% of deaths from liver disease versus the observed 9±6%, and the model predicted 10% progression to AIDS versus the observed 12±3%. If the follow-up for the Grueb study were extended from 2 to 5 years, the model predicted 30% progression to AIDS and 25% cumulative incidence of cirrhosis. Life expectancy was projected to be 11.5 years and 5.8 quality-adjusted life years. To illustrate the effect of enhanced HIV survival on the cumulative incidence of cirrhosis and the proportion of deaths due to liver disease over time, the table below shows results for a cohort of co-infected 35 year-olds with CD4 count >200 and F2 fibrosis.
For individuals with limited survival as might occur with pre-HAART (e.g., 5 years), the likelihood of liver-related mortality was small. With HAART, projected life expectancy was 14 years and 7 quality-adjusted life years, compared to 9 years pre-HAART. Lifetime direct medical costs excluding antiviral HCV treatment were $279,000.
To examine
the effect of varying individual covariates, the projected 5-year incidence
of cirrhosis (base-case 6% for 35 year-olds) was 2% for 25 year-olds, 18%
for 45 year-olds, 7% for IDU and 4% for non-IDU, 8% for men, 4% for women,
15% for >50 gm alcohol daily, and 2% for CD4 <50. Conclusion Our fibrosis-based Markov model predictions matched observed co-infected HCV outcomes well. The model suggests rapid fibrosis progression. As HAART therapy prolongs survival, increasing proportions of co-infected individuals may experience morbidity and mortality from progressive liver disease. 11/07/03
Reference
Adherence Rates Are Higher and Discontinuation Rates Are Lower in
Academic Centers Compared to Community-based Centers PEG-intron (peg IFN alfa-2b (1.5 μg/kg/wk) + ribavirin (800 mg/d) is effective and approved for treatment of patients with chronic hepatitis C virus (HCV) infection. The medications have many side effects and frequently require dose reduction or discontinuation. Improved adherence to the medical regimen increases sustained response rates. Data currently available regarding dose reduction, discontinuation and SVR are largely derived from registration trials with experienced hepatologists at academic centers. Anecdotal information suggests that dose reduction and discontinuation rates are higher and SVR lower in community practice, where the majority of HCV patients are treated. Actual dose reduction and discontinuation rates and SVR in community practice are unknown. Researchers sought to determine dose reduction and discontinuation rates and SVR in community practice in comparison with academic centers within the context of a prospective, randomized, controlled, multi-center trial. Patients with chronic HCV (+HCV RNA) were evaluated at academic centers and community sites within the context of a randomized trial comparing Peg IFN α (1.0 μg/kg/wk) + ribavirin (800-1400 mg/d) vs. Peg IFN α (1.5 μg/kg/wk) + ribavirin (800-1400 mg/d). Demographic, serological (ALT), virological (HCV RNA level and genotype) and histological data were obtained. Eligible patients were randomized to one treatment group. Medications were administered for 24 weeks (HCV GT non-1) or 48 weeks (HCV GT 1). Tolerability (dose reduction rates, adverse events and discontinuation rates) through week 24 of therapy was determined and comparisons were made between academic (AC) and community-based centers (CC). Study Results 294 patients have been enrolled, 74 in AC and 220 in CC. 6 patients in AC and 80 in CC remain on therapy within the initial 24 weeks and are not included in this report. Genotype, histology, gender and age profiles were similar in the 2 groups. * designates a significant difference p<0.05. By week 24, 7/68 (10 %) in AC discontinued medications in comparison to 29/140 (21%) in CC*. 3/68 (4%) discontinuations were due to AE/SAE in AC in comparison to 10/140 (7%) in CC. 2/55 (4%) patients in AC who did not discontinue by wk 24 received Peg IFN dose reduction in comparison to 23/108 (21%) in CC*. 14/55 (25%) patients in AC who did not discontinue by week 24 received ribavirin dose reduction in comparison to 31/108 (29%) in CC. At week 24, 34/61 (56%) patients were HCV RNA negative in AC vs. 62/111 (56%) in CC. Conclusions: 1) Discontinuation rates in community-based practice with Peg IFN α 2b + ribavirin are significantly greater than in academic centers. 2) Peg IFN α dose reduction rates (within the context of a clinical trial) are significantly lower in AC vs. CC, whereas ribavirin dose reduction rates are similar between the two groups. 3) 24-week treatment response rates are equal in AC vs. CC if patients can be maintained on therapy for the full 24 week period. 4) Increased efforts to improve medication adherence in CC may optimize SVR for the majority of patients undergoing therapy for HCV. 10/27/03
Reference
Epoetin Alfa Significantly Improves Quality of Life in HCV
Patients Receiving Interferon plus Ribavirin and May Improve Adherence to
Therapy Anemia associated with IFN/RBV therapy can lead to significant impairment in patients' health-related quality of life (HRQL). Interventions that improve HRQL may increase adherence to IFN/RBV. The objectives of the current study were to: (1) Document the HRQL of anemic HCV-infected patients (pts) receiving IFN/RBV and compare it to the HRQL of the general population, as well as pts with other chronic conditions; (2) Quantify the impact of EPO treatment on the HRQL of the study population. HRQL scores were obtained from 185 anemic HCV-infected patients who had been receiving IFN/RBV for 12-14 weeks (study population) (Afdhal et al., DDW 2003). During the double-blind phase (DBP), pts were randomized to receive EPO 40,000 U SC QW or placebo (PL) for 8 weeks. Following the DBP, both EPO and PL pts were allowed to receive EPO for the 8-week open label phase (OLP). HRQL was assessed at baseline and weeks 9 and 17 using the Short Form-36 Health Survey (SF-36) and the Linear Analog Scale Assessment (LASA). The SF-36 is an accepted and validated tool that measures 8 domains of HRQL, and the LASA measures constructs of energy, activity and overall quality of life. The baseline HRQL scores of the study population were compared with age- and gender-matched data from the general population, as well as with pts with congestive heart failure, diabetes, clinical depression, and untreated chronic HCV infection (SF-36 Health Survey Manual and Interpretation Guide; Bonkovsky et al., Hepatology. 1999). All baseline comparisons were completed using independent sample t-tests. To evaluate the effect of EPO on the HRQL of the study population, the following comparisons were performed: (1) the change in HRQL between the EPO and PL group during the DBP; (2) the within-group change of the EPO and PL groups during the OLP. The between-group comparisons were performed using analysis of covariance, with baseline score as a covariate; the within-group comparisons were analyzed using paired t-tests. Study Results At baseline, the study population had clinically and statistically significantly lower HRQL (P<.001) in all 8 domains of the SF-36 (physical functioning [PF], role physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role emotional [RE], and mental health [MH]) when compared with the general population, as well as with untreated chronic HCV-infected pts. Of note, the VT, BP, and SF domain scores were consistently significantly lower (P<.001) in the study population than in any of the other chronic conditions used for comparison. The EPO group demonstrated statistically significant improvements (P<.001 to P<.033) in the PF, RP, BP, VT, SF, RE, and MH domains of the SF-36 during the DBP. The GH domain did not reach statistical significance. The three LASA scales significantly improved in the EPO group (P<.001). Similar results were demonstrated during the OLP; the PL group that initiated EPO at week 9 experienced statistically significant increases in the PF, RP, GH, VT, SF, RE, and MH domains of the SF-36, as well as all scales of the LASA compared to prior to EPO therapy. Pts who received EPO in the DBP maintained their HRQL improvement in the OLP. The authors conclude, “Anemic HCV-infected pts receiving IFN/RBV therapy suffer from significant impairment in HRQL when compared with the general population and other chronic conditions. “The use of EPO significantly improved HRQL in these pts. These improvements in HRQL related to EPO were large and robust and may positively impact adherence to IFN/RBV therapy.” 11/12/03
Reference
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