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DDW Liver Conference Report
Written by Andrew Talal, MD, MPH, Cornell-Weill Medical Center GI & Hepatitis Clinic
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Review of abstracts presented at American Association for the Study of Liver Disease Section of Digestive Disease Week
TOPICS
HCV TREATMENT IN SELECTED PATIENT SUBGROUPS
--Histological improvement in patients with pegylated interferon alpha 2b plus ribavirin who were previously non-responders to rebetron (interferon+ribavirin)
--The safety, efficacy, and pharmacokinetics of peginterferon alfa-2a (40kD) in children with chronic hepatitis C.
--Pharmacokinetics, pharmacodynamics, and antiviral response in patients with chronic hepatitis C infection on methadone maintenance therapy receiving peginterferon (40kD) alfa-2a (Pegasys).
-- Interferon and interferon plus ribavirin in hepatocellular carcinoma prevention. A prospective study on patients with HCV related cirrhosis.
--Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial in prior monotherapy or combination therapy nonresponders and in combination therapy relapsers: Final Results.
ADVERSE EFFECTS OF HCV AND ANTI-HCV TREATMENT
--Clinical significance of pegylated interferon induced neutropenia; Results from the WIN-R trial.
-- Aggressive psychiatric intervention based on clinical suspicion, not standardized depression scores, increases adherence to pegylated interferon and ribavirin therapy for hepatitis C.
-- Epoetin alfa treatment of anemic HCV-infected patients allows for maintenance of ribavirin dose. Increases hemoglobin levels, and improves quality of life vs. placebo: a randomized, double-blind, multicenter study.
PREDICTORS OF RESPONSE TO INTERFERON-BASED THERAPY
--Steatosis influences the early virologic response rate in patients with chronic hepatitis C infection.
HIV/HCV CO-INFECTION
--The impact of protease inhibitors (PI) on the histologic spectrum of liver disease in HCV-HIV co-infection.
-- The association of hepatitis C virus (HCV)-specific immune responses with liver histology in subjects with HIV/HCV co-infection.
HCV PATHOPHYSIOLOGY
--Viral clearance occurs very early during the natural resolution of transfusion-acquired hepatitis C virus infection.
-- Comparison of hepatitis C virus (HCV)-related liver disease between caucasians (C) and African-Americans (AA): Analysis of HCV in the Virgiinia Department of Corrections (DOC).
HEPATITIS B VIRUS INFECTION
--Adefovir dipivoxil (ADV) results in a consistent and significant improvement in liver histology and clinical status regardless of baseline knodell fibrosis score in patients with HBeAg+ chronic hepatitis B.
--Changes in alanine aminotransferase (ALT) and YMDD mutation profile associated with switching from lamivudine (LAM) to either adefovir dipivoxil (ADV) or combination LAM plus ADV in chronic hepatitis B (CHB) patients with LAM resistance.
--Comparison of Viral Replication Fitness of Wild-Type and Lamivudine Resistant HBV in Patients
-- Safety of Adefovir in HBV: 48 and 109 weeks follow-up
--Tenofovir Treatment in Hepatitis B Monoinfected Patients With Lamivudine-Resistant Virus
--Clevudine: 28-day study of new once daily HBV drug
SELECTED POSTERS
--Early virologic response to interferon and ribavirin treatment in patients co-infected with HCV and HIV.
--Effect of therapy with pegylated interferon-alfa on platelet activation and apoptosis in patients with chronic hepatitis C.
--Non-invasive assessment of fibrosis resolution/progressive in chronic hepatitis C patients who received anti-viral therapy.
--Effect of silybum marianum on serum ALT and well-being in chronic hepatitis C.
--Efficacy of daily interferon in combination with ribavirin in patients with chronic hepatitis C: Final results of a VA multicenter study.
--Efficacy of daily interferon in combination with ribavirin in patients with chronic hepatitis C: Final results of a VA multicenter study.
--Early viral kinetics in chronic hepatitis C virus genotype 4 infection.
In this report, a few standard definitions and abbreviations that are as listed below:
SVR-sustained virologic response
ETR-end of treatment response
RBV-ribavirin
PEG IFN alfa-pegylated interferon alfa,
ALT-alanine aminotransferase
SAE-serious adverse event
AE-adverse event
HCV-hepatitis C virus
HIV-human immunodeficiency virus infection
HBV-hepatitis B virus
HBeAg-hepatitis B E antigen (a marker of active virus production)
Additional comments:
--HCV RNA-Many of the results of HCV RNA are presented in terms of "log10 reduction". This refers to a decrease of 10-fold (i.e. a three log decrease would be from 1,000,000 to 1,000 IU/ml). It has become standard clinical practice that HCV monoinfected patients who do not have at least a two log10 reduction in HCV RNA by week 12 should not be continued on PEG-IFN alfa/RBV.
--Pegylated interferon versus standard interferon alfa - In the early 1990's standard interferon alfa at a dose of three million units three times per week was the standard treatment of HCV infection. In the mid-1990s, RBV when added to IFN alfa, was noted to have increased antiviral activity when compared with IFN monotherapy. The current standard of care is pegylated interferon alfa in combination with RBV.
-- PEG-IFN alfa-2a and 2b dosing: Current practice dictates that PEG IFN alfa-2a is usually given as a fixed dose 180 mg/wk while PEG IFN alfa2b is usually given as a weight-based dose of 1.5 mg/kg/wk. RBV is currently prescribed according to either a fixed or a weight-based (13.6 mg/kg/d) dosing scheme.
--Duration and outcome of therapy: In HCV mono-infected patients, those infected with genotype 2 are usually treated for 24 weeks while those infected with genotype 1 are usually treated for 48 weeks. Non-responder refers to patients who do not have a significant decrease in HCV RNA while on therapy, sustained virologic responders are those patients who don't have detectable HCV RNA in the peripheral blood six months after stopping treatment (thought to be eradication of HCV), and relapsers are patients who have HCV RNA below detection during treatment, but after stopping therapy, HCV RNA becomes detectable. A note on HCV genotypes. Genotype 1 is more common in this country, but is not as responsive to therapy as genotypes 2 or 3.
HCV TREATMENT IN SELECTED PATIENT SUBGROUPS
217. Histological improvement in patients with pegylated interferon alpha 2b plus ribavirin who were previously non-responders to rebetron (interferon+ribavirin)
Approximately 60% of the patients who are treated with pegylated interferon and ribavirin will fail to have a viral response to therapy. However the question remains whether they will achieve improvement in liver histology. The goal of this study was to determine the effect of 48 weeks of therapy with pegylated interferon and ribavirin using the HAI (measure of liver inflammation) and fibrosis scores. Patients who failed to respond to a prior course of pegylated interferon and ribavirin were treated with one of two regimens of pegylated interferon and ribavirin. A total of 193 patients were enrolled and 102 completed 48 weeks of therapy of whom 71 were HCV RNA positive and 31 were HCV RNA negative. 70% of the patients were male, the mean age was 49 years, 70% were Caucasian, and 89% of the patients were infected with HCV genotype 1. At baseline, 5% of the patients had no fibrosis, 45% had mild/moderate liver fibrosis, and 50% had severe fibrosis or cirrhosis.
Of the patients enrolled in the study, 43/71 of HCV RNA+ patients have had post treatment liver biopsies and 16/31 of the HCV RNA - have had post treatment liver biopsies. During this time period, a significant improvement has been observed in inflammation but not in fibrosis. Those who were HCV RNA negative have had the most significant change in inflammation compared with those who were HCV RNA positive. The sustained virologic response among patients enrolled in this trial was 9%, which is consistent with other trials of patients who failed to respond to interferon and ribavirin who were treated with pegylated interferon and ribavirin.
Commentary: This is an important study given the large number of patients who fail to achieve a viral response to therapy. There are several other points that should be remembered regarding the importance of this study: 1) the majority of the damage in HCV infection occurs in the liver, 2) the amount of HCV RNA in the peripheral blood does not correlate with liver damage, 3) even if patients fail to have a viral response, they can still have improvement in liver histology with interferon. This study demonstrates that even patients who fail to have a viral response can have an improvement in liver histology. However, additional follow-up will be needed to determine if the improvement observed in inflammation will translate into improvements in fibrosis, particularly among those who are still HCV RNA positive.
215. The safety, efficacy, and pharmacokinetics of peginterferon alfa-2a (40kD) in children with chronic hepatitis C.
Currently, there are no FDA approved therapies for HCV in patients under the age of 18 years. It is estimated that HCV seroprevalence is 0.2-0.4% in children 12-18 years of age, which translates into 150,000 to 250,000 HCV-infected children in the United States. New infections occur primarily via vertical transmission and there are no effective measures that can be used to interrupt vertical transmission. HCV infection in children is usually asymptomatic, is associated with normal ALT, and is associated with tremendous social stigma in younger age patients. The objective of this study was to investigate the viral response and pharmacokinetics of pegylated interferon in children 2-8 years of age with HCV. Dosing was based upon body surface area (BSA). Blood samples were obtained at weeks 1, 4, 8, 12, 24, 40, and 48 during therapy and at 1, 24, and 48 post-treatment.
14 patients were enrolled in the study, 8 boys and 6 girls. 13 patients were HCV genotype 1 infected and 11 had acquired HCV through vertical transmission. In this study, HCV RNA was below detection in 8 (57%) of the subjects by week 24, 7 (50%) of the subjects by week 48, and 6 (42%) of the subjects by week 72. The clinical characteristics of the subjects with an SVR are as follows: all but one was male, all were infected with HCV genotype 1, all had low HCV RNA, and all had low ALT values. No SAEs were reported. The most frequent AEs included fever (11%) and headache (6%).
Commentary: This study convincingly demonstrates that interferon monotherapy can be dosed effectively in children based upon BSA resulting in an SVR of 42%. After the presentation, the question was posed whether combination therapy with ribavirin is needed in children. The presenter reminded the audience that in an uncontrolled trial that was presented at AASLD in 2002, children who were treated with interferon combined with ribavirin syrup achieved an SVR of 57%. The results of the study described above justify larger prospective studies that should be conducted in children. The issue of whether ribavirin is required in adolescents will necessitate further evaluation. Avoidance of RBV, a potential agent that can cause birth defects, in adolescent females may be advisable unless absolutely required.
#231. Pharmacokinetics, pharmacodynamics, and antiviral response in patients with chronic hepatitis C infection on methadone maintenance therapy receiving peginterferon (40kD) alfa-2a (Pegasys).
Methadone may suppress IFN-alfa mediated antiviral activity. The objective of this study was to evaluate methadone's effect on IFN-alfa activity and the effect of IFN-alfa on methadone safety and tolerability. Patients were excluded from this study if they were actively using illicit drugs, if they had been treated in the past six months for HCV, or if they were co-infected with HIV or HBV. HCV RNA, PEG-IFN levels, and 2'5' OAS (a measure of IFN activity) were assessed at Day -7, baseline, and at study weeks 1, 2, 3, and 4. A total of 24 subjects, 18 males, 13 Caucasian were enrolled in this study. One half of the participants also had significant psychiatric conditions.
The authors noted that there was an increase in methadone levels in 64% of the participants (by 10-15%) from week 0-4. 2'5' OAS increased immediately after baseline and the maximum increase occurred by week 4. 12 of the patients had a HCV RNA response with a 2 log decrease in HCV RNA by week 4. Overall, the combination of methadone and IFN-alfa were well tolerated, there were no serious adverse events during the course of the study and none of the patients required methadone dose modification. In summary, the authors concluded that methadone does not impair IFN-alfa's antiviral activity. Methadone levels increased 10-15% between baseline and Week 4. Therefore, methadone appears to be safe to administer at the same time with PEG-IFN and RBV.
Commentary: Since HCV is very rarely transmitted via sexual exposure or through blood transfusions, infection in injection drug users accounts for almost all new HCV cases. Consequently, HCV treatment of active or former injection drug users is an important area for further investigation. Methadone is commonly used to treat substance abuse, and many HCV-infected former substance abusers are prescribed methadone. Therefore, assessment of the interaction between the two drugs, and making sure that the activity of one drug is not impaired by the other, is an important consideration. This study is important because it demonstrates that methadone does not impair the antiviral activity of IFN and that IFN-alfa does not significantly alter methadone concentrations. The implications are that both drugs can be given together safely.
233. Interferon and interferon plus ribavirin in hepatocellular carcinoma prevention. A prospective study on patients with HCV related cirrhosis.
All cells in the body are required to divide in order to keep growing and to reproduce themselves. Cancers can block the normal signals that tell cells to stop dividing so that cancerous cells continue to grow and to divide long after normal cells would have stopped. IFN-alfa decreases a cell's ability to divide. Therefore, investigators have thought that IFN's ability to decrease cell division might delay or prevent liver cancer (hepatocellular carcinoma). The aim of this study was to address the question whether adding RBV to IFN-alfa is better at preventing liver cancer compared with IFN-alfa alone. 101 patients were enrolled in this study. All patients underwent a liver biopsy and an ultrasound to document the presence of HCV-related cirrhosis and the presence or absence of liver cancer. Sections from the liver were stained with an antibody (AgNOR) to detect dividing liver cells to evaluate whether the likelihood of liver cancer is increased in patients with more dividing hepatocytes. 41 patients were treated with IFN monotherapy 6 MU each day for 12 months and were followed for 5 years. Another sixty patients, thirty in each arm, were randomized to receive either no therapy or combination therapy with interferon and ribavirin.
There were nine cases of liver cancer in the group that received no treatment, 2 in the IFN monotherapy arm, and none in the arm that received combination therapy. The number of dividing liver cells was decreased in the group after treatment with IFN-alfa. Liver cancer was increased significantly in the group with more dividing liver cells compared with the patients who had few dividing liver cells. The authors concluded that IFN monotherapy and combination therapy have beneficial effects on delaying or preventing the development of liver cancer.
Commentary: This study shows, as have other studies, that IFN-alfa monotherapy can prevent liver cancer. However, the small number of patients who developed liver cancer comparing those who were treated with IFN monotherapy and those who were treated with IFN and RBV limits the conclusions that can be drawn as to whether one drug or two are better able to prevent liver cancer. Additional studies with larger numbers of patients and/or longer follow-up time will be required to determine whether RBV when added to IFN monotherapy has a beneficial effect on inhibiting liver cancer.
504. Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: A trial in prior monotherapy or combination therapy nonresponders and in combination therapy relapsers: Final Results.
The question of whether to treat patients with pegylated interferon and RBV who were treated in the past and who failed to respond remains an important area of investigation. Several studies have demonstrated that combination therapy with pegylated interferon and ribavirin is superior to interferon monotherapy or combination therapy with standard interferon and ribavirin. The aim of this study was to test the efficacy and optimal dose of pegylated interferon in three categories of patients: 1) interferon monotherapy nonresponders (i.e. patients who failed to respond when they were given interferon as a single agent), 2) "combination therapy" nonresponders (i.e. patients who failed to respond to standard IFN and RBV), and 3) "combination therapy" relapsers (i.e. those patients in whom HCV RNA recurs after stopping therapy). Patients were divided into two groups: A) Lower dose PEG IFN and standard RBV (PEG-IFN alfa-2b 1.0 ug/kg/wk and RBV 1000-1200 mg/d [n = 114]) or B) Standard PEG IFN with lower dose RBV (PEG-IFN alfa-2b 1.5 ug/kg/wk and RBV 800 mg/d [n = 105]). Patients were treated for 48 weeks and treatment was discontinued if HCV RNA was detectable at 24 weeks. Ninety percent of the patients in both groups were infected with HCV genotype 1, and 38% and 42% of the patients in each group had stage 3-4, respectively.
The overall sustained virologic response was 42% for combination therapy relapsers, 21% for interferon monotherapy nonresponders, and 8% for combination therapy nonresponders. There were no significant differences in SVR rates between the groups (A: 6% vs. B: 10%). There were no significant differences in the number of adverse events or the number of patients who had to have the dose of the medication reduced between the two groups. The authors concluded that retreatment with pegylated interferon and ribavirin results in the highest SVR in relapsers who were treated previously with combination standard interferon and ribavirin.
Commentary: This is an important study because it shows that all patients who failed to respond to a prior course of interferon or interferon and ribavirin should be retreated with pegylated interferon and ribavirin. However, the question remains how should people who fail to respond to pegylated interferon and ribavirin be treated. These patients will have to wait for the development of new agents that have specific action against HCV. In the case of severe liver disease, these patients should be considered for maintenance therapy with low dose PEG IFN alfa monotherapy usually given for an extended period of time.
ADVERSE EFFECTS OF HCV AND ANTI-HCV TREATMENT
213. Clinical significance of pegylated interferon induced neutropenia; Results from the WIN-R trial.
In cancer patients, a low white blood cell count (particularly of the neutrophil line) can lead to an increased risk of infection. The thought has been that a decrease in these cells, which can occur in 18-20% of patients who are treated with PEG IFN alfa, can also lead to an increase in infection. The custom has been to treat patients who become neutropenic either with a reduction in the dose of interferon or to add another medication (granulocyte colony stimulating factor-GCSF) to increase the neutrophil count. However, no standard guidelines have been issued to tell doctors how GCSF should be given. The aim of this study was to assess the relationship between the number of cases of infections and low white count among patients who are being treated as part of a large prospective study, which is testing the difference in SVR between patients treated with standard (800 mg) and weight-based RBV.
During the larger trial, 64 of 4802 patients have had an infectious complication the most common of which were pneumonia, abscesses, cellulitis, and urinary tract infections. The authors evaluated the association between neutrophil count and infectious complications in a variety of ways: 1) the average neutrophil count during treatment did not differ significantly in those patients who had infectious complications and those who did not, 2) the percentage of patients with severely low neutrophil counts did not differ comparing those with infections and those without, and 3) only one third of patients with an infection had the infection within five weeks of the lowest neutrophil count. The lowest neutrophil counts were similar comparing Caucasians with African Americans. Those individuals with advanced fibrosis had a lower average neutrophil count than those with more modest forms of liver scarring.
The authors concluded that the frequency of infectious complications did not differ significantly in patients based upon the average neutrophil count, the lowest neutrophil count, or number of new infections. Consequently, other factors besides a low neutrophil count are associated with infection, that a low neutrophil count should not preclude treatment in African-Americans, and that prospective trials are needed to assess the optimal strategy for the use of GCSF. During the question/answer period, Dr. Hoofnagle from the NIH commented that he has noticed that significant neutropenia occurs in two types of HCV-infected patients: 1) those with cirrhosis and 2) in African-Americans who are particularly susceptible to a type of low white count "constitutional neutropenia". The etiology (cause) of neutropenia in cirrhotics remains to be fully defined, although there are marked differences in the immune system between individuals with advanced scarring of the liver and those with cirrhosis. Constitutional neutropenia is a benign condition that occurs in up to 20% of African-Americans. Of note, patients with constitutional neutropenia do not usually have reduced numbers of neutrophils when they are treated with interferon.
214. Aggressive psychiatric intervention based on clinical suspicion, not standardized depression scores, increases adherence to pegylated interferon and ribavirin therapy for hepatitis C.
Only 70% of HCV-infected patients are able to tolerate the full-dose of PEG IFN/RBV for the recommended duration. The most common reason that patients are not able to complete therapy is depression. There are several questionnaires that have been developed that are used to test patients for depression. The aim of this study was to test the ability of two measures of depression, the Beck Depression Index (BDI) and the Center for Epidemiologic Study (CES-D) to test whether changes in these two measurements could predict depression. Another goal was to evaluate whether treatment of depression, either through medications or through standard counseling would improve a patients' ability to tolerate the medication. 55 patients who had never received treatment were enrolled and 48 completed therapy and follow-up. 39 patients completed at least one set of depression scales. The BDI and CES-D were completed at weeks 0, 4, 12, 24, 48, and 24 weeks post treatment.
During treatment, none of the patients withdrew secondary to depression. The use of medications to treat psychological problems increased from 26% at baseline to 68% during therapy. Approximately one quarter of the participants had to use agents to induce sleep during therapy, another quarter had to use agents to control anxiety, and one half had to use antidepressants. Neither the BDI nor the CESD were able to predict the need for antidepressants. It appears that there were large variations in individual scores between participants, which may be the reason why these scales failed to predict patients' need for treatment.
The authors concluded that aggressive treatment of psychiatric problems during treatment meant that dose reduction or medication discontinuation was not required in any of the subjects. After 24 weeks of treatment, most of the subjects' psychiatric conditions continued and had not returned to baseline. One of the potential limitations of this study is how generalizable are the results. In other words, can these findings be applied to patients who are being treated in other centers who also have depression. This study was conducted at a single center with a single psychiatrist who was responsible for all treatment decisions. There was minimal need for dose reduction, the patients were very compliant with therapy, and there was close follow-up of the patients.
505. Epoetin alfa treatment of anemic HCV-infected patients allows for maintenance of ribavirin dose. Increases hemoglobin levels, and improves quality of life vs. placebo: a randomized, double-blind, multicenter study.
Anemia is a frequent adverse event in patients treated with ribavirin, which can result in a decrease in SVR if RBV dose reduction is required, particularly during the first three months of therapy. Erythropoietin is a chemical that is normally produced by the kidneys that increases the hemoglobin concentration in the blood. Hemoglobin is responsible for carrying oxygen to the tissues. A decrease in the hemoglobin concentration results in anemia. A multicenter, double-blind randomized trial was conducted designed to evaluate the effect of recombinant human erythropoietin (rHuEPO-a drug that is given to increase the hemoglobin concentration) to: 1) maintain ribavirin levels, 2) alleviate anemia, and 3) improve quality of life. The study was designed so that when the hemoglobin concentration decreased below 12 gm/dL 4 weeks after initiation of PEG-IFN and RBV, patients were randomized to receive either rHuEPO or placebo for 8 weeks. After a total of 12 weeks, patients in the placebo group who had hemoglobin below 12 gm/dL were crossed over and were treated with rHuEPO. At randomization, the baseline characteristics of each group were well matched (rHuEPO vs. placebo- genotype 1: 71% vs. 76%, naive to IFN: 60% vs. 60%, advanced fibrosis in the liver: 35% vs. 37%, hemoglobin concentration at randomization: 10.8 + 0.8 vs. 10.8 + 0.1 gm/dL), respectively.
The authors reported that 88% of the patients who received rHuEPO were able to maintain full-dose RBV compared with 60% of the patients who received placebo (p = 0.001). In the group that received rHuEPO, hemoglobin increased by 1.5 gm/dL during the first 4 weeks of treatment and 2 grams by 8 weeks of treatment while the group that was treated with placebo had no change in hemoglobin concentration. In terms of quality of life, by week 9 of treatment there was a significant increase in quality of life (detected by linear analogue scores 12.7 vs. 4.7, p = 0.001) in the patients who received rHuEPO compared with the placebo group. By week 17, the patients who had received placebo who were subsequently treated with rHuEPO had similar quality of life scores to the group that was initially randomized to receive rHuEPO (17.8 vs. 17.9, p = 0.001). Another tool that was used to measure quality of life, the SF-36, was also significantly improved in the group that received rHuEPO. After cross-over, the group that had initially received placebo also had an improvement in the quality of life.
In terms of severe adverse events, one patient had a stroke that was thought to be possibly related to the drug. In terms of changes in HCV RNA measurements, there were no significant differences reported in the two groups. The authors concluded that rHuEPO in anemic patients who are taking RBV can: 1) enable the patients to maintain full-dose RBV, and 2) result in a significant increase in hemoglobin and quality of life.
PREDICTORS OF RESPONSE TO INTERFERON-BASED THERAPY
232. Steatosis influences the early virologic response rate in patients with chronic hepatitis C infection.
Current therapy for HCV is unsatisfactory on many levels: approximately one half of the patients who take it will fail to respond, the treatment is associated with significant side effects, and it is not suitable for all patients. The ability to predict or to identify patients who are likely to achieve an early response to therapy is important so that patients who are not likely to respond do not have to be exposed to the therapy. The aim of this study was to evaluate the effect of steatosis (fat in the liver) on the outcome of treatment for HCV.
574. HCV-infected drug naive patients had a single liver biopsy and were treated with IFN or PEG-IFN/RBV combination therapy.
170 patients responded to therapy and 72% had an early viral response. Genotype 1 infected patients with stage 0 were more likely to achieve an early response to therapy compared with those with more severe forms of fibrosis (71% vs. 42%, p = 0.003). In multivariate modeling, genotype 1 (p = 0.007) and fat percent (p = 0.046) were significant predictors of an early response to therapy. One of the limitations of this study concerns the manner in which the statistical modeling was performed. The authors pointed out that the modeling assumes that fat in the liver increases in a linear fashion up to a certain point, which may not be completely valid. The authors concluded that fat in the liver (steatosis) should be evaluated in prospective trials as a predictor of an early viral response.
Commentary: This study identifies another potentially important factor that is associated with an early viral response to treatment, fat in the liver. Further studies should be performed to follow-up on these results to see if they are confirmed in other prospective trials.
HIV/HCV CO-INFECTION
249. The impact of protease inhibitors (PI) on the histologic spectrum of liver disease in HCV-HIV co-infection.
The aim of this study was to assess the impact of HIV protease inhibitors on the spectrum of liver disease in HIV/HCV co-infected patients. The effect of HAART or protease inhibitors on the liver of co-infected patients remains controversial. To answer this question, the authors reviewed the medical records of consecutive patients (retrospective analysis) who were seen in the Liver Clinic at Virginia Medical College in Richmond between 1997-2002. To be included in the analysis, patients had to be HCV and HIV RNA+, to be negative for hepatitis B surface antigen, to have a CD4 cell count > 50 cells/mm3, creatinine > 1.5 mg/dL, platelet count > 80,000/mm3, to be free of opportunistic infections within three months of the liver biopsy and to not have any active opportunistic infections. Advanced liver disease was defined as bridging fibrosis or cirrhosis. A group of patients were used as controls who were HIV RNA + and HCV RNA -. The Knodell histologic activity index (HAI) was used blindly to assess the liver biopsy and advanced fibrosis was defined as bridging fibrosis or cirrhosis.
A total of co-infected 101 patients drawn from an urban HIV clinic were included in the analysis. The mean HIV RNA was 1.52 + 2.2 log copies/mL (33 copies/ml) and the mean CD4 cell count was 528 + 348 cells/mm3, the mean age was 43 years, 75% of the patients in the analysis were male, 82% were African American, 11% had CD4 count <200; and this reflects their liver clinic patients. 92% of the patients were taking a mean of 3 antiretroviral medications, 98% were on nucleoside reverse transcriptase inhibitors (NRTI), 45% were taking nonnucleoside reverse transcriptase inhibitors (NNRTI) and 54% were taking protease inhibitors (PI). After stratification by PI or NNRTI use, there were no significant differences in histologic, biochemical, or virologic parameters.; CD4 counts were about the same; the number of patients with CD4 <200 were similar in patients taking PI or NNRTI regimens; ALT was the same; and the HAI was similar between patients on HAART with PI< on HAART without PI, or controls (HIV+, HCV-). The percent of patients with advanced fibrosis was similar whether patient was on PI or NNRTI regimen.
The authors concluded that neither PIs nor NNRTIs have an effect on the spectrum of liver disease observed in HIV/HCV co-infected patients and that a large number of co-infected patients have normal ALT. ARV should not be limited in co-infected patients as these medications do not appear to adversely affect liver histology. Other authors have found that ARV therapy actually may protect against liver damage, although this finding still remains controversial. (editorial note: there were study limitations restricting how much you can conclude from this study. Since this was a retrospective analysis, a one time look at patient clinic records, you could not perform biopsies before ARV treatment and after. There was only 1 biopsy. This limitation prevents you from evaluating change in the liver over time. This limitation prevents you from considering ARV prior to current regimens as prior ARV experience probably differed between patients. The authors are trying to compose prospective study in which they can perform biopsy before starting therapy and afterwards to evaluate change in liver while on HAART. The current analysis from this study lacks reliable information upon which to draw conclusion regarding the effect of PI or NNRTI based HAART on the liver.
344. The association of hepatitis C virus (HCV)-specific immune responses with liver histology in subjects with HIV/HCV co-infection.
This study was conducted using samples derived from AIDS Clinical Trials Group study 5071, a randomized trial comparing pegylated interferon alfa-2a and ribavirin to standard interferon and ribavirin. Immune responses can be divided into two subsets depending upon the pattern of cytokine secretion. T helper 1 (Th1) responses are usually associated with defense against viral infections and are usually measured assessing interferon gamma secretion. T helper 2 (Th2) responses are usually associated with defense against other types of infections and are usually measured by interleukin 4 or 10 secretion. One reason for failure to eradicate HCV infection may be the dominance of a Th2 response that may be responsible for dampening the Th1 response. These investigators sought to test the hypothesis that vigorous HCV-specific T helper 1 interferon gamma responses are correlated with protection from liver damage in co-infected patients. Interferon gamma and interleukin 10 secretion were measured in peripheral blood mononuclear cells in response to portions of the hepatitis C virus (core, NS3, and NS5) on a total of 108/133 HIV/HCV co-infected patients enrolled in A5071. Responses to candida and PHA (positive control) were also assessed.
The mean CD4 cell count was 479 cells/mm3, 83% of the subjects were male, 79% of the subjects were infected with genotype 1, and 88% were taking antiretroviral therapy. The spearman rank correlation demonstrated a significant inverse association between inflammatory score and HCV-specific IFN-gamma secretion in responses to core and to NS5. There was also a significant inverse association between fibrosis score and IFN gamma secretion in response to NS5. There was no association between IL10 secretion and inflammation or fibrosis. Similarly, there was no association between HCV-specific responses and CD4 cell count.
The authors concluded that HCV-specific Th1 responses in PBMCs correlate with milder inflammation and fibrosis on baseline liver histologic assessment. This is an important finding because it suggests that the stronger the immune response against the virus, the better the control of the virus, and the less liver injury will occur. An interesting extension of this investigation would be to look in the liver, where the immune responses directed against HCV are much stronger and broader.
HCV PATHOPHYSIOLOGY
250. Viral clearance occurs very early during the natural resolution of transfusion-acquired hepatitis C virus infection.
The question of why some people are able to clear HCV while others go onto develop chronic infection has not yet been adequately answered. Cohorts of hemophiliacs, who were infected with HCV via transmission of infected clotting factor, are a good environment in which to seek answers to these questions as the date of onset of the infection is more precisely known in comparison with injection drug users. Prior to 1987, clotting factor was not heat inactivated, so almost all hemophiliacs who received clotting factor before that date have been exposed to HCV. This study evaluated HCV responses in a cohort of hemophilia patients who had peripheral blood samples collected serially to address the question of the factors are responsible for clearance and when does natural clearance of HCV occur in patients who acquire the infection. This study evaluated these factors in 12 HCV+/HIV- hemophiliac subjects who were infected prior to 1987 and who cleared HCV spontaneously. The analysis was conducted using archived specimens that had been collected within 2 months to four year of primary HCV infection. The duration of infection in these patients ranged from 15-24 years. A cohort of eight controls of similar age, gender, and duration of exposure to blood products (which is important since the blood products serve as the primary route of infection) as the hemophiliac cases was selected for comparison.
The authors found that HCV RNA is cleared very early after infection. 8/12 (66%) of the patients did not have HCV RNA detected in the first sample. Eight of the twelve subjects had been infected by age 8.5 years. HCV RNA was significantly increased in the controls compared with the subjects who cleared spontaneously. Three out of 4 subjects with HCV RNA detectable by PCR on the first sample cleared virus during the next year. One patient was infected for five years before clearance, indicating that clearance can occur during chronic infection. Reinfection of HCV was observed in one patient who received nonsterilized factor concentrates.
The authors concluded that clearance of HCV usually occurs in the first 1-2 years after infection and is more likely in those subjects with lower HCV RNA. Coincidentally, HCV clearance in HIV/HCV coinfected subjects is much lower (6%).
Commentary: Our impression has been that HCV infection is cleared very quickly. In the clinical setting, most practitioners have waited three to six months after the exposure prior to treating acute HCV in anticipation that a large number of subjects would clear the infection. Recent data suggest that treatment as soon as possible during acute infection may be warranted because of a high cure rate (98%) with interferon monotherapy. The data presented above are important because they reinforce our clinical impression that HCV clearance occurs quickly after exposure to the infection. They also demonstrate that clearance after the onset of chronic infection is possible, implying that HCV RNA + patients who elect to defer treatment should be followed periodically to assess whether they clear the infection.
252. Comparison of hepatitis C virus (HCV)-related liver disease between caucasians (C) and African-Americans (AA): Analysis of HCV in the Virgiinia Department of Corrections (DOC).
Several studies have demonstrated that there are important differences in liver inflammation and response to therapy between African Americans and Caucasians in the general population. The goal of this study was to describe biochemical, virologic and histologic changes in the liver in African Americans and Caucasians in the State of Virginia Department of Corrections. This study is important because it focuses on a particular subgroup of HCV-infected patients, those who are inmates. A retrospective analysis of inmates with consecutive liver biopsies between October 1998 and July 2002 was conducted. To be included in the analysis, subjects had to have a platelet count > 70,000/mm3, an INR < 1.4 and no evidence of hepatic decompensation. Patients were excluded if they were HIV+, HBV+, had other forms of liver disease, or had a creatinine > 2.0 mg/dL.
A total of 302 inmates were included in the analysis. 30% had no fibrosis, 40% had portal fibrosis, 18% had bridging fibrosis, and 8% had cirrhosis. 80% of the patients were infected with HCV genotype 1. The mean age was 41 years, 91% were male, and 51% were Caucasian. The authors found important differences between the two ethnic groups. African Americans were more likely to be infected with HCV genotype 1, to have lower ALT, and to have similar degrees of inflammation compared with Caucasians. African Americans tended to have lower fibrosis stage, but the percentage with advanced fibrosis did not differ between the two ethnic groups. Inmates with mild disease had lower ALT values and a high percentage had normal ALT.
The authors concluded that there are no significant biochemical, clinical or histologic differences between African American and Caucasian HCV-infected inmates. The vast majority had evidence of liver injury, and 24% had advanced fibrosis/scarring in the liver. ALT had poor accuracy in predicting the severity of liver injury, indicating that a liver biopsy is essential to identify those with advanced fibrosis who might benefit from anti-HCV therapy. This study reaffirms that ALT is a poor marker of liver injury and that a liver biopsy should be considered in all patients to assess the degree of liver injury. Although several markers that are measured in peripheral blood are being evaluated for their ability to accurately assess the degree of fibrosis, they are not yet sensitive enough to replace the liver biopsy.
HEPATITIS B VIRUS INFECTION
507. Adefovir dipivoxil (ADV) results in a consistent and significant improvement in liver histology and clinical status regardless of baseline knodell fibrosis score in patients with HBeAg+ chronic hepatitis B.
Lamivudine (3TC), an oral medication, has been used for many years to treat HBV. The problem with the long-term use of 3TC is that most patients will become resistant to it (up to 90% at 4 years). Another drug that has activity against HBV is adefovir (ADV). This compound can stop HBV replication, and it was approved last September (2002) by the US FDA for the treatment of HBV. Although kidney problems were noted in the past when ADV was used at a dose of 50 mg for the treatment of HIV, a much lower dose, 10 mg. per day, is effective against HBV. When used for 48 weeks, ADV's safety profile is similar to placebo. The objective of this study was to compare the efficacy of ADV vs. placebo for the treatment of chronic hepatitis B virus infection in patients who are hepatitis E antigen positive. (E antigen is a marker that hepatitis B is actively circulating in the bloodstream).
167 patients were randomized to receive placebo and 171 were randomized to receive ADV for 48 weeks. At baseline, the two groups were fairly well matched in terms of the amount of scarring in the liver, the amount of HBV in the blood, and the ALT level in the blood. About a fifth of the patients in each group had received treatment for HBV in the past. The primary endpoint of the study was at least a two-point improvement in the amount of scarring in the liver at 48 weeks. Follow-up on these patients was particularly thorough since 298/338 (88%) of the patients had paired liver biopsies. Those patients who did not undergo the second biopsy were considered to have no improvement.
In terms of the study results, 70% of the patients with advanced fibrosis (F3 or F4) who were given ADV showed improvement compared with 34% of those patients in the placebo group. For the patients with either no or minimal fibrosis (F2 or F0), 46% of those on adefovir showed improvement compared with 20% of those given placebo. Other outcomes that were evaluated in this study included the median change in HBV DNA- 3 log10 (i.e. decreasing from 1,000,000 to 1,000) among the patients who received ADV compared with a less than 1 log10 among the patients who received placebo. ALT normalized in 62% or 43% (depending upon fibrosis score) of those in the ADV group compared with 18% or 14% of those in the placebo group. In terms of fibrosis progression, 6% of those who received ADV compared with 13% of those patients who received placebo progressed from F0/F2 to F3/F4 during the 48 weeks of the study. Improvement in fibrosis (F3/F4 to F0/F2) was seen in 38% of the patients who received ADV and 22% of the patients who received placebo.
Commentary: This study demonstrates that adefovir can significantly improve virologic, biochemical, and histologic parameters in HBV patients who are positive for the E antigen positive. Other important outcomes that have been measured in other studies are the incidence of seroconversion in patients who are treated with ADV. In particular, these outcomes are: 1) the loss of E antigen and the acquisition of antibodies to E portion of the HBV genome, and 2) the loss of HBV surface antigen and the acquisition of surface antibody.
508. Changes in alanine aminotransferase (ALT) and YMDD mutation profile associated with switching from lamivudine (LAM) to either adefovir dipivoxil (ADV) or combination LAM plus ADV in chronic hepatitis B (CHB) patients with LAM resistance.
Lamivudine (3TC-LAM) has been the standard therapy for active HBV infection for the past several years. However, one of the limitations of 3TC therapy has been the development of resistance, which occurs in approximately 70% of HBV mono- and 85-90% of HBV/HIV co-infected patients after 3-4 years of treatment with the drug. Adefovir (ADV) has demonstrated activity against wild type (virus that is not resistant) and LAM-resistant strains. The objective of this study was to evaluate the effect of switching LAM to ADV or adding ADV to LAM compared with continuing LAM in hepatitis E antigen positive HBV-infected patients.
Entry into the study required HBV DNA of at least 1 million copies, the presence of YMDD mutation (the most common type of mutation that confers lamivudine resistance), positivity for HBV E antigen, and an increase in ALT levels. LAM was given at a dose of 100 mg per day and ADV was given at a dose of 10 mg per day. Patients were treated for a total of 48 weeks. At baseline, the three groups (LAM, ADV, and LAM/ADV) were well balanced with regards to levels of ALT and HBV DNA. The YMDD mutation (specific for ADV) was present in 100% of the patients enrolled in the study.
The results of the study are as follows: HBV DNA: At 48 weeks, the patients in the ADV group alone had a mean 4 log10 decrease compared with baseline, those in the LAM/ADV had a 3.6 log10 decrease, and those in the LAM group had no change in HBV DNA. (Note: A 4 log10 decrease is a decrease by 4-tens places. For example decreasing from 10,000,000 to 1,000, quite a considerable decrease). ALT: 60% of the patients in the ADV group had normalization of ALT, 40% of the patients in the LAM/ADV group had normalization of ALT, and 5% of the patients in the LAM group had normalization of ALT. Genotypic analysis: 37% of the patients in the ADV group had reversion to wild type (lost the resistance mutation) during the 48 week study, LAM/ADV one person had reversion, LAM-100% of the patients continued to have the YMDD mutation. (Comment: Loss of the YMDD mutation means that the patients are no longer resistant to LAM. The fact that a considerable number of the patients who got ADV alone lost the YMDD mutation is an important finding). There were no differences in the degree of decrease in HBV DNA in those patients in the ADV group who had the YMDD mutation or in those who lost it. Adverse events: One patient during the study had a transient increase in ALT. The patient was able to continue on therapy and eventually showed signs of improving. The authors concluded that ADV or ADV added to LAM results in a significant decrease in HBV DNA and ALT normalization.
Commentary: Overall, these two well-designed and well-executed studies have demonstrated that adefovir appears to be a superior therapy to lamivudine for the treatment of hepatitis B virus infection. To date, there have not been any reports of kidney problems in patients who are taking a dose of 10 mg. Several years ago, when the drug was used as a treatment for HIV, the drug was eventually taken off the market because of kidney problems. As study #508 demonstrates, the drug has activity in patients who are resistant to lamiviudine. In terms of how to treat patients with HBV who are currently on lamivudine and who have the YMDD mutation, the question has recently arisen regarding what should be done with the lamivudine. Based on the findings of the second study presented above, it seems safe to discontinue lamivudine in patients who are being treated with adefovir.
HEPATITIS B VIRUS INFECTION
Here is link to DDW Report covering these abstracts from DDW on HBV:
http://www.natap.org/2003/DDW/day17.htm
--Comparison of Viral Replication Fitness of Wild-Type and Lamivudine Resistant HBV in Patients
-- Safety of Adefovir in HBV: 48 and 109 weeks follow-up
--Tenofovir Treatment in Hepatitis B Monoinfected Patients With Lamivudine-Resistant Virus
--Clevudine: 28-day study of new once daily HBV drug
SELECTED POSTERS
T1215. Early virologic response to interferon and ribavirin treatment in patients co-infected with HCV and HIV.
It is known that patients with HCV who have a virologic response to IFN and ribavirin usually respond within the first 12 weeks. The goal of this study was to determine if the same pattern was true for patients co-infected with HIV and HCV. Of 31 patients (predominantly genotype 1), 12 (38%) had an end of treatment response. Of those 12, 11 had either completely non-detectable HCV RNA by 12 weeks or had at least a 2-log reduction in viral load. The authors concluded that co-infected patients who don't have at least a 2-log reduction by week 12, discontinuation of therapy should be considered.
Commentary: This study raises an important issue, whether or not the viral response rules for genotype 1 infected patients (i.e. discontinuation of treatment in patients who fail to achieve a 2-log10 reduction in HCV RNA by week 12 or HCV RNA below assay detection by week 24) apply to HIV/HCV co-infected patients. In general, the SVR is decreased approximately 10 percent in co-infected patients treated with PEG-IFN/RBV compared with mono-infected patients treated with the same regimen. The strength of this study is that it is one of the first to address the issue of an early viral response in HIV/HCV co-infected patients. It is limited because SVR data were not presented, only a small number of patients were evaluated, and the statistical methods that were used to analyze the data. Calculation of the sensitivity, specificity, positive and negative predictive values would be helpful in determining the predictive value of the 12 week HCV RNA on viral outcome in co-infected patients.
T1218. Effect of therapy with pegylated interferon-alfa on platelet activation and apoptosis in patients with chronic hepatitis C.
Low platelet counts are a frequent reason for medication discontinuation in HCV-infected patients who are treated with pegylated interferon. Unlike anemia and neutropenia that can both be treated with growth factor supplementation (GCSF or erythropoietin), the results using medications that have been used to raise the platelet count (primarily IL-11) have not been as successful. This study is important because it attempts to investigate the reasons for low platelets in patients who are treated with PEG IFN-alfa and RBV. Specifically, the goal of this study was to assess the relationship between the decrease in platelet count and platelet activation, as platelet activation may increase the likelihood that platelets will undergo activated cell death (apoptosis). This study evaluated 10 patients who were infected with HCV genotype 3a who were treated with PEG-IFN a2b 1.0 mcg/kg/qwk for four weeks. The authors reported no change in the level of platelet activation or apoptosis.
Commentary: While the conclusions of this study were negative, it is well done and rules out an important mechanism that might account for thrombocytopenia. The most common reason for thrombocytopenia is splenic sequestration (trapping) of platelets. As liver disease progresses and the liver becomes more fibrotic, the blood in the portal system encounters much more resistance. The increase in pressure in the portal system causes the spleen to enlarge. As the spleen is one of the major sites of platelet clearance, the enlarged spleen causes the platelets to become trapped resulting in a decrease in their number in the circulation.
T1208. Non-invasive assessment of fibrosis resolution/progressive in chronic hepatitis C patients who received anti-viral therapy.
The main way that hepatitis C virus causes damage to the body is by causing liver fibrosis. Currently, the most accurate way to assess liver fibrosis is through a liver biopsy in which a pathologist is able to see the liver tissue under the microscope. The goal of this study was to assess whether measurement of certain substances that are products of liver fibrosis in the peripheral blood could provide an accurate indication whether fibrosis was improving in patients who were on therapy. Thirty-seven patients who received a daily injection of 6 to 10 million unit (MU) of interferon-alfa 2b three times a week for 24-26 weeks were enrolled. PIIIP levels, cytokines contributing to fibrosis production (PDGF, TGF-beta), and the enzymes regulating fibrosis degradation (MMP-1, TIMP-1) in serum were measured during therapy, at the completion of therapy, and 24, 48, and 72 weeks after the end of therapy. These investigators found that the levels of two enzymes in particular, PIIIP and TIMP-1 were significantly decreased in viral responders compared with nonresponders comparing baseline values with values at the end of treatment.
Commentary: This study identifies two substances, PIIIP and TIMP-1, that can be measured in serum and may differentiate responders from nonresponders. There are also several noninvasive markers that are being evaluated in prospective studies that may permit us to assess the stage of fibrosis without the need for a liver biopsy. While many of these have shown promise, there is a need for prospective studies to evaluate them in more detail before they can replace the liver biopsy.
T1204. Effect of silybum marianum on serum ALT and well-being in chronic hepatitis C.
Many patients who are infected with HCV try "alternative treatments" to try to treat the infection. Of these, silybum marianum (milk thistle) is one of the most common alternative remedies used. The goal of this study was to evaluate the effect of milk thistle on serum ALT levels and on patients' quality of life. 17 patients enrolled in double blind, placebo controlled study. No significant differences were found in the patients who received milk thistle compared with those who did not in the following variables: ALT, AST, gamma GT (another substance that can be elevated in chronic liver disease), and in other liver related chemistries. Quality of life was measured using a standardized, validated instrument (the state trait anxiety inventory (STAIS), which tests several different physical, mental, and psychological traits associated with quality of life. Quality of life was decreased in the anxiety domain in the patients treated with placebo compared with those treated with milk thistle. In conclusion, milk thistle appears to have limited efficacy in the treatment of HCV as it did not significantly alter ALT, other serum chemistries, or quality of life.
1219. Efficacy of daily interferon in combination with ribavirin in patients with chronic hepatitis C: Final results of a VA multicenter study.
This study evaluated the efficacy of daily interferon and ribavirin in U.S. Veterans. A total of 158 patients were enrolled in this study. They were randomized to receive either 3 MU of IFN alfa-2b QD plus RBV (1000 - 1200 mg/d) for 24 weeks (daily therapy group) or 3 MU of IFN alfa-2b TIW plus RBV (1000 - 1200 mg/d) for 24 weeks (genotype 2 & 3) or 48 weeks (genotype 1) (standard therapy group). At baseline, there were no significant differences in the percentage of patients with HCV genotype 1, the stage of liver disease, or the number of African-American subjects in each group. The sustained virologic response rates 24 weeks after treatment in the daily IFN group were higher than in the standard group for all genotypes (30.8% vs. 16.3%, P = 0.03) and for those with genotype 1 (19.7% vs. 6.3%, P = 0.03), but did not differ for those with genotype 2 and 3 (70.6% vs. 56.3%, P = 0.48). Therapy was associated with significant improvement in all domains tested as part of quality of life. The authors concluded that the SVR for Veterans is approximately 10% lower than it is for other HCV-infected patient groups. They also concluded that daily interferon is significantly better for genotype 1 infected patients than IFN three times per week, while the dosage frequency does not make a significant difference in the SVR for genotype 2-3 patients.
1220. Early viral kinetics in chronic hepatitis C virus genotype 4 infection.
The decay of HCV RNA in genotype 1 infected patients in response to treatment with interferon and ribavirin has been useful in predicting those patients who are likely to respond compared with those who are not. Specifically, if patients fail to achieve a two-log reduction in HCV RNA by week 12, they are virtually guaranteed not to achieve an SVR. Although rather rare in this country, genotype 4 is relatively common in Egypt and in Southern Europe. The goal of this study was to determine whether viral kinetics can be used to predict whether genotype 4 patients are likely to achieve a therapeutic response to interferon and ribavirin. In this study, 33 (29 Egyptian and 4 Austrian) IFN naive, genotype 4-infected patients were given a single dose of IFN alfa 10 MU 7 days before the start of the study. Subsequently between day 0 and 14, patients received IFN 5 MU per day. They were then treated for 48 weeks with the following regimens: IFN alfa 5 MU three times per week (n = 6), PEG IFN alfa2b 1.5 ug/kg/wk (n = 7), or PEG IFN alfa2a 180 ug/wk (n = 20). All patients received RBV 1 or 1.2 gm/day. The primary outcome was virologic response after 6 months of treatment with IFN/RBV or PEG IFN alfa2b/RBV or 3 months after treatment with PEG IFN alfa2a/RBV.
Patients who achieved a virologic response had more pronounced decreases in HCV RNA levels after a single dose of IFN or during 14 days of daily IFN therapy. A 0.6 log10 decrease in HCV RNA 24 hours after a single dose of IFN 10 MU has a sensitivity of 100%, a specificity of 92.3%, a positive predictive value of 77.8% and a negative predictive value of 100% for nonresponse. Consequently, the authors concluded that the 24-hour decline in HCV RNA levels after a single dose of IFN 10 MU has a high predictive value for subsequent outcome after treatment with combination therapy in patients infected with HCV genotype 4.
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