pegylated interferon in cmbination with lamuvidine in hbv,reduced.final ,ghrelin, leptindoc

Pegylated interferon and lamuvidine in the Treatment of Egyptian patients with HBe Ag positive chronic hepatitis B infection; Serum Ferritin as a

marker of improvement. Shendy Mohammed Shendy*, Naema Al-Ashry**, Alaa Awad Taha*, Moetaz Sery Siam*. Theodor Bilharz Research Institute: *Tropical medicine, Hepatology and gastroenterology department, **Clinical biochemistry department.

-Accepted For Publishing at Medical journal of Cairo university, 27-5-2007.

Abstract:In Egypt, treatment of chronic HBV is not extensively studied and there were no comparative

studies between different treatments all together. Also, worldwide, few such studies were performed with little or no significant differences in achieving both end of treatment and sustained virological responses when comparing lamuvidine to the combination of interferon and lamuvidine. The aim of this work is to compare the three arms of treatment; pegylated interferon, lamuvidine and combination of both agents; of chronic HBV infection who are HBe Ag positive in our Egyptian patients. Also, the effect of these treatments on the serum level of ferritin, ghrelin and leptin will be studied. Patients and methods: This study included 71 Egyptian patients with chronic HBe Ag positive HBV infection divided into three arms: group I including 23 patients treated with lamuvidine 100 mg once daily for one and half year, group II including 23 patients treated with pegylated interferon alfa 2b 1.5 µg/kg/ week for one and half year and group III including 25 patients treated with both agents for one and half years also. All patients were subjected to clinical, biochemical, histological and virological evaluation before, during and for about one and half years after treatment. History of schistosomiasis, antischistosomal treatment, in addition to ultrasonographic features of thickened portal tracts and antischistosomal antibody positivity were taken as evidences of presence of associated schistosomiasis. Hepatitis serologies including HBsAg, HBsAb, HBeAg, HBeAb, anti HBcIgG, and anti HCV were determined by a microparticle enzyme immunoassay method and anti-HDV was determined by an enzyme immunoassay. Serum HBV DNA was determined by a sandwich capture hybridization assay. Real time polymerase chain reaction (PCR)-based quantification of HBV DNA was performed with serum samples obtained at baseline, at the end of therapy and one and half year after. The YMDD (tyrosine, methionine, aspartate, and aspartate) motif was tested on the serum samples at the end of first year of therapy or after by line probe assay. Results: In lamivudine group, 30.4% showed complete biochemical and virological response to therapy with the mean ALT level of 35.29 ± 5.06 u/dL and AST level of 30.00 ± 2.52 u/dL in responding patients in comparison to 121.81 ± 28.23 u/dL and AST level of 107.25 ± 39.48 u/dL in non-responding patients after treatment. After 24 months, YMDD mutants were found in five patients in this group (21.7%). In pegylated IFN group, 47.8% showed complete biochemical and virological response to therapy with the mean ALT level of 29.82 ± 5.72 u/dL and AST level of 22.64 ± 3.53 u/dL in responding patients in comparison to 122.65 ± 40.50 u/dL and AST level of 112.33 ± 23.02 u/dL in non-responding patients after treatment. No YMDD mutants were detected during or after treatment. In combination therapy group, 32 % showed complete biochemical and virological response to therapy with the mean ALT level of 30.00 ± 3.12 u/dL and AST level of 23.75 ± 2.55 u/dL in responding patients in comparison to 110.33 ± 22.74 u/dL and AST level of 144.71 ± 44. 18 u/dL in non-responding patients after treatment. YMDD mutants were detected in 3 patients after the end of treatment (12%). HBsAg and HBeAg seroconversion were detected more in patients treated by pegylated interferon and combination therapy but not statistically significant. Serum ferritin was higher than normal in all patients before treatment (239.0141±59.23693 ng/ml). After treatment, it was reduced significantly in all groups with p <0.01(195.86 ± 50.471ng/ml) and this reduction was significantly higher in responding than non-responding patients in all groups (175.18

±3.26 vs. 209.12 ± 8.55). The change in histological activity index (HAI score) is significantly better for interferon than lamuvidine therapy (P=0.014). The changes in histological activity index (HAI score) in combination therapy group is more than lamuvidine group but didn’t reach statistical significance. Conclusion: In this study, no significant differences in biochemical and virological response between

the three arms of treatment. Thus, from the virological point of view, three types of therapy are similar and still far from the hope of treatment oh HBV. However, the development of YMDD resistance with the use of lamuvidine is a major concern and if a new nucleoside analogue can be added to or replace this drug to delay the development of resistance, such medications would be the best for their safety, route of administration and cost. The more HBsAg and HBeAg seroconversion in patients treated by combination therapy and pegylated interferon than lamuvidine, in addition to the rare development of YMDD mutants and the significantly better histological response; puts pegylated interferon in front of lamuvidine in the treatment of this disease. However, still the seroconversion and viral response is far beyond the goal and the door is widely open for more trials and different combinations to get the best effect adding new drugs recently approved for such infection such as adefovir, enticavir and others. Also, the dynamic observation of serum ferritin, leptin and ghrelin levels in patients with chronic viral hepatitis B during treatment might be helpful for monitoring and predicting patients' responses to the therapy.

IntroductionHepatitis B virus (HBV) infection remains a serious global health concern. [1] Of the 2

billion people who have been infected with HBV, more than 350 million have chronic infections.[2] Chronic hepatitis B (CHB) is the tenth leading cause of death worldwide, resulting in 1.2 million deaths each year. An additional 320 000 people die annually from liver cancer that is attributable to HBV infection. [3]

Two types of therapies are currently available for the treatment of chronic hepatitis B: (i) antiviral agents inhibiting HBV polymerase such as lamivudine, an oral nucleoside analogue of cytidine, and adefovir dipivoxil, a nucleotide analogue of adenosine monophosphate and (ii) interferons.[4-14] Both types of therapy have less than optimal efficacy. Fifty-two weeks of treatment with lamivudine is associated with hepatitis B e antigen (HBeAg) seroconversion rates of 16-18%.[11] Similar treatment outcomes were achieved in patients receiving treatment with 3-10 MIU of conventional interferon-α treatment for 4-6 months.[12,13,19] It is also associated with dose-limiting adverse reactions. Lamivudine and adefovir are better tolerated but require long-term administration which in addition to incomplete viral suppression in the presence of selective pressure exerted by the drug, nucleoside analogue treatment has been associated with development of drug resistance [20,21] which reaches up to 14-32% per year.[5-7,15]

Interferon treatment is associated with a high relapse rate[21,22,23] and prolonged treatment up to 2 years has been advocated.[24-26] Lamivudine treatment is also associated with a high relapse rate after drug discontinuation.[27]

In the light of the suboptimal therapies currently available, more efficacious therapies are needed in the treatment of CHB. In a more recent study peginterferon α -2a (40 kDa) was found to be superior in efficacy to conventional interferon α -2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT. (18) HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon α -2a (40 kDa) 90, 180 and 270 µg, respectively, compared with 25% of patients on conventional interferon α -2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon α -2a (40 kDa) doses combined was twice that achieved with conventional interferon -2a (24%vs 12%; P = 0.036). Thus it seems that pegylated interferon will soon replace conventional agents in the treatment of both HBV and HCV. But what is the situation of combination therapy of pegylated Interferon and lamuvidine in treatment of chronic HBV? Combination treatment with two or more drugs has long been regarded as a viable and reasonable approach to more effectively combat chronic hepatitis B infection and to shorten treatment duration.[19, 20]

Egyptian patients with chronic HCV infection were found to have a significantly higher level ferritin (Elsammak et al., 2005) (40). In Japan, sequential determination showed that lamivudine treatment significantly reduced ferritin levels in chronic hepatitis B patients. The reduction in HBV DNA-negative group was significantly more obvious than that in HBV DNA-positive group at 6 mo during the treatment (P=0.013). Also, the ferritin levels at 3 mo of treatment were obviously decreased as compared with the baseline levels (P<0.05) in HBeAg-negative group, and the decrease of serum ferritin levels in patients with normalized ALT was more significant than that in patients with abnormal ALT at the end of the 12-mo treatment (Liu et al., 2004) (41). In another study, multivariable analysis revealed that body mass index (BMI) and serum ferritin level were independent predictors of NASH (Naoki et al., 2006) (42). Thus ferritin can be considered as an inflammatory and prognostic marker in chronic liver diseases.

The role of leptin and ghrelin in the course of liver disease due to chronic viral hepatitis (CVH) remains controversial. It was found that, in cirrhosis and HCC due to HBV or HDV, serum ghrelin levels were found to be increased with a corresponding decrease in serum leptin concentrations, acting as a physiological counterpart of ghrelin (Ataseven et al., 2006). Another study found decreased serum leptin in HBV and HCV patients compared with healthy individuals and the nonviral liver disease group (Nikolaos et al., 2006). These studies suggested that leptin system might be involved in the immunopathology of chronic viral hepatitis in addition to the effect on nutrition both of which can directly and indirectly affect the response to therapy and the prognosis of the liver disease.

Optimization of treatment is thus clearly indicated and combination therapy seems to be a reasonable approach. Combination of LAM with IFN is attractive since (i) both agents are potent antivirals themselves and (ii) LAM and IFN have different modes of action. If these different modes of action are complementary, better treatment response can be expected.

The aim of this work is to compare the three arms of treatment; pegylated interferon, lamuvidine and combination of both agents of chronic HBV infection who are HBe Ag positive in order to have a comparative study and put a final conclusion about the value of these medicines in our Egyptian patients. Also, the effect of these treatments on the serum level of ferritin, ghrelin and leptin will be studied.

Patients and methods:This study included 71 Egyptian patients with chronic HBe Ag positive HBV infection

divided into three arms:Group I: 23 patients treated with lamuvidine 100 mg once daily for one and half year.Group II: 23 patients treated with pegylated interferon alfa 2b 1.5 µg/kg/ week for one and half year.Group III: 25 patients treated with both agents for one and half years.

Patients were recruited at the Department of Gastroenterology of Theodor Bilharz Research Institute, 6’ October University, Ministry of agriculture hospital at Dokky and Agoza general hospital. Informed consents were obtained from all patients. Patients in all centres were randomized to one of the three groups.

Inclusion criteria were documented hepatitis B infection and HBeAg (+), anti-HBe (-) chronic hepatitis B infection of at least 6 months duration. All patients had to have detectable HBV DNA levels by a molecular hybridization assay at the time of screening which was within 1 month before study began and HBV DNA levels above 100,000 copies/ml. Before the study

at two time points, at least 1 month apart, alanine aminotransferase (ALT) levels had to be 1.3-10 × the upper limit of normal. Patients with antibody against hepatitis C, and hepatitis delta viruses were excluded. Further exclusion criteria included decompensated liver disease, a coexisting serious medical or psychiatric illnesse, an albumin below 3.5 g, bilirubin above 4 mg/dL, an increased prothrombin time for more than 3 s above normal, white blood and platelet counts of less than 3000 and 100,000 mm3, respectively, and a serum creatinine level that was more than 1.5 times the upper limit of normal range. All patients had a liver biopsy done within 1 year of study entry and all had an histology activity index of at least three according to Knodell et a (36). Any significant disease which might have interfered with the conduct of the study was also an exclusion criteria. None of the patients had previously received LAM or any other nucleoside analogue or interferon treatment.

History of schistosomiasis, antischistosomal treatment, in addition to ultrasonographic features of thickened portal tracts and antischistosomal antibody positivity were taken as evidences of presence of associated schistosomiasis

All patients were subjected to clinical, biochemical, histological and virological evaluation before, during and for about one and half years after treatment. Serum ferritin was quantified using IMx ferritin assay which is a Microparticle Enzyme Immunoassay (MEIA) (Abbot Laboratories, Diagnostics division, Abbot Park, IL 60064 USA). Also, serum ghrelin and leptin were measured before and after treatment using specific ELISA kits. Hepatitis serologies including HBsAg, HBsAb, HBeAg, HBeAb, anti HBcIgG, and anti HCV were determined by a microparticle enzyme immunoassay method and anti-HDV was determined by an enzyme immunoassay (Abbott Laboratories, Chicago, IL, USA). Serum HBV DNA was determined by a sandwich capture hybridization assay (Digene Diagnostics, Gaithersburg, MD, USA) with a lower detection limit of 5 pg/mL.

Real time polymerase chain reaction (PCR)-based quantification of HBV DNA was performed with serum samples obtained at baseline, at the end of therapy or one and half year of follow-up later on, as previously described.[24] The sensitivity of the assay was 102

copies/mL. Patients included in this study should have HBV DNA levels above 500,000 copies/ml.

Irrespective of whether patients had clinical breakthrough, the genotype of the YMDD (tyrosine, methionine, aspartate, and aspartate) motif was tested on the serum samples at the end of first year of therapy or after by line probe assay according to the instructions of the manufacturer (INNO-LiPA HBV DR, Innogenetics NV, Belgium).

Leptin ELISA:

The quantitative measurement of leptin in serum was performed using a leptin enzyme immunoassay or ELISA kit (DRG Diagnostics, Marburg, Germany), according to the manufacturer’s instructions. Briefly, 100 µl of diluted leptin conjugate were dispensed into each well of the microtiter plate and incubated at room temperature for 1 h. The contents of the wells were shaken out and the wells rinsed three times with diluted wash solution. Into each appropriate well were dispensed 50 µl of samples (diluted 1:5) and standards at concentrations of 0, 0.8, 1.6, 3.1, 6.2, 12.5, and 25 ng/ml. Fifty microliters of leptin antibody were then dispensed into the center of each well to achieve complete mixing, and the plate was incubated overnight at 4°C in a humidity chamber. The contents of the wells were shaken out, the wells rinsed thrice, and residual droplets removed. One hundred microliters of diluted second antibody were dispensed into each well and incubated at room temperature for 1.5 h. The contents of the wells were shaken out and the wells washed three times. One hundred microliters of horseradish peroxidase enzyme

complex were dispensed into each well and incubated at room temperature for 45 min. Removal and washing of the wells were repeated before 100 µl of tetramethylbenzidine substrate solution were added and then incubated at room temperature for 20 min. The enzymatic reaction was terminated by adding 50 µl of sulfuric acid stop solution into the center of each well, and the absorbance at 450 nm was determined using an ELISA microtiter plate reader (Tecan, Salzburg, Austria). A standard curve was constructed by plotting a graph of the absorbance of each reference standard against its corresponding concentration in nanograms per milliliter. The leptin concentration of each serum sample was determined by using the corresponding absorbance to extrapolate the value from the standard curve and multiplying this by the dilution factor of 5. The manufacturer claims that the lowest detectable level of leptin distinguishable from the zero standard is 0.2 ng/ml and that the correlation of the enzyme immunoassay with a commercially available radioimmunoassay is 0.95. Interassay and intra-assay reproducibility was analyzed by the manufacturer by determining the coefficients of variation, which ranged between 3.6 and 7.8 and between 4.1 and 5.4%, respectively.

Serum Ghrelin ELISA:Serum Ghrelin level is measured by the Desacyl-Ghrelin ELISA which is an enzymatically amplified

"two-step" sandwich-type immunoassay. In the assay, standards, controls and unknown plasma samples are incubated in microtitration wells which have been coated with anti-desacyl ghrelin monoclonal antibody. After incubation and washing, the wells are treated with another anti-ghrelin detection antibody labeled with the enzyme horseradish peroxidase (HRP). After a second incubation and washing step, the wells are incubated with the substrate tetramethylbenzidine (TMB). An acidic stopping solution is then added and the degree of enzymatic turnover of the substrate is determined by absorbance measurement at 450 nm. The absorbance measured is directly proportional to the concentration of desacyl ghrelin present. A set of desacyl ghrelin standards is used to plot a standard curve of absorbance versus desacyl ghrelin concentration from which the desacyl ghrelin concentrations in the unknowns can be calculated (Hosoda, H. et al. 2000 and Matsumoto, M. et al.2001)

Patients were followed at monthly intervals during the treatment and follow up period and for the first 6 months of end of treatment. After 6 months of follow-up; patients were seen in 3 months intervals. Blood was drawn during each visit for biochemistry and for subsequent virological testing. Response to treatment was assessed as normalization of ALT (biochemical response), suppression of HBV DNA to <500 000 copies/mL and a ≥2 decrease of the Knodell score on liver biopsy (histologic response). The second liver biopsy was done at the end of therapy. Biochemical and virologic responses were assessed at the end of treatment, at 6 months of follow-up (short-term follow-up) and after a median follow-up of 18 months (long-term follow-up). Clinical relapse was defined as return of HBV DNA to detectable levels on two consecutive measurements performed 1 month apart after treatment cessation and clinical breakthrough as detectable HBV DNA during treatment after a period where HBV DNA levels were not detectable. Secondary measures of response included loss of HBsAg and HBsAg seroconversion (loss of HBsAg and presence of HBsAb) and undetected HBV DNA. Adverse events and side effects were reported on each visit

Statistics

Pretreatment and postreatment liver biopsy comparisons were made using the paired t -test. Biochemical and virological responses were analysed with the χ 2 test and Fischer Exact test. The Wilcoxon signed rank test was used for real time HBV DNA level comparisons. For comparisons of patients baseline values the Mann-Whitney U -test was applied. The Mann-Whitney U -test and the chi-square tests were used for evaluation of baseline ALT and HBV DNA levels between short-term relapser and nonrelapser patients. A P -value of less than 0.05 was considered as statistically significant. The protocol treatment population was used for

analysis of biochemical and virologic efficacy measures and included only patients who continued treatment and follow up.

Results:

This study included 82 patients; Eleven cases were withdrawn prematurely either because of loss of follow up or due to severe side effects of medications. They are divided into the 3 the groups of treatment as shown in table 1. Their ages, sex distribution and some clinical findings are presented in tables 1 and 2. History of schistosomiasis was found in 10/23, 9/23, and 12/25 in the three groups.

In the LAM arm one patient developed acute variceal bleeding in the eighth month of the treatment period and was not further evaluated; another female was withdrawn because she wants to get pregnancy. All patients used the 100 mg LAM dose throughout the study. In the IFN arm three patients (one male and 2 females) discontinued IFN because of side effects and one lost follow up. In the LAM + IFN arm, four patients discontinued IFN because of side effects and another patient discontinued treatment as a result of private problems. There was no difference in the three treated groups with respect to age, gender, baseline ALT and HBV DNA levels and the proportion of cirrhotic cases

There was overall significant reduction in liver transaminases and bilirubin but normal values are attained in lower cases in all groups. In lamivudine group, 30.4% showed complete biochemical and virological response to therapy with the mean ALT level of 35.29 ± 5.06 u/dL and AST level of 30.00 ± 2.52 u/dL in responding patients in comparison to 121.81 ± 28.23 u/dL and AST level of 107.25 ± 39.48 u/dL in non-responding patients after treatment. Similar response of bilirubin to therapy was observed (tables 5,7,10,13). The mean viral load after treatment in responding cases reached 114286 ± 1951.8 copies /ml while in non-responding cases it was not reduced significantly below the accepted level of 5 X 105 /ml (4991875.00 ± 2663483.23). (tables 13). Two cases showed initial biochemical and virological response at the third month of treatment but relapsed again with increase of their enzymes and viral load (breakthrough). These two patients were found positive for YMDD mutants at the end of first year. Discontinuation of treatment didn’t lead to any relapse in this group. However, the response rate is relatively low in this study. After 24 months, YMDD mutants were found in five patients in this group (21.7%). There are no significant adverse reactions or side effects in patients continuing treatment (table1).

In pegylated IFN group, 47.8% showed complete biochemical and virological response to therapy with the mean ALT level of 29.82 ± 5.72 u/dL and AST level of 22.64 ± 3.53 u/dL in responding patients in comparison to 122.65 ± 40.50 u/dL and AST level of 112.33 ± 23.02 u/dL in non-responding patients after treatment. Similar response of bilirubin to therapy was observed (table 5,8,11, & 14). The mean viral load after treatment in responding cases reached 672.73 ± 647.83copies /ml while in non-responding cases it was not reduced significantly below the accepted level of 5 X 105 /ml (4991875.00 ± 2663483.23). (table 14). No YMDD mutants were detected during or after treatment. The most common adverse events were those known to occur with conventional interferon alfa therapy, including pyrexia, fatigue, myalgia, and headache. Depression was recorded in 2 patients, but was not severe to stop the medicine (table 1).

In combination therapy group, 32 % showed complete biochemical and virological response to therapy with the mean ALT level of 30.00 ± 3.12 u/dL and AST level of 23.75 ±

2.55 u/dL in responding patients in comparison to 110.33 ± 22.74 u/dL and AST level of 144.71 ± 44. 18 u/dL in non-responding patients after treatment. Similar response of bilirubin to therapy was observed (table 6,9,12,&15). In responding cases the mean virus level was 340.00 ± 367.25 copies/ml after treatment while the mean viral load in non-responding cases was 5818742.94 ± 3448750.88 /ml which was not reduced significantly below the accepted level of 5 X 105 /ml (4991875.00 ± 2663483.23). (table 15). YMDD mutants were detected in 3 patients after the end of treatment (12%). Side effects were the same as in group II, with depression detected in 4 patients. Also it was not severe to stop the medicine (table 1).

HBeAg and HBsAg seroconversion were detected more in patients treated by pegylated

interferon and combination therapy an but not statistically significant (table 16&17). HBeAg seroconversion was detected in 26.09%, 39.13 % and 52% while HBsAg seroconversion was found in 17.39%, 30.43% and 28% in patients treated by lamuvidine, interferon and combination therapy; respectively; after treatment.

The mean serum ferritin levels in all patients and each group were found higher than normal (tables 19-21) and were reduced significantly after treatment also in all groups with significantly more reduction in responding than non-responding patients (P< 0.01).

Table 22 showed the values of serum ghrelin and leptin before and after treatment in all groups. There are statistically significant differences between the levels of ghrelin and leptin before and after treatment in all groups (P <0.05), which is more significant in those responding to treatment (P < 0.01) than those not responding with correlation between the changes in these factors and the decrease of viral load. No significant differences between the three groups in the serum levels before or after treatment in these factors.

Histological activity index (HAI score) was found in this study to be correlated with liver

enzymes, Bilirubin, HBsAg and HBeAg sero-positivity, and viral load before treatment. The change in histological activity index (HAI score) is significantly better for interferon than lamuvidine therapy (P=0.014). The changes in histological activity index (HAI score) in combination therapy group is more than lamuvidine group but didn’t reach statistical significance. Improvement of HAI score by two or more scores was found in 21.74%, 47.83% and 40% and improvement by only one score is found in 43.48%, 34.78% and 52% in patients treated by lamuvidine, interferon and combination therapy; respectively; after treatment. The changes in histological activity index (HAI score) is significantly better for responding patients than non-responding in all group (P < 0.01) (tables 18).

DISCUSSION:The treatment of hepatitis B virus (HBV) infection continues to evolve rapidly. As more

data become available, the therapeutic options will increase, but it may be increasingly difficult to develop consensus guidelines. Currently, 3 oral agents, as well as interferon, are approved by the US Food and Drug Administration (FDA) for the treatment of hepatitis B. Interferon alfa-2b was approved in 1992; lamivudine in 1998; adefovir in 2002; and entecavir was recently approved in 2005. The pegylated interferons are not yet approved for treatment of hepatitis B in the United States (37).

There are 2 strains of HBV, one that produces the early or "e" antigen (wild-type) and one that does not. The latter is often called the precore mutant due to a translational defect, and worldwide, this variant is an increasingly prevalent form of the virus, now comprising 30% to

50% of all hepatitis B cases. The predominant difference in the therapeutic approach to these 2 viral strains is the endpoint of treatment. In hepatitis B e antigen (HBeAg)-positive patients, the endpoint of treatment is the disappearance of HBeAg and, ideally, the development of hepatitis B e antibody (HBeAb). Absence of both HBeAg and HBeAb might represent precore mutants. Loss of HBeAg is generally accompanied by loss of HBV replication. However, when this endpoint is achieved, the duration of therapy needed to "solidify" the results is not truly known.

In Egypt, treatment of chronic HBV is not extensively studied and there were no comparative studies between different treatments all together. Also, worldwide, few such studies were performed. Some compared the use of lamuvidine to the combination of interferon and lamuvidine with little or no significant differences in achieving both end of treatment and sustained virological responses. However, LAM/IFN combination did appear to decrease the development of YMDD mutant strains compared with LAM monotherapy (27, 28). Another study compared pegylated interferon with combination therapy. In this study the rate of HBeAg seroconversion in patients who received pegylated interferon monotherapy was slightly better than that observed in patients receiving combination pegylated interferon and lamivudine (32% vs 27%), even though viral suppression was much more robust in the combination therapy group (69% of patients achieved suppression of HBV DNA < 400 copies/mL vs only 25% of the pegylated interferon monotherapy group).

In this study, the three arms were comparable showing no significant differences in biochemical and virological response. Thus, from the virological point of view, three types of therapy are similar and still far from the hope of treatment of HBV. However, the development of YMDD resistance with the use of lamuvidine is a major concern and if a new nucleoside analogue can be added to or replace this drug to delay the development of resistance, such medications would be the best for their safety, route of administration and cost.

Also, it was found that no significant differences in HBsAg and HBeAg seroconversion between the three groups despite more seroconversion in patients treated by combination therapy and pegylated interferon than lamuvidine. This, in addition to the rare development of YMDD mutants and the significantly better histological response; puts pegylated interferon in front of lamuvidine in the correct road to combat the disease. However, this is far from ideal and needs very big work.

Some approaches were explored to increase the response rate in chronic HBV infection. One approach was to use lamuvidine alone for 2 months before the combination therapy to reduce the viral load which might give better virological response but on the other hand it also reduced the transaminase levels that might reduced such response (29). Another approach was using pegylated IFN for 2 months before a 6 month therapy of LAM/IFN combination with further LAM monotherapy for an additional 28 weeks. With this regimen, the seroconversion rate was reported as 50% in the combination treatment group compared with 10% in the LAM monotherapy group.[30] However, these data are still preliminary and are based only on the first 40 patients who finished treatment and 6 months of follow-up.)

The more recently introduced nucleotide analogue of adenosine monophosphate; adefovir, does not share cross-resistance with nucleoside compounds such as lamivudine, emtricitabine, telbivudine, and entecavir. The latter makes this agent an optimal choice for patients with resistance to any of these other compounds. Additionally, as a first-line agent, it appears that each additional year on therapy continues to yield better results. In one study HBeAg

seroconversion rate improved from 12% at 48 weeks to 29% at 96 weeks, and to 43% by week 144. HBeAg loss occurred in 51% of patients by week 144, and 56% of patients had serum HBV DNA < 1000 copies/mL at week 144 (31). These findings suggest that therapy with adefovir should be continued beyond 48 weeks to increase HBeAg loss and seroconversion if it has not yet occurred.

Entecavir, the most recently approved of the oral antiviral therapies for hepatitis B, is a nucleoside analog of 2'-deoxyguanosine. In 3 separate studies (32-34) submitted to the FDA for registration, this agent was evaluated in HBeAg-positive (0.5-mg dose), HBeAg-negative (0.5-mg dose), and lamivudine-resistant patients (1-mg dose), and was found to be equivalent to lamivudine in terms of HBeAg seroconversion, but superior in terms of viral suppression. In HBeAg-negative patients, viral suppression was also found to be superior to that observed with lamivudine

The most profound seroconversion rates were reported by Wursthorn and colleagues [35] in a small trial assessing the virologic and serologic outcome in patients with chronic hepatitis B treated with combination pegylated interferon alfa-2b (1.5 mcg/kg/week) and adefovir (10 mg/day). This study involved 26 patients treated for 48 weeks; 23 of these patients (the majority were men and 15 were HBeAg-positive) had been analyzed and found to have 54% HBeAg loss, 28% seroconversion, and, most impressively, a 2.2-log10 reduction in closed circular (ccc) DNA in paired liver biopsies (cccDNA is a key intermediate in HBV replication and intracellular cccDNA is the reservoir responsible for the persistence of chronic hepatitis B infection and for disease reactivation after stopping therapy). All subjects in this study will be continued for an additional 96 weeks of adefovir monotherapy after the 48 weeks of combination therapy.

In this study, the mean serum ferritin level was found to be higher than normal and was reduced significantly after treatment in all groups with significantly more reduction in responding than non-responding patients. Thus, all types of treatment given in this study have a beneficial effect on this parameter that has been consider as an inflammatory marker in patients with chronic viral hepatitis. As might be expected, the effect is more pronounced in patients showing response to treatment than the non-responding patients with no differences between groups. Thus, it is not drug- related effect but it may be due to reduction of inflammatory process even without complete or sustained response. Similar results were found in a previous study where lamivudine treatment was found to reduce the serum ferritin levels in chronic viral hepatitis B patients and decreases of ferritin levels was found to be more significant in patients exhibiting virological, serological and biochemical responses (Liu et al., 2004) (41). Thus, the dynamic observation of serum ferritin levels in patients with chronic viral hepatitis B during treatment might be helpful for monitoring and predicting patients' responses to the therapy.

In one study, the high ferritin levels in patients with HCV infection and those with combined HCV + DM were attributed most probably to HCV infection and the associated damage of hepatic cells (cases with congenital iron overload were excluded from this study). Also, patients with HCV and those with both HCV and diabetes mellitus had a significantly higher serum level of ferritin in comparison to patients with DM and the control subjects. This high ferritin most probably represents an increase in the acute phase reactants (Elsammak et al., 2005) (40). It has been shown that increased hepatic iron overload may be a cofactor in the expression of many liver diseases including HCV(43) and HBV (40) and it has been postulated that iron overload may exacerbate inflammation and fibrosis in chronic hepatitis viral infection.(44,45) Furthermore, such chronic infection has been associated with mild to moderate liver iron

loading (46,47). Iron can catalyze the conversion of poorly reactive free radicals into highly active free radicals. The highly active radicals can attack cell membrane lipids, proteins and DNA causing tissue damage (48,49).

This study showed statistically significant differences between the levels of ghrelin and leptin before and after treatment in all groups, which were more significant in those responding to treatment than those not responding. Serum ghrelin was found to increase and leptin to decrease in all groups after treatment without significant differences between these groups. Such changes seam to be related to the disease process which can be explained by these similar changes in all groups and the significant correlation with viral load found in this study before and after treatment. It was mentioned before that, the hyper-catabolic state frequently encountered in chronic liver disease, anorexia and reduced food intake worsen the malnutrition. Also, ghrelin was found to act as a counterpart of leptin in regulation of food intake and fat utilization. It induces appetite and increases food intake in humans, thus responsible for long-term regulation of body weight (54). Also, in cirrhosis and HCC due to HBV or HDV, serum ghrelin levels were found to be increased with a corresponding decrease in serum leptin concentrations, acting as a physiological counterpart of ghrelin (52). Another study found decreased serum leptin in HBV and HCV patients compared with healthy individuals and the nonviral liver disease group (55). However; in another study, patients with cirrhosis (due to HBV or HCV) were found to have higher serum leptin levels compared to those with lower fibrosis stage and hepatitis B patients with lower leptin levels responded better to antiviral treatment with lamivudine than those with higher leptin levels (56). In another one, patients with chronic hepatitis B virus (HBV) infection were found to have higher serum levels of leptin than healthy individuals, and the amount of the hormone increased significantly with increasing severity of liver fibrosis, and decreased after peginterferon alfa-2a treatment (57). These studies suggested that leptin and ghrelin systems might be involved in the immunopathology of chronic viral hepatitis (53).

The results of this study are matching with results from other areas as discussed earlier. Therefore, it seems that no role for the association of HBV with schistosomiasis nor for the genotypes of the virus. Also it seems that no racial differences in response of the patients to different treatments.

Conclusion: In this study, no significant differences in biochemical and virological response between the three arms of treatment. Thus, from the virological point of view, three types of therapy are similar and still far from the hope of treatment oh HBV. However, the development of YMDD resistance with the use of lamuvidine is a major concern and if a new nucleoside analogue can be added to or replace this drug to delay the development of resistance, such medications would be the best for their safety, route of administration and cost. The more HBsAg and HBeAg seroconversion in patients treated by combination therapy and pegylated interferon than lamuvidine, in addition to the rare development of YMDD mutants and the significantly better histological response; puts pegylated interferon in front of lamuvidine in the treatment of this disease. However, still the seroconversion and viral response is far beyond the goal and the door is widely open for more trials and different combinations to get the best effect adding new drugs recently approved for such infection such as adefovir, enticavir and others. Also, the dynamic observation of serum ferritin, leptin and ghrelin levels in patients with chronic viral hepatitis B during treatment might be helpful for monitoring and predicting patients' responses to the therapy.

Table 1: Patient characteristics and adverse events in all groups of treatment.

groups Total

Lamivudine group Peg IFN groupCombination

therapy

SexDistrib

maleTreated Withdrawn Treated Withdrawn Treated Withdrawn

4815 1 15 2 18 2

female 8 1 8 2 7 3 23Total number 23 2 23 4 25 5 71History of schistosomiasis

10/23 1/2 9/23 1/4 12/25 2/5 31/71

Adverse events:

PyrexiaFatigueMyalgiaarthralgiaHeadacheAnorexiaAlopeciaDiarrheaInsomniaVertigoNauseaVomitingSore throatRigorsCoughPruritus

1423112110011102

1715123732112211122

1816135641011322123

363527111485233544347

Haematolog.AbnormalitiesNeutropeniaThrombocytopeniaAnaemia

001

211

110

321

Discontinuation -adverse reaction-loss of follow up

11

31

31

73

Table 2: age and some clinical data of patients in all groups.

Item groups

Lamivudine group Peg IFN group Combination therapyMean Std Deviation Mean Std Deviation Mean Std D.

age 41.13 7.93 35.30 9.84 35.92 8.28liver/MCL 14.17 .80 13.77 1.14 13.46 .77liver/ML 9.90 1.20 9.77 1.14 9.48 1.63PV 12.00 1.04 11.37 .98 11.95 .95Spleen/long axis 13.96 1.34 14.68 1.74 15.18 1.20Spleen/short axis 5.71 .70 6.56 .69 6.50 .63SV 9.30 1.18 8.91 .72 8.74 1.07

Table 3: patient biochemical response in different groups

7 30.4% 11 47.8% 8 32.0%

16 69.6% 12 52.2% 17 68.0%

responding patients

Non-responding patients

Count Col %

lamivudine group

Count Col %

peg IFN group

Count Col %

combination therapy Group

groups

Table4: ALT in lamuvidine group according response.

groups

Responding patients Non-responding patients Total patients

Mean Std Deviation Mean Std Deviation Mean Std DeviationALT/before treatm. 152.43 17.77 177.88 39.46 170.13 35.93ALT-1 month 72.43 29.70 110.94 44.62 99.22 43.89ALT-3 month 72.86 34.15 110.25 49.24 98.87 47.76ALT-6 month 55.57 22.17 114.13 50.66 96.30 51.41ALT-12 month 44.86 11.08 142.69 46.62 112.91 60.28ALT-18 month 41.29 4.11 145.44 56.26 113.74 67.56ALT-24 month 37.43 4.12 120.56 37.99 95.26 50.18ALT-30 month 35.29 5.06 121.81 28.33 95.48 47.03ALT/36 month 31.43 2.07 111.19 38.45 86.91 49.16

Table 5: ALT in peg-IFN group according response

groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationALT/before treatment 125.64 22.19 167.83 53.44 147.65 46.00ALT-1month 76.18 22.84 144.17 55.16 111.65 54.44ALT-3 month 59.91 20.51 144.17 46.58 103.87 55.93ALT-6 month 60.64 31.32 157.50 56.12 111.17 66.85ALT-12 month 50.36 21.75 129.17 32.91 91.48 48.75ALT-18 month 43.64 16.36 131.50 16.75 89.48 47.71ALT-24 month 40.91 6.53 134.00 32.02 89.48 52.85ALT-30 month 34.64 6.22 114.17 20.30 76.13 43.29ALT/36 month 29.82 5.72 110.33 22.74 71.83 44.32

Table 6: ALT in combination therapy group according responsegroups


Mean Std Deviation Mean Std Deviation Mean Std Deviation

ALT/before treatm. 151.50 64.05 155.53 37.50 154.24 46.23

ALT-1 60.75 12.66 143.35 38.98 116.92 51.05

ALT-3 51.75 10.59 143.47 27.30 114.12 49.36

ALT-6 45.00 5.76 146.59 35.43 114.08 56.44

ALT-12 40.75 2.96 155.59 30.07 118.84 59.96

ALT-18 36.75 2.31 135.00 24.46 103.56 50.88

ALT-24 39.25 5.57 123.12 29.95 96.28 46.92

ALT-30 32.50 3.25 141.65 44.80 106.72 63.57

ALT/36 30.00 3.12 122.65 40.50 93.00 55.15

Table 7: AST in lamuvidine group according response

groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationAST/before treatment 138.29 37.17 149.00 50.80 145.74 46.50AST-1 month 85.29 15.14 126.63 51.85 114.04 47.68AST-3 month 70.29 35.07 104.69 62.78 94.22 57.31AST-6 month 53.14 17.83 101.13 45.41 86.52 44.74AST-12 month 38.57 9.90 112.00 45.39 89.65 51.24AST-18 month 31.71 10.63 108.56 26.76 85.17 42.73AST-24 month 27.29 5.68 107.50 42.45 83.09 51.59AST-30 month 28.29 7.39 103.88 33.32 80.87 45.13AST-36 month 30.00 2.52 107.25 39.48 83.74 48.84

Table 8: AST in peg-IFN group according response

groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationAST/before treatment 79.09 10.32 164.67 45.12 123.74 54.56AST-1 month 57.27 6.36 142.83 52.52 101.91 57.51AST-6 month 41.55 4.89 141.50 56.55 93.70 64.93AST-12 month 35.45 4.99 116.83 35.67 77.91 48.74AST-18 month 31.09 4.70 113.00 23.34 73.83 45.08AST-24 month 26.09 5.87 116.83 25.62 73.43 49.92AST-30 month 25.45 2.42 101.83 13.01 65.30 40.11AST-36 month 22.64 3.53 112.33 23.02 69.43 48.68

Table 9: AST in combination therapy group according response.

groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationAST/before treatment 131.00 58.42 183.76 45.68 166.88 54.93AST-1 month 60.75 10.57 167.88 40.97 133.60 61.26AST-3 month 44.50 3.59 155.00 33.15 119.64 59.19AST-6 month 38.75 2.66 156.47 36.76 118.80 63.59AST-12 month 34.50 2.33 154.65 35.46 116.20 64.12AST-18 month 30.00 3.63 153.35 35.93 113.88 65.68AST-24 month 28.50 5.04 141.94 30.68 105.64 59.60AST-30 month 25.25 4.43 151.59 41.02 111.16 68.89AST-36 month 23.75 2.55 144.71 44.18 106.00 67.97

Table 10: Bilirubin in lamuvidine group according response groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationBilirubin/before ttt 1.40 .19 2.41 .87 2.10 .87Bilirubin-1 month 1.33 .17 2.36 .73 2.04 .78Bilirubin-3 month 1.24 .13 2.34 .66 2.01 .76Bilirubin-12 month 1.23 .05 2.37 .87 2.03 .90Bilirubin-18 month 1.23 .20 2.40 .63 2.04 .77Bilirubin-24 month .90 .21 2.57 .79 2.06 1.03Bilirubin-36 month .91 .07 2.53 .60 2.03 .91

Table 11: Bilirubin in peg-IFN group according response


Mean Std Deviation Mean Std Deviation Mean Std DeviationBilirubin/before ttt 2.07 .51 2.70 .70 2.40 .68Bilirubin-1 month 1.67 .37 2.68 .52 2.20 .68Bilirubin-3 month 1.27 .20 2.40 .42 1.86 .66Bilirubin-12 month 1.51 .36 2.53 .52 2.04 .68Bilirubin-18 month 1.14 .21 2.62 .51 1.91 .85Bilirubin-24 month 1.03 .19 2.55 .60 1.82 .90Bilirubin-36 month .85 .09 2.48 .60 1.70 .94

Table 12: Bilirubin in combination therapy group according responsegroups


Mean Std Deviation Mean Std Deviation Mean Std DeviationBilirubin/before ttt 2.05 .34 2.86 .70 2.60 .71Bilirubin-1 month 1.75 .37 2.72 .65 2.41 .73Bilirubin-3 month 1.53 .24 2.52 .69 2.20 .74Bilirubin-12 month 1.25 .18 2.48 .86 2.09 .92Bilirubin-18 month .95 .12 2.40 .57 1.94 .84Bilirubin-24 month .75 .05 2.42 .61 1.88 .94Bilirubin-36 month .75 .12 2.42 .68 1.88 .97

Table 13: Viral load in lamuvidine group according response

groups


Mean Std Deviation Mean Std Deviation Mean Std DeviationViremia before ttt 1492857.14 605824.90 6921875.00 3959375.74 5269565.22 4160849.43Viremia after 6 month 448571.43 210984.09 4121250.00 3083454.50 3003478.26 3079004.57

Viremia after 12 months 8157.14 8831.36 3881968.75 3012436.45 2702982.61 3083657.74

viremia after 18 months 1828.57 2592.76 4133237.50 2378065.99 2875852.17 2762939.60


Table 14: Viral load in peg-IFN group according response

groups


MeanStd

Deviation Mean Std Deviation Mean S. DeviationViremia before ttt 2172727.27 1323511.17 10268333.33 3588367.15 6396521.74 4932696.67Viremia after 6 month 388509.09 412438.18 8916666.67 3266450.21 4837982.61 4938124.61



Viremia aftter 24 months 672.73 647.83 7870000.00 2728902.54 4165306.52 4410486.68

Table 15: Viral load in combination therapy group according responsegroups


Mean Std Deviation Mean Std Deviation Mean Std Deviation

Viremia before ttt 1972500.00 770727.86 10151764.71 4374320.28 7534400.00 5300357.76

Viremia after 6 month 13775.00 7668.26 7652776.47 3927052.85 5208296.00 4848521.87



Viremia aftter 24 months 350.00 395.16 5818742.94 3448750.88 3956745.20 3950149.72

Table 16: HBe seroconversion in patients of all groups before, during and after treatmentgroups

Time of measurement

HBe Ag positivity 6m




Lamivudine group

positive 17 17 15 17negative 6 6 8 6

Peg IFN group


Combination therapy


Table 17: HBs Ag seroconversion in patients of all groups before, during and after treatment

groups

Time of measurement

HBs`AgPositivity 6m

HBs`Ag positivity 12m



Lamivudine group

positive 23 21 19 19

negative 0 2 4 4

Peg IFN group

positive 18 18 16 16

negative 5 5 7 7

Combination therapy


Table 18: Histopathological score changes after treatment in all groups

GroupsResponse Subgroup (Number of patients)

Responding patients Non-responding patientsHAI score changes HAI score changes

lamivudine group improvement by 2 or more 4 1

improvement by one 3 7no improvement 7worsening 1

peg IFN group

improvement by 2 or more 9* 2improvement by one 2 8no improvement 2

combination therapy Group

improvement by 2 or more 7 3improvement by one 1 12no improvement 2

*The change in histological activity index (HAI score) is significantly better for interferon than lamuvidine therapy (P=0.014). No significant differences in the changes in histological activity index (HAI score) between combination therapy group and other groups. The change in histological activity index (HAI score) is significantly better for responding patients than non-responding in lamivudine group (P < 0.01). The change in histological activity index (HAI score) is significantly better for responding patients than non-responding in peg-IFN group (P < 0.01). The change in histological activity index (HAI score) is significantly better for responding patients than non-responding in combination therapy group (P < 0.01)

Table 19: Serum ferritin (ng/ml) before and after treatment in all patientsSerum ferritin in total patients Mean Std. Deviation

S. Ferittin before treatment 239.0141 59.23693

S. Ferritin after treatment 195.8592 50.47441

There is significant reduction of serum ferritin in all patients after treatment (P < 0.01)

Table 20: Serum ferritin (ng/ml) before and after treatment in all patients according response (Normal ferritin in male = 30-233 ng/ml and in females = 6-186 ng/ml

There is more significant reduction after treatment in responding patients than non-responding (P < 0.01)

Table 21: Serum ferritin (ng/ml) before and after treatment in all groups according response (Normal ferritin in male = 30-233 ng/ml and in females = 6-186 ng/ml):

S ferritin according response Mean Std. Deviation

Ferritin before treatment in Responders 247.4167 12.72383Ferritin after treatment in Responders 175.1759 3.26109

Ferritin before treatment in Non-responders 237.1961 17.51759

Ferritin after treatment in Non-responders 209.1156 8.55865

254.0000 69.98333

177.8571 48.67042

235.5000 48.58120

205.3125 46.35475

249.6364 64.76615

171.5455 58.75604

255.5000 73.15053

218.9167 54.48846

232.7500 54.72464

176.1250 34.49405

220.5882 54.03362

203.1176 47.29546

S. Ferittin beforetreatment

S. Ferritin aftertreatment











ResponseResponding toLamuvidine

Non-responding tolamuvidine

Responding to Peg IFN

Non-responding to PegIFN

Responding toCombination therapy

Non-responding tocombination therapy

GroupLamuvidine group

Peg IFN group

CombinationTreatment Group

Mean Std. Deviation

There is significant reduction of serum ferritin in all patients and in all groups with more significant reduction in responding patients than non-responding (P < 0.01)

Table 22: Serum ghrelin and leptin (ng/ml) before and after treatment in all groups

179.6087 196.0000 15.6652 11.7913

29.29434 26.70036 5.15828 4.55052

168.1739 198.6522 16.8348 11.9130

25.55325 30.29943 5.05907 3.57699

154.4167 188.5000 16.9250 12.0958

19.22389 20.42164 5.08299 4.04082

167.2143 194.3000 16.4814 11.9357

26.71096 26.03863 5.05851 4.01754

Mean

Std. Deviation

Mean

Std. Deviation

Mean

Std. Deviation

Mean

Std. Deviation

GroupLamuvidine group

Peg-IFN group

Combination group

Total

SerumGhrelin before

treatment

SerumGhrelin after

treatment

Serum leptinbefore

treatment

SerumLeptin aftertreatment

There are statistically significant differences between the levels of ghrelin and leptin before and after treatment in all groups (P <0.05), which is more significant in those responding to treatment (P < 0.01)than those not responding with correlation between the changes in these factors and the decrease of viral load. No significant differences between the three groups in the serum levels before or after treatment in these factors

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إستخدام التنترفيرون طويل المفعول واللوموفيدين فصصى عل ج المرضصصى المصصصريين المصصصابين)Hbe Ag positiveباللتهاب الكبدى المزومن ب ايجابي الدللة (

شندى ومحمد شندى شريف* و تنعيمة العشرى** وعل ء عوض* و ومعتز صيام * ومعهد تيودور بلهارس للبحاث الكيميا ء اللكلينيكية* قسمى الومراض المتوطنة والكبد والجهاز الهضمى و**

العربى الملخص

فى ومصر لم يتم حتى وقت اجرا ء هذا البحث دراسة عل ج الفيروس الكبدي ب دراسة ومستفيضة لكم أتنه ل يوجصصد دراسصصات ومقارتنة بين العل ج بالتنترفيرون والعل ج باللوموفيدين والتى أثبتت الدراسات العالمية عدم وجود أو وجود فصصروق قليلصصة بينهصصا فى تنتائج العل ج. ولذلك لكان الهدف ومن البحث هو ومقارتنصصة تنتائصصج عل ج هصصذا النصصوع ومصصن الفيصصروس الكبصصدى المزومصصن ب ايجصصابي

فى المرضى المصريين باستخدام التنترفيرون طويل المفعول أواللوموفيدين أو لكلهما ومعا. و قد تم عمل الفحوصe الدللة وومتابعة المرضى بالتحاليل اللزومة للفيروس بجميع دللته وومستواه فى الدم وأثاره على الكبد قبل وأثنا ء وبعد العل ج وعينة

الكبد واختبار ظهور الطفرة المناعية للفيروس ضد اللوموفيدين.

% ومن المرضى فى ومجموعة اللوموفيدين قد استجابوا للعل ج استجابة فيروسية ولكيميائية٤,٣٠و قد أثبتت النتائج أن%). أوما فى ومجموعة التنترفيرون فقد اسصصتجاب حصصوالى (٧,۲١لكاوملة ومع ظهور طفرة ومناعية ضد الدوا ء فى خمسة ومرضى (

%) استجابة فيروسية ولكيميائية لكاوملة ومع عدم ظهور طفرات ومناعية ضد الدوا ء. وفى ومجموعة العل ج بالدوائين ومعصصا٥,٤٧ %). ١۲ %) ومن المرضى للعل ج وظهرت طفرة ومناعية ضد اللوموفيدين فى ثلثة ومرضى (٣۲فقد استجاب(

) أفضل تنسبيا فى المرض الذين تم علجهم بالتنترفيرون أوHBs Ag & HBe Ag و لكان اختفا ء دللت الفيروس ( بالدوائين ومعا عن ومجموعة اللوموفيدين ولكن بدون دللة إحصائية. أوما التحسن فى الفحص النسيجى لعينة الكبد فكصصان أفضصصل

إحصائيا فى المرض الذين تم علجهم بالتنترفيرون عن غيرهم.

فيروسية والكيميائية للمرضى فى الثلث ومجموعات لم تكن ومختلفة اختلفا ذويستنتج ومن هذا البحث الستجابة الكاوملة الدللة إحصائية ومع أتنها جميعها لم تصل إلى المستوى المرجو ومنها فى عل ج هذا المرض.

ولكان لظهور طفرة ومناعية ضد اللوموفيدين أهمية خاصة للبحث عن دوا ء أخر لستخداومه بدل ومنه أو ومعه لتجنب ذلصصك و عندئذ يكون استعمال هذه الدوية أفضل لسهولة تناولها وعدم خطورتها ورخص ثمنها. وقد لكان التنترفيرون طويصل المفعصول أفضل فى عل ج هذا المرض ومن حيث اختفا ء دللت الفيروس و التحسن فى الفحص النسيجى لعينة الكبد و عدم ظهور طفصصرة

ومناعية للفيروس. هذا وومازالت هذه الدوية بعيدة عن العل ج الومثل المرجو لهذا المرض.

pegylated interferon in cmbination with lamuvidine in hbv,reduced.final ,ghrelin, leptindoc

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