Of the estimated 170 million HCV carriers worldwide, almost 13% live in the Eastern Mediterranean region where prevalence rates of HCV genotype 4 ranges from 60% in Saudi Arabia to 90% in Egypt.

Sustained response of HCV Genotype 4 chronic active hepatitis (CAH) cases to standard interferon (IFN) treatment is very poor. The advent of pegylated–IFN and its reported superior response with other HCV genotypes prompted our clinical trial.  

Presented at the 53^rd AASLD in Boston, the current study evaluates Pegasys as monotherapy and in combination with ribavirin among 120 genotype 4 patients in Saudi Arabia. Following is the abstract summary:

Aim: To determine the efficacy and safety of Peg-IFN alfa-2a plus ribavirin at the end of 48 weeks treatment of HCV Genotype 4 histologically proven CAH cases.

Design: An open label, multicenter, clinical trial in which 120 Genotype 4 (Innolipa, Innogenetics) CAH patients meeting strict inclusion/ exclusion criteria were enrolled and randomized into two treatment groups of 60 each, as follows: Group A: Peg-IFN (180 mg / 0.5ml) qw plus ribavirin (400mgs bid); Group B: Peg-IFN (180 mg / 0.5 ml) qw;

Patients demographic data are shown in Table 1. Treatment duration is for 48 weeks to be followed for 24 weeks for sustained response. Patients are being monitored biochemically using serum ALT, virologically using serum HCV-RNA (COBAS AMPLICOR HCV MONITOR™ version 2.0) and histologically using liver biopsies, pre- and post treatment.  

Results: Using the reduction of 2 log drop and/ or HCV-RNA clearance at week 12 and week 24 to predict response and then at week 48 to confirm end of treatment response, 67% of patients on combination therapy and 59% of patients on PEG-IFN alfa-2a monotherapy responded virologically to treatment as shown in Table 2. Eighty percent  and 42% responded biochemically respectively. The drop-out rate was 10% and 7% among the two treatment groups; Peg + Rib and Peg monotherapy, respectively.

Conclusion: PEG-IFN alfa-2a (40 KD) plus ribavirin has a significantly higher virological (67%) and biochemical (80%) responses at week 48 than PEG-IFN alfa-2a monotherapy (59%, 42% respectively) for the treatment of Genotype 4 chronic active hepatitis cases. Hepatitis C genotype 4 CAH is responsive to Pegylated interferon.

TABLE 1:  Baseline characteristics and demographic data of HCV Genotype 4 Chronic Active Hepatitis patients      

Reference
O Shobokshi and others. PEG-IFN ALFA-2a (40KDA) AS A MONOTHERAPY OR IN COMBINATION WITH RIBAVIRIN SIGNIFICANTLY IMPROVE END OF TREATMENT RESPONSE RATE IN HCV GENOTYPE 4 CHRONIC ACTIVE HEPATITIS (CAH) PATIENTS. 53^rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.

The study included 290 patients (143 men, 147 women) with CHC and liver biopsy. The mean body mass index (BMI) was 24.1+/- 3.8 (38 % had BMI>25).

The proportion of genotype 1 and 3 were respectively 56 % and 21 %.135 patients (46.6%) had hepatic steatosis (mild = 21%; moderate = 10%; marked = 15%).
Fibrosis score was F0-F1 for 181 patients (62 %), F2 for 73 patients (25%), and F3-F4 for 36 patients (13%).

When comparing patients with or without liver steatosis, age, gender, source and duration of infection, alcohol consumption, cholesterol, triglycerides, were not significantly different.

Using univariate analysis, liver steatosis was associated with higher BMI (p = 0.005), higher serum ALT levels (p<10-3), higher glycemia (p=0.002), higher ferritinemia (p<10-3), HCV genotype 3 infection (p=0.001), high grade of necro-inflammation (p<10-3), and high stage of fibrosis (p=0.003).

When multivariate analysis was performed, liver steatosis was associated with HCV genotype 3 infection (p=0.033), higher ferritinemia (p=0.004) and at the limit of significance with BMI (p=0.05).

There was no significant association between fibrosis and liver steatosis.

Conclusion: Liver steatosis is a frequent histologic feature of CHC. Using multivariate analysis, liver steatosis is significantly and independently associated with HCV genotype 3 infection and higher ferritinemia (iron protein complex found in the liver and elsewhere).

The association of high BMI with steatosis was at the limit of significance.
Moreover, in multivariate analysis, liver steatosis is associated with HCV genotype 3 and not with the stage of fibrosis. Risk factors associated with liver steatosis could be different in different populations.

02/07/03

Reference
T Asselah and others. LIVER STEATOSIS IS ASSOCIATED WITH HCV GENOTYPE 3 BUT NOT WITH FIBROSIS. Abstract 734. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.
 

http://www.hivandhepatitis.com/hep_c/news/032103b.html

Abstract Summary

Some patients treated for chronic hepatitis C (CHC) still relapse after an end-of-treatment (EOT) virologic response (VR), particularly patients infected with HCV genotype 1.

The present study was a multicenter trial to determine the frequency of relapse in patients treated with Pegasys (peginterferon alfa-2a) plus Copegus (ribavirin) and to identify baseline parameters associated with viral relapse.

1375 CHC patients received Pegasys 180 mcg/week plus ribavirin 800-1200 mg/day for 24 or 48 weeks. Sustained VR was defined as undetectable HCV RNA at the end of follow-up; and relapse, as detectable HCV RNA following a documented EOT response.

At follow up, high baseline viral load, and, to a lesser degree, cirrhosis, were found to be associated with relapse, particularly in HCV genotype 1 patients.

Conclusions:

- Treatment with Pegasys/ribavirin results in lower relapse rates than monotherapy in all patients;

- CHC genotypes 2/3 patients experience lower relapse, regardless of ribavirin dose given, compared with HCV genotype 1 patients whose relapse is dependent on ribavirin dose and duration of treatment.

- More than 48 weeks treatment for CHC patients with high baseline viral loads, HCV genotype 1, and cirrhosis may be necessary and should be investigated.

03/21/03

Reference
V Balan and others. PREDICTORS OF VIROLOGIC RELAPSE IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) TREATED WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS) ALONE OR IN COMBINATION WITH RIBAVIRIN (COPEGUS). Abstract 3671.00. Abstracts of the 38th Annual Meeting of the European Association of the Study of the Liver (EASL).

HCV Genotype 6 Is More Responsive to Therapy Than Genotype 1

http://www.hivandhepatitis.com/hep_c/news/032103g.html

By Brian Boyle, MD
Hepatitis C virus (HCV) is a significant cause of chronic hepatitis which frequently progresses to cirrhosis or hepatocellular carcinoma. HCV has 6 distinct genotypes, labeled (understandably) 1 through 6.

While a significant amount of research has been conducted on genotypes 1-4, little is known about the treatment of genotype 6, which is uncommon in the United States but occurs with higher frequency in several Asian countries, including China, Vietnam and Thailand.

In a study published in The Journal of Infectious Diseases, researchers in Hong Kong investigated the treatment of HCV genotype 6 with interferon and ribavirin. The prospective study enrolled 40 patients with chronic HCV, 16 and 24 of who had genotype 6 and 1, respectively. The patients were treated with subcutaneous recombinant interferon a-2b and ribavirin for 12 months.

Of the 40 enrolled patients, an end-of-treatment response was detected in 12 (75%) patients with genotype 6 and in 10 (41.6%) patients with genotype 1 (P = .05). A sustained virological response (SVR) was present in 10 (62.5%) patients with genotype 6 and in 7 (29.2%) patients with genotype 1 (P = .04).

The authors conclude, “HCV genotype 6 has a better response to IFN treatment than HCV genotype 1 and is associated with a significantly higher SVR. A higher dose of IFN does not seem to increase the SVR rate in Chinese patients with genotype 1. Future trials should be performed to determine whether 6 months of combination therapy is adequate for patients with genotype 6.”

03/21/03

Reference
C Hui and others. Interferon and Ribavirin Therapy for Chronic Hepatitis C Virus Genotype 6: A Comparison with Genotype 1. The Journal of Infectious Diseases 2003; 187:1071–4.
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Short (14 Weeks) Combination Treatment with PEG-Intron Plus Ribavirin Produces a High Sustained Response Rate in Patients with HCV Genotype 2/3

Abstract Summary

The objective of this multicenter Norwegian trial is to determine the virological response rate after 14 weeks of combination treatment with PEG-Intron (peginterferon alfa-2b) and ribavirin in patients with hepatitis C virus (HCV) genotype 2/3 who experience early HCV clearance.

82 HCV RNA positive patients with genotype 2 or 3 have been included. All patients are treated with PEG-Intron 1.5 mcg/kg once weekly and ribavirin (800-1200 mg) daily. Treatment is stopped at week 14 in patients who are HCV RNA negative (Cobas Amplicor HCV monitor test, lower detection limit 100 copies/ml) at week 4 and 8. The remaining patients continue treatment until week 24.

63 patients have completed eight weeks or more of combination treatment. HCV RNA was negative at both week 4 and 8 in 45 (71%) patients and treatment is therefore discontinued at week 14 in these. The remaining 18 patients are receiving 24 weeks treatment.

The preliminary results show that 80% of those who receive short combination treatment with PEG-Intron plus ribavirin obtain sustained virological response 24 weeks after treatment stop (see table below).

Conclusion: This preliminary analysis suggests that in patients with HCV genotype 2/3 infection, a high sustained response rate may be obtained after 14 weeks of combination treatment.

03/28/03

Reference
O Dalgard and others. SHORT TREATMENT (14 WEEKS) WITH PEGYLATED INTERFERON ALPHA-2B AND RIBAVIRIN FOR THE TREATMENT OF HEPATITIS C GENOTYPE 2/3 INFECTION. Abstract 3818.00. Abstracts of the 38^th Annual Meeting of the European Association of the Study of the Liver (EASL).

The Degree of Steatosis Is Related to That of Fibrosis and the Impact Is More Marked in Genotype 1 Than in Genotype 3 Patients with Chronic HCV

Abstract Summary

A relationship between the degree of steatosis and the severity of fibrosis has been suggested in patients with chronic hepatitis C. Since the mechanism of steatosis in these patients may differ according to genotype, the aim of this French study was to evaluate whether or not the relationship between steatosis and fibrosis is dependent on genotype.

For this purpose, 310 consecutive patients (208 men, 102 women, mean age 42.8 * 10.8 years) with chronic hepatitis C: genotype 1=191, genotype 3=119 were studied.

Steatosis was graded as none, mild (< 10% of hepatocytes), moderate (10 to 30%) or marked (> 30%). Activity and fibrosis were determined according to METAVIR score.

The distribution of steatosis was as follows: none in 80 patients (26%), mild in 118 patients (38%) and moderate or marked in 112 patients (36%). The proportion of patients with moderate or marked steatosis was significantly higher in genotype 3 patients than in genotype 1 patients: 65/119 patients (55%) versus 47/191 patients (25%). A relationship between steatosis and fibrosis was observed in both groups of patients, but it was statistically significant only in those with genotype 1.

*p<0.001, **p=0.26.

Conclusions: These results confirm that in chronic hepatitis C, the degree of steatosis is related to that of fibrosis. They suggest however that the impact of steatosis on fibrosis seems to be more marked in genotype 1 patients than in genotype 3 patients.

03/28/03

Reference
C Hezode and others. RELATIONSHIP BETWEEN STEATOSIS AND FIBROSIS IN CHRONIC HEPATITIS C: EFFECT OF HCV GENOTYPE. Abstract 4345.00. Abstracts of the 38^th Annual Meeting of the European Association of the Study of the Liver (EASL).

 

It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis (fatty liver). In an international, multicenter, randomized trial, researchers assessed the effect of treatment with peginterferon or interferon alfa-2b (Intron A) and ribavirin on steatosis.

The investigators analyzed 1,428 naïve patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment.

At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes.

The variables associated with steatosis in logistic regression were genotype 3, triglycerides greater than 1.7 micromolar/L, body mass index greater than 27, age greater than 40 years, and septal fibrosis.

Patients were randomized to 1 of 3 treatment arms:

(1)     standard interferon (interferon alfa-2b [Intron A], 3 million units 3 times a week subcutaneously) plus ribavirin 1,000 to 1,200 mg/d for 48 weeks;

(2)     peginterferon alfa-2b [PEG-Intron] 1.5 microgram per kg per week for the first 4 weeks, followed by 0.5 microgram/kg per week for the next 44 weeks plus ribavirin 1,000 to 1,200 mg/d;

(3)     peginterferon alfa-2b 1.5 microgram/kg per week plus ribavirin 800 mg/d.

For patients in the groups receiving ribavirin 1,000 to 1,200 mg/d, the dose was adjusted for body weight (1,000 mg for <75 kg and 1,200 mg for 75 kg).

Liver biopsy specimens were processed using standard techniques and evaluated for stage of fibrosis and grade of activity according to the METAVIR scoring system,

In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors.

Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively. In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment.

Commentary

This study confirms the high prevalence (65%) of steatosis among patients with chronic hepatitis C and the association with genotype 3, overweight, high fasting serum glucose, triglycerides, male gender, and age. Steatosis was also associated with fibrosis stage.

There was an expected association between fibrosis and male gender, glucose, and BMI. Therefore, the inclusion of fibrosis in the multivariate model reduces the strength of the association between steatosis and male gender, BMI, and glucose.

Serum glucose and serum triglycerides also had significant impact on steatosis, independent of BMI, suggesting that insulin resistance without being overweight may be associated with steatosis.

For the first time, it has been clearly demonstrated that effective treatment of HCV leads to a reduction or disappearance of liver steatosis. The impact was particularly observed in patients with HCV genotype 3 infection.

In patients infected with genotype 3 HCV, most will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged.

The authors conclude, “The better understanding of factors related with steatosis will permit us to improve the management of patients. In patients infected with genotype 3 HCV, most of them will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged.”

07/04/03

Source

T Poynard and others. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 38(1): 75-85.

Selected References

LE Adinolfi and others. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33:1358-1364.

D Kumar and others. Hepatitis C virus genotype 3 is cytopathic to hepatocytes. Genotype-specific reversal of hepatic steatosis after sustained response to antiviral therapy. Hepatology 2002; 36:1266-1272.

A Monto and others. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002; 36:729-736.

L Rubbia-Brandt and others. Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 2001; 39:119-124.

L Serfaty and others. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. Journal of Hepatology 2001; 34:428-434.

In patients with hepatitis C virus (HCV)-genotype 1b and a high virus load (more than 1 Meq/ml by the DNA probe assay) the clearance of HCV-RNA was achieved in only 10% with a 6-month interferon (IFN) course.

The researchers therefore assessed the efficacy of prolonged IFN therapy in patients with HCV-genotype 1b and a high virus load.

A total of 51 patients with HCV genotype 1b who were given 6 million units (MU) of natural IFN-alfa daily for 8 weeks followed by three-times-weekly treatment with natural IFN-alfa for 16 weeks, were enrolled in this trial.

These 51 patients were randomly assigned to one of two schedule groups at the time of termination of the first IFN therapy.

The 48-week-group patients (n = 25) were given 6 MU of natural IFN-alfa by intramuscular injection three times weekly for 24 weeks, beginning within a week after the termination of the first IFN therapy.

The 72-week-group patients (n = 26) were given 6 MU of IFN-alfa by intramuscular injection three times a week for 48 weeks, beginning within a week after the termination of the first IFN therapy.

The therapeutic efficacy was evaluated 24 and 30 months after the initiation of the first IFN treatment. A virological response (VR) to IFN therapy was defined as the normalization of serum alanime amino transferase (ALT) level (ALT &lsim; 50 IU) and HCV-RNA negativity at the two time points. Biochemical response (BR) was defined as the normalization of serum ALT, but positivity for HCV-RNA, assessed by commercial Amplicor HCV qualitative assays, at the two time points.

The efficacy of IFN treatment was assessed in relation to the IFN administration schedule by intention-to-treat (ITT) analysis and per-protocol analysis.

With respect to the IFN regimen, VR occurred in 16.6% (4/24) of the patients in the 48-week-group with additional IFN and in 20% (5/25) in the 72-week-group with additional IFN by ITT analysis.

The BR rate was 33.3% (8/24) in the 48-week group and 48% (12/25) in the 72-week group.

The investigators conclude, “We found that prolonged IFN therapy could be a worthwhile treatment strategy for patients with HCV genotype 1b and a high serum virus load.”

06/11/03

Reference
Y Arase and others. Efficacy of prolonged interferon therapy for patients with chronic hepatitis C with HCV-genotype 1b and high virus load. Journal of Gastroenterology. Abstract Vol 38 (2):158-163. 2003.

Only few data on viral kinetics in hepatitis C virus genotype 4 infection are currently available. The initial sensitivity to IFN in genotype 1 identifies patients resistant to standard IFN/ribavirin (Jessner et al., Lancet 2001) or unlikely to achieve a sustained response to Pegasys (peginterferon alfa-2a / PEG-IFNa2a) plus ribavirin therapy. The researchers aimed to examine IFN sensitivity in genotype 4 infection.

Viral load was measured using the Cobas Amplicor Monitor HCV Assay v2.0 before and 24h after 10 MU PEG-Intron (IFNalfa2b) (days 0, 1), and before and during daily 5 MU IFNalfa2b (days 7, 8, 14, 20) administration. Thereafter, combination therapy (1-1.2g ribavirin daily) with either 5MU IFNalfa2b every other day (n=5), 1.5 mg/kg PEG-IFNalfa2b weekly (n=7) or 180mg PEG-IFNalfa2a weekly (n=10) was given.

24h log change after 10 MU IFNalfa (24lc10) was 1.34 (0.25-2.48; median-range) and after 5 MU IFNalfa was 0.99 (0.13-2.22, p<0.001). 24lc10 was 1.47 (0.40-2.48) for month 6 responder (n=18), 0.36 (0.25-0.57; p=0.006) for nonresponder (n=4) and highly predictive on ROC analysis (AUC=0.867; p=0.007).

Currently 6 responder have completed follow-up, one relapsed after stopping treatment at month 8 (24lc10=1.88), one relapsed after the full 12 month course (24lc10=0.44), and 4 became sustained responder (24lc10=1.59 [1.26-1.91])

Conclusion: Primary interferon resistance as in genotype 1 occurs in genotype 4 as well although at a lower rate. Overall response to IFN is therefore significantly better than in genotype 1. A 24h response to standard interferon has high predictive power for on treatment response as in genotype 1.

05/21/03

HepCgen genotyping service helps fight Hepatitis C, a ‘silent epidemic’

Genotyping provides route to tailored treatment at lower cost with less side effects

 http://www.bioportfolio.com/news/hepcgen_1.htm

Should PEG-Intron Be Given Twice Weekly to Improve HCV Clearance in Genotype 1 Patients?

The decline in hepatitis C viral load on treatment with peginterferon alfa-2b (PEG-Intron) is not continuous, according to the authors of this study. The aim of their study was to investigate whether twice weekly dosing of peginterferon alfa-2b may improve viral kinetics.

Ten interferon-naïve patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0 microgram/kg peginterferon alfa-2b once (group A) or twice weekly (group B) for 4 weeks.

Viral load and serum concentrations of peginterferon alfa-2b were measured. Peginterferon alfa-2b reached maximal blood concentrations 24 h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon alfa-2b was undetectable in nine patients in group A (once weekly dosing).

The same pattern was observed during the next 3 weeks of therapy. In group B (twice weekly dosing) peginterferon alfa-2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2 days after the first dose of peginterferon alfa-2b, but increased again on day 3.

In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (P < 0.001).

The authors conclude, “To achieve continuous drug exposure and to improve initial viral clearance, peginterferon alfa-2b has to be given at least two times weekly.”

08/04/03

Reference
E Formann and others. Journal of Viral Hepatitis 10(4): 271-277. July 2003

HCV Patients with Genotype 4 Are Significantly More Likely to Develop Severe Fibrosis or Cirrhosis Post Liver Transplantation
 

Predictors of hepatitis C virus (HCV)-related liver disease following transplantation are still unclear. The impact of HCV genotype on outcome of transplantation has been studied, but there is no agreement on the findings of these studies. The role of HCV genotype 4 on the result of liver transplantation requires further trials.

The aim of the current study, conducted at Queen Elizabeth Hospital, Birmingham, England, was to evaluate the outcome of liver transplantation for patients with HCV genotype-4 infection.

The study group included 128 patients who underwent transplantation for HCV infection: 28 patients, genotype 1; 11 patients, genotype 2; 19 patients, genotype 3; and 32 patients, genotype 4.

For 64 of 128 patients, genotype was known and an assessable histological specimen was available. Median interval from transplantation to biopsy was 1.92 years (range, 0.24 to 11.48 years).

Twenty-six percent (26%) of HCV genotype-4 patients developed either severe fibrosis or cirrhosis versus 6.7% in the genotype non-4 group (P =.04). A statistically significant greater fibrosis progression rate was observed in genotype-4 than genotype non-4 patients.

In univariate and multivariate analysis, rapid liver fibrosis was associated with the presence of HCV genotype-4 infection. In addition, donor and recipient age and graft warm ischemic time also were associated with rate of fibrosis progression.

Five-year cumulative rates for the development of cirrhosis or severe liver fibrosis were 84% in genotype-4 and 24% in genotype non-4 patients (P =.02). Five-year survival rates for patients with genotypes 1, 2/3, and 4 were 72%, 80%, and 79%, respectively (P =.8).

The authors conclude, “Five-year survival for patients who underwent transplantation for HCV genotype-4 infection was similar to that of genotype non-4 patients; however, more severe fibrosis and rapid fibrosis progression was observed after transplantation in patients with genotype-4 infection.”

08/04/03

Reference
MH Wali and others. Outcome of liver transplantation in HCV patients with infected by hepatitis C, including those infected by genotype 4. Liver Transplantation 9(8): 796-804. August 2003.

Following Treatment with Interferon and Ribavirin, Fibrosis Regression Is Greater in HCV Genotype 1 Sustained Responders But Also May Decrease in Non Responders

Interferon and ribavirin decrease necro-inflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established.

Researchers at the Upstate Medical University in Syracuse, New York evaluated the effect of combination therapy on virological and liver histopathological outcomes in 52 treatment-naive patients and 79 patients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C.

One hundred four patients completed interferon and ribavirin treatment after 24-48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in naive patients and 22% in re-treated patients.

In virological responders and nonresponders, fibrosis and necroinflammation scores decreased by -0.91 (P = 0.04) and -0.5 (P = 0.02) and by -2.8 (P = 0.001) and -0.66 (P = 0.06), respectively.

The authors conclude, “Interferon and ribavirin had greater benefit for fibrosis when associated with clearance of HCV RNA.  Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes.”

08/08/03

Reference
A Arif and others. Regression of fibrosis in chronic hepatitis C after therapy with interferon and ribavirin. Digestive Diseases and Sciences 48(7): 1425-1430. July 2003.
 

Sustained Viral Response to Treatment Is Associated with a Reduction of Steatosis in Genotype 3 HCV Patients

It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. In this study, researchers in France assessed the effect of treatment with peginterferon alfa-2b or interferon alfa-2b (PEG-Intron and Intron A, respectively) and ribavirin (Rebetol) on steatosis.

The investigators analyzed the database on 1,428 naive patients who were included in a large, international, multicenter, randomized trial randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment.

At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001).

The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007).

In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001).

Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons).

In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001).

This study confirms the high prevalence (65%) of steatosis among patients with chronic hepatitis C and the association with genotype 3, overweight, high fasting serum glucose, triglycerides, male gender, and age.

The authors conclude, “For the first time, it has been clearly demonstrated that effective treatment of HCV leads to a reduction or disappearance of liver steatosis. The impact was particularly observed in patients with HCV genotype 3 infection. Like other studies, we found that genotype 3 was more strongly associated with steatosis (83% of 210 patients in the present cohort) than other genotypes.”

“This study, like previous publications, also suggests that steatosis induces a mechanism of resistance to interferon and ribavirin combination treatment. This mechanism is unknown but seems independent of other known response factors (genotype 1, high viral load, extensive fibrosis) as well as independent of metabolic factors assessed in this study (BMI, serum glucose, and triglycerides).”

“In conclusion, the better understanding of factors related with steatosis will permit us to improve the management of patients. In patients infected with genotype 3 HCV, most of them will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged.”

08/06/03

Reference
T Poynard and others. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 38(1): 75-85. July 2003.
 

Summary and Introduction

Summary

Patients infected with hepatitis C virus genotype 4 (HCV-4) respond to interferon alpha (IFN) as poorly as those infected with genotype 1. However, there is no information on the viral dynamics of HCV-4. Interferon-ribavirin treatment was administered to untreated patients infected with HCV-4. Viral load was assessed with Versant 3.0. Viral dynamics parameters were estimated based on the bi-phasic model for HCV during IFN treatment. Viral kinetics of HCV-4 follow a bi-phasic decline pattern also. The mean effectiveness of IFN in blocking production of HCV-4 was a decline of 77.8% during the first day of treatment. The half-life of free virions was estimated at 3.5 h and that of infected cells from 1.9 to over 70 days. The viral dynamics parameters of HCV-4 appear similar to those of HCV-1 and slower than those of HCV-2. HCV-4 infected patients should be grouped with those with HCV-1 when therapeutic schemes are considered in relation to genotype.

Introduction

Chronic hepatitis C infection affects nearly 300 million people worldwide and is one of the main causes of non A non B chronic hepatitis.^[1] Interferon alpha2b plus ribavirin given for 24 or 48 weeks constitutes the most effective initial therapy for the treatment of chronic hepatitis C.^[2,3] Studies of the kinetics of hepatitis C virus (HCV) following initiation of interferon (IFN) monotherapy have revealed that IFN-alpha 2b causes a rapid dose-dependent (3 < 5 < 10 < 15 MU) reduction in HCV RNA levels within 24 to 48 h, which is best explained by an effect of IFN on viral production or release.^[4,5] Mathematical modelling reveals that HCV has a serum half-life of 3 h and a viral production rate of 1.0 × 10¹² virions/day.^[5] After this rapid decline, there is a slower phase of viral decline that varies widely among patients and is attributed to the death rate of infected liver cells. The rate of decline of the second phase, with a half-life of 1-70 days is the best viral kinetic predictor of early viral clearance and is probably mediated by immune clearance of infected liver cells,.^[5-7] Many studies have shown that patients infected with HCV of genotype 2 or 3 respond better to IFN-alpha treatment than genotype 1 patients.^[2,3] The mechanisms responsible for this difference may be related to the finding that the viral dynamics of genotype 1 are slower and the effectiveness of IFN in blocking virus release is lower compared with genotypes 2-3.^[8]

Hepatitis C Virus of genotype 4 (HCV-4) is the major HCV subtype in the Middle East (up to 80% in Egypt) where a large number of patients is chronically infected.^[9] There is evidence to suggest that patients infected with HCV-4 respond to IFN as poorly as those infected with genotype 1, in contrast to patients with genotype 2-3 who respond well.^[10] However, there is no information on the viral dynamics of HCV-4.

In this study, viral dynamics during IFN plus ribavirin treatment were determined. Nonlinear fitting of the viral kinetic data to a mathematical model of the IFN effect in HCV infection was performed for each patient. The antiviral effectiveness of IFN in blocking virus production, the free virion clearance rate, and the HCV-infected cell death rate were assessed.

Patients and Methods

Interferon-ribavirin combination treatment was administered to six previously untreated patients chronically infected with HCV-4. Five patients received 3-6 million IU of IFN-alpha2a QD and ribavirin 1200 mg/day and were used for the whole kinetic study. One patient who received 6 million IU of IFN-alpha2a TIW and ribavirin 1200 mg/day, and was not used to estimate the second stage kinetics.

The HCV viral load was frequently assessed during the first month of treatment (daily during the first week, and weekly thereafter) using the bDNA and Versant (Bayer Cergy Pontoise, France) version 3.0 assay (limit of detection 3200 Eq/mL). Genotype 4 assignment was based on sequence and phylogenetic analysis of the 5' noncoding and NS5B regions of the genome.^[11]

Mathematical model and statistical analysis: viral dynamics parameters were estimated based on the biphasic model for HCV dynamics during IFN treatment.^[5] The logarithm of the bDNA viral load data was fit to the logarithm of the viral load data by a nonlinear least-squares method using the DNLS1 subroutine from the Common Los Alamos Software Library, which is based on a finite-difference Levenberg-Marquardt algorithm. The nonparametric Wilcoxon rank sum test was used to determine statistical significance of differences in viral fraction and slopes between dosing groups. The Spearman nonparametric test was used to assess the correlation between continuous variables. Significance was established at P < 0.05.

 

Results The viral kinetics of HCV-4 follow a bi-phasic decline pattern also (see Fig. 1). The mean effectiveness of IFN in blocking production of HCV-4 was 77.8% (SD = 13.5%) or 0.7 log Eq/mL (SD = 0.3) decline during the first day of treatment. In four patients with frequent samples during the first day it was possible to estimate the half-life of free virions at 3.5 h (SD = 1.3). The half-life of the second phase, i.e. that of elimination of infected cells was estimated at 1.9 to over 70 days.   Figure 1. (click image to zoom) Viral kinetics of six patients (nos 1 to 6) infected by HCV genotype 4 during treatment with interferon and ribavirin. The mathematical estimation of the overall viral decline was based on the mathematical model of Neumann et al.[5]

Discussion Mathematical models can provide insights into the dynamics of viral diseases.[12,13] Methods that were introduced to analyse human immunodeficiency virus dynamics in vivo can be modified to give insights into HCV dynamics, the mechanism of action of interferon, and the consequences of giving different dosages of interferon.[5] The high turnover rates of HCV explain the rapid generation of viral diversity and the opportunity for viral escape from the host immune surveillance and antiviral therapy.[14] The poor response to treatment in patients infected with HCV of genotype 4 can be attributed to the low effectiveness of IFN in blocking its virion production as compared with genotypes 2-3. We found that the effectiveness of IFN at 3 million IU in blocking production of HCV-4 was 77.8% during the first day of treatment, which is highly comparable with that of previous studies with genotype 1 using the same treatment regimen (68-74%).[4,12] We also estimated the half-life of free virions at 3.5 h, again comparable with the 3-4 h half-life measured for genotype 1[5] and slower by 2 h in comparison with genotype 2.[8,15] The half-life of infected cells ranged from 1.9 to over 70 days, similar to the large variation in second slope kinetics observed in genotype 1 infected patients.[5] The findings of HCV kinetic studies, will inevitably lead to the consideration of more aggressive initial dosing regimens (especially daily doses), but also tailorius therapy individually according to pretreatment parameters and initial decline of viral load. HCV genotype 4 infected patients should then be grouped with genotype 1 when therapy schemes are considered in relation to genotype.[16] As studies on genotype 2 and 3, this study on genotype 4 also showed a difference in viral dynamics between subtypes of the same virus and underline the importance of subtype-specific virus-host-drug interactions. HCV resistance to IFN treatment can be better understood by looking for the common viral properties of genotypes 1 and 4, as compared with those of genotypes 2 and 3. Additional studies are needed to evaluate more fully the kinetics of the genotype 4 decline, as well as its dose dependence, and its predictive power with regard to eradication of HCV. CLICK HERE for subscription information about this journal.

Journal of Viral Hepatitis Volume 10 Issue 5 Page 351  - September 2003 doi:10.1046/j.1365-2893.2003.00433.x

Slow viral dynamics of hepatitis C virus genotype 4

P. Halfon, A. U. Neumann, M. Bourlière, A. Rieu, S. Chadapaud, H. Khiri, D. Ouzan and P. Cacoub

Summary. Patients infected with hepatitis C virus genotype 4 (HCV-4) respond to interferon alpha (IFN) as poorly as those infected with genotype 1. However, there is no information on the viral dynamics of HCV-4. Interferon-ribavirin treatment was administered to untreated patients infected with HCV-4. Viral load was assessed with Versant 3.0. Viral dynamics parameters were estimated based on the bi-phasic model for HCV during IFN treatment. Viral kinetics of HCV-4 follow a bi-phasic decline pattern also. The mean effectiveness of IFN in blocking production of HCV-4 was a decline of 77.8% during the first day of treatment. The half-life of free virions was estimated at 3.5 h and that of infected cells from 1.9 to over 70 days. The viral dynamics parameters of HCV-4 appear similar to those of HCV-1 and slower than those of HCV-2. HCV-4 infected patients should be grouped with those with HCV-1 when therapeutic schemes are considered in relation to genotype

 

By Peggy Peck

BOSTON (Reuters Health) Oct 27 - Among patients with chronic hepatitis C (HCV) genotype 2 or 3 infection, 24 weeks of PEG-interferon alfa-2b plus ribavirin treatment is as effective as a 48-week regimen, according to results of a study of presented at the 54th Annual Meeting of the American Association for the Study of Liver Diseases.

The shorter course has the added bonuses of lower cost and fewer side effects

"Look at the response rates: 81% of patients achieved sustained viral response with just 24 weeks of treatment," said principle investigator Dr. Stefan Zeuzem of Saarland University Hospital, Homburg, Germany.

Two hundred twenty-four HCV patients (42 genotype 2, 182 genotype 3) were enrolled in the study in which they were treated with PEG-interferon alfa-2B 1.5g/kg plus ribavirin 800-1000 mg/day. The results were compared with those achieved in historical controls treated with the same combination for 48 weeks.

In an interview with Reuters Health, Dr. Zeuzem said that HCV treatment is often compromised by "the side-effects that cause patients to reduce dose or discontinue therapy. But if you look at the historical data from studies of 48 weeks, what we see is a response at 24 weeks and then the side effects become evident during the second half of treatment. By shortening treatment, we are significantly reducing the depression, fatigue, headaches -- the side effects that make the treatment so difficult."

The end-of-treatment response rate with the shortened course was 94% (versus 95% among historical controls), and the estimated sustained virologic response rate at 48 weeks was 84%.

Dr. Zeuzem also pointed out that "standard 48-week treatment costs about 20,000 euros, so 24-weeks costs about 10,000 euros." He predicted similar reductions in cost in the U.S.

"Twenty-four weeks should now be considered the standard for patients with genotype 2 and 3," he said.

Dr. Zeuzem noted that the shortened treatment regimen is much better tolerated by patients as evidenced by improved compliance: only 5% of patients discontinued treatment, while the discontinuation rate in historical controls is 14%. Likewise, 22% of patients required dose reduction during the 24 weeks, while doses were reduced in 49% of historical controls.

The study was funded by Schering-Plough Research Institute, Kenilworth, NJ.

Race, Insulin Resistance, Visceral Adiposity and Hepatic Steatosis in Genotype 1 HCV Patients

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