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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

In patients chronically infected with hepatitis C virus (HCV) genotype 4, the optimum duration of therapy and the predictors of sustained virologic response (SVR) have not been adequately determined. In this study, 358 patients with chronic hepatitis C genotype 4 were randomly assigned to pegylated interferon (PEG-IFN) alpha-2b (1.5 μg/kg/week) plus oral ribavirin (10.6 mg/kg/day) for a fixed duration of 48 weeks (control group, n = 50) or for a variable duration (n = 318). In the variable-duration group, patients with undetectable HCV RNA at week 4 were treated for 24 weeks (group A, n = 69), patients with undetectable HCV RNA at week 12 were treated for 36 weeks (group B, n = 79), and the rest of the patients were treated for 48 weeks (group C, n = 160). The primary endpoint was SVR (undetectable HCV RNA 24 weeks after treatment cessation). Groups A-C and the control group had SVR rates of 86%, 76%, 56%, and 58%, respectively. After the study was controlled for predictors, a low baseline histologic grade and stage were associated with SVR (P < 0.029) in all groups. In addition, among patients in group C, older age (P = 0.04), a higher baseline body mass index (P = 0.013), and low baseline HCV RNA (P < 0.001) were also associated with SVR attainment. The incidence of adverse events and the rate of discontinuation were higher in patients in the variable-duration and fixed-duration groups treated for 48 weeks. Conclusion: In patients with chronic hepatitis C genotype 4 and undetectable HCV RNA at weeks 4 and 12, treatment with PEG-IFN alpha-2b and ribavirin for 24 weeks and 36 weeks, respectively, is sufficient. (HEPATOLOGY 2007.)

Hepatitis C virus (HCV) genotype 4 is the most frequent cause of chronic hepatitis C in the Middle East, North Africa, and sub-Saharan Africa.1 In countries such as Egypt, more than 90% of cases of chronic hepatitis C are caused by HCV genotype 4.2 Furthermore, recent epidemiological reports indicate that HCV genotype 4 is beginning to spread from its native African and Middle Eastern origins into countries of Southern Europe such as France, Italy, and Spain and in some foci in the United States, particularly among intravenous drug users.3–5

Genotype 4 is the least studied of the HCV variants and until recently has been considered difficult to treat because conventional interferon monotherapy has resulted in disappointing virologic responses.6–8 However, recent reports show that a combination therapy with pegylated interferon (PEG-IFN) alpha and ribavirin markedly improves treatment outcomes, resulting in a sustained virologic response (SVR) in 44%-69% of cases.9–12 However, determining the optimal treatment duration is crucial for the minimization of unnecessary or prolonged therapy and for the maximization of the cost effectiveness of therapy. In addition, little is known about predictors of response within populations infected with genotype 4; therefore, a tailored approach to treatment, which has proved successful in other HCV genotypes, remains elusive because of a lack of reliable data.

In genotype 1 patients, an individualized approach to therapy designed according to host and viral characteristics has been adopted that encourages the use of the aforementioned treatment regimens. The rapid virologic response (RVR; defined as undetectable HCV RNA at week 4) is a key element in this tailored approach that can aid in the early identification of patients who may benefit from treatment regimens that have been either lengthened or shortened in comparison with the standard 48-week approach. In genotype 1 patients with undetectable HCV RNA at week 4, SVR rates are similar, regardless of whether patients are treated for 24 or 48 weeks.13, 14 In contrast, SVR rates are higher in patients with detectable HCV RNA at week 4 when they are treated for 72 weeks rather than 48 weeks.15 Thus, RVR is now regarded as a valuable tool in the clinical management of genotype 1 HCV; however, little is known about its value in the management of genotype 4 patients.

We have therefore conducted a randomized multicenter trial to assess the predictability of response in patients with chronic hepatitis C genotype 4 and to determine the efficacy of shorter duration therapy with PEG-IFN alpha-2b plus ribavirin. In particular, we have assessed the value of an adaptive treatment regimen that is based on the viral load at weeks 4 and 12 for the establishment of optimal treatment durations for achieving SVR.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This randomized multicenter controlled trial was conducted in 4 centers in Egypt. Enrollment started in January 2004, and the trial was completed in November 2006. Patients participating in the study gave written informed consent before enrollment and before the initiation of any study-related procedures. The study protocol was approved by the institutional review boards of the participating centers and was conducted according to the 1975 Declaration of Helsinki and the International Conference on Harmonization/Committee for Proprietary Medicinal Products (Good Clinical Practice) guidelines.

Study Population.

Adult men and women, 25-55 years old, with documented chronic hepatitis C were enrolled in the study. Inclusion criteria consisted of elevated serum alanine aminotransferase at least 2 times the upper limit of normal (40 U/L) on 2 occasions during the preceding 6 months, detectable anti-HCV antibody status assessed by a second-generation enzyme-linked immunosorbent assay (Roche Diagnostics, Branchburg, NJ), detectable HCV RNA by a polymerase chain reaction (Cobas Amplicor HCV monitor, version 2.0, Roche Diagnostics; lower limit of quantitation of 50 IU/mL), an infection with HCV genotype 4, and histologic evidence of chronic hepatitis C in a liver biopsy specimen obtained within the preceding year.

Patients were excluded if they had received interferon-alpha therapy previously or showed evidence of other liver diseases, including hepatitis A, hepatitis B, autoimmune hepatitis, alcoholic liver disease, drug-induced hepatitis, and decompensated liver disease with a history of variceal hemorrhage, ascites, or hepatic encephalopathy. Patients coinfected with schistosomiasis or human immunodeficiency virus and those with a leukocyte count lower than 3000/mm3, neutropenia (<1500 cells/mm3), a hemoglobin level lower than 12 g/dL for women and lower than 13 g/dL for men, thrombocytopenia (<90,000 cells/mm3), a creatinine concentration 1.5 times the upper limit of normal, organ transplantation, neoplastic disease, severe cardiac or pulmonary disease, unstable thyroid dysfunction, a psychiatric disorder, current pregnancy or breast feeding, or therapy with immunomodulatory agents within the last 6 months were also excluded.

Study Design.

Patients were randomized in a 1:5 ratio to PEG-IFN alpha-2b (1.5 μg/kg; PegIntron, Schering-Plough Corp, Kenilworth, NJ) plus oral ribavirin (10.6 mg/kg/day; Rebetol, Schering-Plough Corp) for either a fixed duration of 48 weeks (control group) or a variable duration of 24, 36, or 48 weeks based on the HCV RNA status at weeks 4 and 12 (variable-duration treatment group). Both the investigators and patients were blinded to the treatment duration assigned (fixed versus variable) at randomization. All patients were followed for 24 additional weeks following the completion of their assigned treatment (Fig. 1).

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Figure 1. Patient flow diagram. AE indicates adverse event; EVR, early virologic response; PEG-IFN, pegylated interferon; RBV, ribavirin; and RVR, rapid virologic response. *One patient was discontinued for more than one reason. **Sixty patients were initially randomized to the control group but 10 patients declined treatment so 50 patients were assigned to the control fixed group and received treatment.

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Every effort was made to ensure that compliance was maximized, that patients continued to take the allocated treatments, and that all patients were accounted for in the trial report. To ensure compliance, PEG-IFN alpha-2b was administered by qualified nurses, and the number of empty vials and used syringes was recorded. Good compliance is defined as the completion of 80% of the prescribed treatment.

Among those assigned to the variable-duration group, patients with undetectable HCV RNA at week 4 were categorized as superresponders, having attained RVR, and were assigned to the 24-week treatment regimen (group A). Patients in the treatment group with detectable levels of virus at week 4 but undetectable HCV RNA at week 12 were defined as having a complete early virologic response (EVR) and were assigned to the 36-week treatment regimen (group B). The remaining patients who had a greater than 2-log drop in HCV RNA levels at week 12 received therapy for 48 weeks (group C). Therapy was discontinued in those with no change in HCV RNA levels after 12 weeks of therapy.

Definitions of the Response and Endpoints.

The primary efficacy endpoint was SVR, which was defined as undetectable serum HCV RNA 24 weeks after the discontinuation of treatment (Amplicor HCV, Roche Molecular Systems; a lower limit of detection of 50 IU/mL confirmed by HCV transcription-mediated amplification with a lower limit of detection of 6 IU/mL; Versant HCV RNA 3.0, Siemens AG, Tarrytown, NY). The end-of-treatment response was defined as undetectable serum HCV RNA (<50 IU/mL) at the end of the scheduled treatment. RVR was defined as undetectable HCV RNA levels after 4 weeks of therapy. Although EVR is commonly defined as a greater than 2-log10 decline in serum HCV RNA from the pretreatment baseline or undetectable serum HCV RNA at treatment week 12, we discriminated between the 2 outcomes. Patients with undetectable HCV RNA (<50 IU/mL) at week 12 were defined as having a complete EVR and assigned to group B, whereas those with a minimum 2-log10 decrease from the baseline in HCV RNA at week 12 were defined as having a partial (partial, incomplete) EVR and assigned to group C. Patients with no or minimal change in the HCV RNA titers were defined as nonresponders and enrolled in another study.

Secondary endpoints included the biochemical response, which was defined as the normalization of alanine aminotransferase at the end of the follow-up period, and the histologic response, which was defined as an improvement of greater than 2 points.

Clinic visits for the evaluation of clinical and biochemical laboratory values and adverse event monitoring were scheduled before treatment allocation, at allocation, at weeks 2 and 4, monthly thereafter during treatment, and at 3 monthly intervals until the end of the study. Serum HCV RNA assessments were performed before therapy, after 4 and 12 weeks, at the end of treatment, and at the end of follow-up.

Assessment of Safety.

Safety was assessed through the monitoring of patient-reported adverse events and, as indicated, by clinical and laboratory test results. Patients who completed their assigned treatment were encouraged to remain in the study for assessment at the end of the 24-week follow-up period.

Stepwise reductions in the PEG-IFN alpha-2b or ribavirin dose were used to manage adverse events or laboratory abnormalities that reached predetermined thresholds of severity. The dose of PEG-IFN alpha-2b was reduced stepwise from 1.5 to 1 μg/kg/week if the neutrophil count was lower than 1000 cells/mm3 or if the platelet count was lower than 60,000 cells/mm3. An additional dose reduction to 0.5 μg/kg/week for platelet counts lower than 55,000 cells/mm3 was permissible at the discretion of the investigators. Ribavirin was reduced to 600 mg/day if hemoglobin levels declined to 10 g/dL or by 4 g/dL from the baseline. The doses were restored to the original levels if the adverse event resolved or improved following dose reduction; patients were withdrawn from treatment if there was no improvement after 4 weeks of dose reduction therapy. Therapy was discontinued if adverse events were not alleviated by dose modifications. Growth factors were not used during this study. Patients were withdrawn from treatment if they missed 4 consecutive doses of PEG-IFN alpha-2b.

Liver Histology.

Pretreatment liver biopsies were performed on all patients, and follow-up biopsies were performed on 123 patients. Liver biopsies were obtained within 6 months of enrollment and at the end of follow-up and were analyzed by 2 experienced pathologists who were blinded to the treatment allocation and clinical and biochemical data. All biopsy samples were treated with a hematoxylin-eosin stain and a connective tissue stain (chromotrope–aniline blue) and scored according to the system described by Ishak and colleagues,16 which includes the grading of piecemeal necrosis, confluent necrosis, apoptosis, focal inflammation, and portal inflammation, with a necroinflammatory score of 0-18 and a staging score of 0-6 and with different extents of fibrosis. Steatosis was graded according to the percentage of hepatocytes containing visible macrovesicular steatosis.

Statistical Analysis.

The intention-to-treat principle was applied to all statistical analyses. A comparison of the baseline factors across the treatment and control groups was performed with an analysis of variance or a Kruskall-Wallis test for continuous variables and chi-square or Fisher's exact tests for categorical variables. The Blackwelder test17 was used to test the noninferiority of the treatment groups versus those assigned to the control group. In this test, equivalence was defined as SVR percentages within 1%, and P < 0.025 was considered significant. Ninety-five percent confidence intervals (CIs) of the sensitivity, specificity, positive predictive value, and negative predictive value were calculated with the Wilson method.18 Logistic regression was used to assess the association between the baseline factors, RVR, and EVR19 and to assess the association between the baseline factors and SVR in patients assigned to the treatment group, which was stratified by the initial response (RVR, EVR, or other). The baseline factors that were considered were the age, sex, body mass index, histologic grade and stage, alanine aminotransferase, and HCV RNA. Crude and adjusted odds ratios (ORs) and 95% CIs were calculated with a univariable model and a multivariable model, respectively. A statistical analysis was performed with R statistical software.20

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Of the 435 consecutive patients with proven chronic hepatitis C genotype 4 that were screened, 378 were considered eligible and were enrolled in the study (see Fig. 1). Of those enrolled, 60 patients were initially randomized to the control group but 10 patients declined treatment so 50 patients were assigned to the control fixed group and received the standard 48-week treatment regimen. The remaining 318 patients were allocated to variable-duration treatment groups according to their HCV RNA levels at weeks 4 and 12. There were no significant differences in the baseline measurements between the variable-duration and control groups, with the exception of the degree of steatosis (Table 1).

Table 1. Baseline Demographics and Laboratory Values
 Treatment GroupControl (n = 50)P*
Group A (n = 69)Group B (n = 79)Group C (n = 160)
  • The patients were allocated into groups A, B, and C according to their viral kinetics at weeks 4 and 12. Continuous variables were compared with a Kruskal-Wallis test or an analysis of variance. Categorical variables were compared with chi-square tests or Fisher's exact test. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HCV, hepatitis C virus; SD, standard deviation.

  • *

    Variable-duration group versus the control.

Male [n(%)]37 (54)32 (40)100 (62)26 (52)0.70
Age [years; mean (SD)]41.0 (7.4)40.5 (7.4)42.2 (8.1)43.2 (7.8)0.15
BMI [kg/m2; mean (SD)]28.5 (2.2)27.8 (2.2)28.6 (2.1)28.9 (2.2)0.11
ALT [U/L; mean (SD)]125 (48)112 (52)118 (47)118 (51)0.99
AST [U/L; mean (SD)]128 (44)105 (50)117 (50)116 (48)0.99
Log10 HCV RNA [IU/mL; mean (SD)]6.0 (0.2)5.9 (0.2)6.0 (0.2)6.0 (0.2)0.94
Necroinflammatory histologic grade [mean (SD)]5.9 (1.1)6.2 (1.3)6.6 (1.4)6.8 (1.4)0.90
Histologic stage [n (%)]    0.20
 029 (42)30 (38)54 (34)11 (22) 
 125 (36)26 (33)19 (12)13 (26) 
 27 (10)7 (9)32 (20)7 (14) 
 35 (7)6 (8)40 (25)13 (26) 
 43 (4)9 (11)15 (9)6 (12) 
Steatosis [n (%)]    0.050
 024 (35)21 (26)26 (16)14 (28) 
 0-531 (45)24 (30)44 (28)19 (38) 
 5-3213 (19)19 (24)47 (29)13 (26) 
 32-661 (1)15 (19)39 (24)2 (4) 
 >660 (0)0 (0)4 (2)2 (4) 

Virologic Response at Weeks 4 and 12 and the End of Treatment.

In the variable-duration treatment group, 308 patients achieved RVR or EVR, whereas 10 patients were considered nonresponders (showed no or minimal change in HCV RNA levels at week 12) and discontinued therapy. Of the 308 patients, 69 patients (22%) attained RVR and were assigned to 24 weeks of treatment (group A), 79 patients (26%) had undetectable HCV RNA at week 12 and were assigned to 36 weeks of treatment (group B), and 160 patients (52%) had a greater than 2-log decline in HCV RNA (partial EVR) and were assigned to 48 weeks of treatment (group C). In the control group, 8 patients (16%) attained RVR, 15 (30%) had undetectable HCV RNA at week 12 (complete EVR), 11 (22%) had a greater than 2-log drop in HCV RNA (partial EVR), and 16 (32%) were nonresponders. In total, 90% of patients in group A, 86% of those in group B, 65% in group C, and 70% of the control group had undetectable HCV RNA at the end of treatment (P = 0.01 for group A versus group C and for group B versus group C; Fig. 2).

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Figure 2. End-of-treatment (EOT) and sustained virologic response (SVR) rates (based on an equivalence test).

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SVR by the Treatment Group.

In the control fixed-duration group, 30 of 50 patients (58%) achieved SVR, including 7 of 8 patients (88%) with RVR, 13 of 15 patients (87%) with undetectable HCV RNA at week 12 (complete EVR), and 7 of the 11 patients (64%) with > 2 log drop of HCV RNA at week 12 (partial EVR). Among patients who were initially randomized to the variable-duration treatment group, SVR was achieved in 59 of 69 patients (86%) with RVR (group A), 60 of 79 (76%) with undetectable HCV RNA at week 12 (group B), and 90 of 160 (56%) in group C (Fig. 2) with an overall SVR rate of 68% in groups A, B, and C. Overall, the SVR rate in patients assigned to the variable-duration treatment group was comparable to that attained by control patients (P = 0.024), illustrating that the shorter treatment durations were significantly noninferior to standard therapy. To assess the value of variable treatment durations based on early viral kinetics, we calculated the sensitivity, specificity, positive predictive values, and negative predictive values of RVR and EVR to predict SVR (Table 2). The negative predictive values were generally low in both variable-duration (RVR, 42%; EVR, 40%) and control groups (RVR, 57%; EVR, 54%).

Table 2. Predictive Value of the Rapid Virologic Response (RVR) and Early Virologic Response (EVR) with Undetectable Hepatitis C Virus (HCV) RNA at Week 12 for the Sustained Virologic Response (SVR) in Groups A and B and Control Subgroups
 Sensitivity (95% CI)Specificity (95% CI)PPV (95% CI)NPV (95% CI)
  1. RVR is defined as undetectable HCV RNA at 4 weeks. Complete EVR is defined as undetectable HCV RNA at 12 weeks. Abbreviations: CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value.

RVR    
 Treatment group A (n = 69)0.30 (0.24-0.36)0.91 (0.86-0.96)0.86 (0.77-0.94)0.42 (0.36-0.48)
 Control subgroup (n = 8)0.28 (0.14-0.48)0.96 (0.80-1.00)0.88 (0.53-0.99)0.57 (0.42-0.71)
EVR    
 Treatment group B (n = 79)0.30 (0.24-0.37)0.83 (0.76-0.90)0.76 (0.66-0.85)0.40 (0.34-0.46)
 Control subgroup (n = 15)0.20 (0.09-0.39)0.96 (0.80-1.00)0.83 (0.44-0.99)0.54 (0.40-0.68)

Histologic Response.

All patients underwent liver biopsy before treatment; 123 of these patients also had a liver biopsy performed at the end of follow-up after therapy was completed (23 in group A, 34 in group B, 51 in group C, and 15 in the fixed-duration group). The comparison of histological grading and staging scores of the initial and follow-up biopsies in patients with paired liver biopsies revealed no deterioration or progression of fibrosis in any patient. Overall, SVR was higher among patients with early-stage baseline histology scores than those with more advanced disease. Patients with fibrosis scores of 0 and 1 attained excellent SVR rates (96.8% and 76%, respectively), and patients with fibrosis score of 2 had lower SVR rates (35%). All patients with scores of 3 and 4 at the baseline failed to attain SVR.

In all, 94 of 123 patients (76.4%) with paired biopsies demonstrated histologic improvement (>2-point necroinflammatory score improvement; Table 3). In addition, all patients who attained SVR also demonstrated a histologic response with a decrease of 3-5 points in the necroinflammatory grade score and an overall regression in the fibrosis score. In contrast, patients who relapsed after attaining an end-of-treatment response demonstrated a less than 2-point improvement in the necroinflammatory grading score (data not shown).

Table 3. Histological Response in 123 Patients with Paired Liver Biopsies
 Number (%)Group A (n = 69)Group B (n = 79)Group C (n = 160)Control (n = 50)
  • *

    A greater than 2-point necroinflammatory score.

Patients with paired biopsies12323 (33.3)34 (43)51 (31.9)15 (30)
Patients with improvement (total)*94 (76.4)18/23 (78.3)26/34 (76.5)40/51 (78.5)10 (66.7)
• 2-3 points66/94 (70.2)12/18 (66.7)20/26 (76.9)35/40 (87.5)9/10 (90)
• 4 points21/94 (22.3)4/18 (22.2)4/26 (15.4)4/40 (10)1/10 (10)
• 5 points7/94 (7.4)2/18 (11.1)2/26 (7.7)1/40 (2.5)0
Patients with no change24 (19.5)5 (21.7)7 (20.6)9 (17.6)3 (20)
Patients with worsening5 (4.1)01 (2.9)2 (3.9)2 (13.3)

Predictors of RVR and EVR.

We identified certain predictors of RVR and EVR, regardless of the group assignment, before and after adjustments for other baseline factors. After the study was controlled for other predictors, for each decade difference in age, those who were younger had higher odds of RVR and EVR (OR, 1.39; 95% CI, 1.02-1.89; P = 0.036); females were more likely to attain RVR and EVR than males (OR, 2.08; 95% CI, 1.28-3.37; P = 0.003), and patients with a lower baseline histologic grade had higher odds of RVR and EVR than those with more advanced histologic disease (OR, 1.27 for each unit difference; 95% CI, 1.15-1.39; P < 0.0001).

Predictors of SVR by Early Viral Kinetics in the Variable-Duration Groups.

Among patients in group A, the histologic grade was a strong predictor of SVR (Table 4). All patients with a necroinflammatory score below 7 attained SVR, and all patients with a histologic grade above 7 failed to attain SVR. After adjustments for all predictors except the histologic grade, patients with a fibrosis score of 0 or 1 were more likely to attain SVR than patients with a histologic stage of 2, 3, or 4 (OR, 45.8; 95% CI, 5.9-354.6; P = 0.0002). Age was not a significant predictor of SVR in this group of patients (P = 0.58).

Table 4. Association of the Baseline Predictors and Sustained Virologic Response (SVR) in the 3 Treatment Groups After Adjustments for Baseline Measurements
 Group A (RVRs)Group B (EVRs with Undetectable HCV RNA at Week 12)Group C (EVRs with >2-Log Drop in HCV RNA at Week 12)
OR95% CIPOR95% CIPOR95% CIP
  • Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; EVR, early virologic response; HCV, hepatitis C virus; OR, odds ratio; RVR, rapid virologic response.

  • *

    All patients with a grade greater than 7 did not attain SVR; all patients with a grade lower than 7 attained SVR. Of the 4 individuals with a grade of 7, 2 attained SVR, and 2 did not.

Baseline age [per decade (older versus younger)]0.690.18, 2.590.580.100.01, 1.860.122.241.04, 4.840.040
Baseline BMI [per kg/m2 (higher versus lower)]0.990.64, 1.530.960.910.50, 1.650.751.561.10, 2.220.013
Gender  0.13  0.10  0.99
 Male (reference)   
 Female0.210.03, 1.55 0.050.01, 1.77 1.000.29, 3.48 
Baseline histologic grade (higher then 7 versus lower than 7)* *2.171.09, 4.550.0291.561.24, 2.00.0003
Baseline histologic stage  0.0002  0.006  <0.0001
 2-4 (Reference)   
 0-145.85.9, 354.6 6166, >999 56.29.8, 323.2 
Baseline ALT [per 10 U/L (higher versus lower)]0.950.79, 1.150.620.820.55, 1.210.321.030.91, 1.170.61
Baseline HCV RNA [per base 10 log (higher versus lower)]3.430.03, 383.20.614.710.03, 686.70.540.010.003, 0.120.0007

Similarly, patients in group B with a low baseline histologic grade were more likely to achieve SVR (OR, 2.17; 95% CI, 1.09-4.55; P = 0.029). Patients with a histologic stage of 0 or 1 at the baseline were 616 times more likely to achieve SVR than those with stage 2, 3, or 4 (P = 0.006). In this population, age was not a significant predictor of SVR (P = 0.12).

Finally, in group C patients, the odds of attaining SVR were reduced with each log10 increase in baseline HCV RNA (OR, 0.01; 95% CI, 0.003-0.12; P = 0.0007). Also, the odds of attaining SVR were improved for each unit decrease in the baseline histologic grade (OR, 1.56; 95% CI, 1.24-2.0; P = 0.0003). Patients with a baseline histologic stage of 0 or 1 were more likely to attain SVR than those with stage 2, 3, or 4 (OR, 56.2; 95% CI, 9.8-323.2; P <0.0001).

Adverse Events.

The adverse events were typical of those previously reported for a combination therapy with PEG-IFN alpha-2b and ribavirin (Table 5). Serious adverse events that led to dose modification or withdrawal included febrile neutropenia, thrombocytopenia, hemolytic anemia, gastroenteritis, anxiety, generalized urticaria, pregnancy of the patient or partner, violent behavior, a severe depressive state, and chorioretinitis.

Table 5. Adverse Events
 Group A (n = 69)Group B (n = 79)Group C (n = 160)Control (n = 50)P (Control Versus All Others)P (Groups A-C)
  1. Continuous variables were compared with a Kruskal-Wallis test or an analysis of variance. Categorical variables were compared with chi-square tests or Fisher's exact test. PEG-IFN alpha-2b indicates pegylated interferon alpha-2b PEG-IFN.

Adverse events      
 Fatigue [n (%)]21 (30.4)28 (35.4)65 (40.1)31 (62.0)0.0010.33
 Influenza-like illness [n (%)]13 (18.8)16 (20.3)48 (30)22 (44.0)0.0100.12
 Headache [n (%)]11 (16)21 (26.5)47 (29)18 (36.0)0.170.10
 Myalgia [n (%)]9 (13)14 (17.7)49 (30.6)14 (28.0)0.480.006
 Pyrexia [n (%)]22 (31.8)27 (34.1)46 (28.7)19 (38.0)0.330.67
 Injection-site erythema [n (%)]25 (36.2)32 (40.5)58 (36.3)18 (36.0)0.990.81
 Depression [n (%)]0 (0)1 (1.3)3 (1.9)4 (8.0)0.0150.81
 Anxiety, insomnia, or irritability [n (%)]2 (2.9)4 (5.1)21 (13.1)6 (6.0)0.090.07
 Anorexia [n (%)]6 (8.6)9 (11.4)12 (7.5)9 (18.0)0.0710.58
 Rigors [n (%)]1 (1.44)3 (3.8)12 (7.5)2 (4.0)0.990.16
 Sore throat [n (%)]8 (11.6)9 (11.4)21 (13.1)7 (14.0)0.820.92
 Cough [n (%)]2 (2.9)4 (5.1)9 (5.6)4 (8.0)0.320.73
 Pruritus/rash [n (%)]5 (7.2)6 (7.5)19 (11.9)3 (6.0)0.600.46
 Back pain [n (%)]7 (10)9 (11.4)12 (7.5)3 (6.0)0.600.55
 Arthralgia [n (%)]5 (7.2)7 (6.9)18 (11.3)8 (16.0)0.210.65
 Dyspnea [n (%)]3 (4.3)9 (11.4)15 (9.4)2 (4.0)0.400.27
 Nausea [n (%)]4 (5.7)3 (3.8)6 (3.8)5 (10.0)0.150.75
 Chorioretinitis [n (%)]0 (0)0 (0)1 (0.6)0 (0)0.990.99
 Diarrhea [n (%)]2 (2.9)5 (6.3)7 (4.4)4 (8.0)0.300.63
 Vomiting [n (%)]3 (4.3)5 (6.3)9 (5.6)3 (6.0)0.750.90
Adverse events among those who discontinued therapy      
 Total [n (%)]1 (1.4)4 (5.1)9 (5.6)8 (16.0)0.0060.39
 Hematologic [n (%)]1 (1.4)4 (5.1)7 (4.4)7 (14.0)0.0090.50
 Psychiatric [n (%)]0 (0)0 (0)2 (1.3)1 (2.0)0.360.99
Adverse events among those with a reduction or omission of 1-2 doses of treatment      
 Total [n (%)]4 (5.8)9 (11.4)20 (12.5)9 (18.0)0.150.34
 PEG-IFN alpha-2b [n (%)]3 (4.4)4 (5.1)11 (6.9)4 (8.0)0.530.81
 Ribavirin [n (%)]1 (1.4)5 (6.3)9 (5.6)5 (10.0)0.180.34

Dose reductions (1-2 doses) were required in 4 patients in group A, 9 in group B, 20 in group C, and 9 in the control group. Hematologic toxicity (anemia and/or neutropenia or thrombocytopenia) was responsible for 70% of all dose reductions of PEG-IFN alpha-2b) and 50% of all dose reductions of ribavirin. Depression, anxiety, confusion, insomnia, and fatigue were also common causes of dose reduction, collectively responsible for 20% of all dose reductions. One patient in group A, 4 patients in group B, 9 patients in group C, and 8 patients in the control group discontinued therapy prematurely because of an adverse event that was not improved by dose modification.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This is the first study to examine shorter treatment regimens with PEG-IFN alpha-2b plus ribavirin on the basis of the virologic response at weeks 4 and 12 in patients infected with HCV genotype 4. Patients with undetectable HCV RNA at weeks 4 and 12 can be effectively treated with shorter regimens (24 weeks and 36 weeks, respectively), which result in outcomes equivalent to those obtained with standard therapy (48 weeks). Shorter treatment regimens offer valuable advantages over standard therapy durations by restricting unnecessary drug exposure while helping to control healthcare expenditures; the latter is a particularly important consideration in many of the African and Middle Eastern countries in which HCV genotype 4 is highly prevalent.1, 2, 12

Despite the high prevalence of chronic hepatitis C genotype 4, until recently relatively little was known about the most efficient, cost-effective way to combat this disease. Large studies of patients with chronic hepatitis C conducted in Western populations have generally included small numbers of patients with genotype 4, and thus little could be derived from those studies regarding the most effective intervention approach for hepatitis C genotype 4. However, because approximately 20% of the 175 million global cases of hepatitis C are caused by HCV genotype 4,12 effective, individually tailored treatment approaches are imperative. Previous open-label studies have assessed a combination therapy with PEG-IFN alpha-2b plus ribavirin for the treatment of patients with chronic hepatitis C genotype 4 in Egypt, Kuwait, and Saudi Arabia with SVR rates between 44% and 68%.10–12 A meta-analysis of small studies that included genotype 4 patients has also indicated that an SVR rate of 55% is attainable with PEG-IFN plus ribavirin therapy.21 Unfortunately, these studies differed with respect to the dosing levels, treatment duration, study design, and patient selection criteria, and this makes comparisons difficult.

Ultimately, the findings of our previous double-blind, randomized study provided the impetus for the design and execution of this study.9 We reported that SVR rates were significantly higher in patients receiving treatment for 36 or 48 weeks than in those receiving treatment for 24 weeks. However, our observations regarding the importance of EVR were of particular significance, as they indicated that patients with EVR might be candidates for shorter, more cost-effective treatment regimens.

In the current study, SVR rates in the variable-duration treatment group were noninferior to those in the control group. Furthermore, the histologic grade and stage at the baseline were predictive of SVR in all 3 groups defined by early viral kinetics, whereas the age, body mass index, and baseline viral load were also significant predictors of SVR in patients who did not attain RVR or EVR. To further understand the role of baseline factors in predicting SVR, we looked at patients who attained RVR or EVR, regardless of the treatment assignment, and found that a younger age, female gender, and lower histologic grade were significant predictors of RVR and EVR. This may suggest that the effect of baseline predictors on SVR is mediated indirectly via an association though RVR and EVR.

These findings are consistent with observations regarding the treatment of HCV genotypes 1, 2, and 3.22 The absence of RVR at week 4 has successfully been used as an indicator for extended treatment durations in genotype 1 patients,15 whereas the presence of RVR is a significant predictor of favorable treatment outcomes in genotype 1 patients.13 The attainment of RVR (defined as undetectable HCV RNA at week 4 or 8 in some studies) is also recognized as an important tool in reducing the treatment duration of genotype 2/3 patients from the standard 24 weeks to 12-16 weeks.23–25 RVR has also been identified as an important predictor of treatment outcome in a pure genotype 2 population.26

In financial terms, the monitoring of viral kinetics during treatment can result in substantial economic benefits. The cessation of therapy at week 12 in genotype 1 patients who do not show a greater than 2-log10 decrease in HCV RNA is associated with significant cost savings.27, 28 These observations have recently been extended to include the importance of RVR in both genotype 1 and genotype 2/3 populations, in which tailoring therapy on the basis of week 4 viral kinetics with a therapy a la carte approach results in significant cost savings.29 Similar cost-effectiveness analyses are now warranted for genotype 4 patients in geographical regions such as Egypt, in which current financial constraints place PEG-IFN plus ribavirin therapy beyond the reach of most of the population. For these patients, shorter regimens may make the treatment of chronic hepatitis C more affordable.12 Unfortunately, RVR and EVR do not aid in the identification of patients who are suitable for shorter treatment durations before the initiation of treatment, and thus it remains necessary for patients to embark on a 48-week treatment program and accept the associated cost implications. It is only when week 4 and/or week 12 viral kinetics are determined that shorter treatments may be advocated and possible cost savings realized. Thus, it is also important to identify baseline predictors of treatment outcome that may help determine suitable treatment regimens before the initiation of treatment. With this goal in mind, the predictors of virologic response that are defined in this study may help to identify additional candidates suitable for shorter treatment regimens. Patients with a low baseline histologic stage and grade may be responsive to even shorter treatments. Also, shorter treatment durations should be explored among patients who have detectable HCV RNA at 12 weeks and low baseline HCV RNA levels.

In conclusion, we have shown that a tailored approach to the treatment of HCV genotype 4 permits shorter treatment durations for patients who have attained RVR or EVR. This, in turn, should help reduce unnecessary medication exposure and the economic burden associated with the treatment of patients with chronic hepatitis C genotype 4. Our data confirm that patients with undetectable HCV RNA during the early stages of treatment attain SVR despite shorter treatment regimens in comparison with those with a slower viral kinetic response and are suitable for reduced treatment durations without SVR rates being compromised.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We thank Ahmed Ismail, M.D., Iman Fathy, M.D., Ayman Hussien, M.D., Amr Muhamad, M.D., Ashraf El Bendary, M.D., Maha Hamdy, M.D., and Ms. Soha Mahmoud for their important contributions to the clinical part of this work.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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