Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort

Abstract

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice.

Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively.

Results: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5.

Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.

Trial registration: ClinicalTrials.gov NCT01344889.

Fig 1. Enrollment and patient disposition.

^aOther reasons (more than one reason may apply to a given patient): no final confirmation from the investigator (n = 56); contraindications to therapy (n = 15); HCV RNA-negative at screening/baseline (n = 12); end-stage renal disease (n = 7); major organ transplantation (n = 2); not treated with peginterferon alfa (n = 1) or ribavirin (n = 2); acute hepatitis C (n = 1); co-infection with HIV (n = 115); co-infection with HBV (n = 74); treatment with regimen other than peginterferon alfa-2a/ribavirin or peginterferon alfa-2b/ribavirin (n = 14); treatment-naive and intended treatment duration of 72 weeks (n = 6).

Fig 2. Cox proportional hazards analysis for time to first safety-related dose reductions or discontinuations in patients treated for 24 or 48 weeks with peginterferon alfa-2a or alfa-2b and ribavirin.

(A) All treatment-naive patients (G1–6) assigned to 24 or 48 weeks of treatment with peginterferon alfa-2a or alfa-2b/RBV (N = 3181); (B) Subgroup 2: treatment-naive Caucasian, G1 noncirrhotic patients assigned to 48 weeks of treatment with peginterferon alfa-2a/RBV (n = 951).

Fig 3. Incidence of safety-related dose reductions or discontinuations (sr-RD) (A) and SVR24 rates (B) according to the number of baseline risk factors for sr-RD in the overall population (N = 2881).

Patients with missing data (n = 300) for risk factors were excluded (BMI n = 18; HCV genotype n = 23; baseline hemoglobin n = 45; baseline platelets n = 56; baseline neutrophils n = 245). Baseline risk factors for sr-RD based on results of Cox proportional hazards analysis include: female sex, age >50 years, body mass index ≤22 kg/m², HCV G1 or 4 infection, presence of cardiovascular disease, presence of pulmonary disease, hemoglobin ≤140 g/L, platelets ≤115 x 10⁹/L, neutrophils ≤2.0 x 10⁹/L.

Fig 4. SVR24 rates by incidence of safety-related dose reductions or discontinuations by Week 4 and Week 12 of treatment in genotype 1 patients assigned to 48 weeks of treatment with peginterferon alfa-2a/ribavirin.

Fisher’s exact test, two-sided P-value. (A) Subgroup 1: all treatment-naive genotype 1 patients (n = 1497); (B) Subgroup 2: treatment-naive, genotype 1, noncirrhotic Caucasian patients (n = 951).

Fig 5. SVR24 rates by baseline predictive score and by incidence of safety-related dose reductions or discontinuations by Week 4 and Week 12 of treatment in subgroup 2 (Caucasian, treatment-naive, G1 noncirrhotic patients assigned to 48 weeks of treatment with peginterferon alfa-2a/ribavirin).

Fisher’s exact test, two-sided P-value. Please note that 34 patients had unknown baseline score.

Fig 6. Multiple logistic regression analysis of baseline and on-treatment factors associated with SVR24 in Caucasian, treatment-naive, G1, noncirrhotic patients assigned to 48 weeks of treatment with PegIFN alfa-2a/RBV.

Patients who discontinued therapy for efficacy or other non-safety reasons were excluded. ^aEffect P-value: P = 0.0316 for sr-RD and 0.0001 for missed ribavirin days in percentage of target.