From December 2011 to June 2012 we screened 87 consecutive menopausal women with HCV genotype 1 infection and a documentation of a failed prior course of PEG-IFN-α/RBV for at least 12 wk, followed up in the out patients clinics of the Liver Units of Modena, Turin, Palermo and Naples.

Inclusion criteria included patients with relapse (undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virological response), prior partial-response (defined as decrease of HCV-RNA ≥ 2 log₁₀ by week 12 of prior therapy but with detectable HCV-RNA throughout the course of therapy), or null-response (decrease of HCV-RNA ≤ 2 log₁₀ by week 12 of prior therapy).

A liver biopsy within the last 2 years with histology consistent with chronic hepatitis C (CHC) and no other etiology was required. In subjects with bridging fibrosis or cirrhosis, an ultrasound within 6 mo of the Screening Visit (or between Screening and Day 1) with no findings suspect for hepatocellular carcinoma (HCC) was mandatory.

Exclusion criteria included co-infection with the human immunodeficiency virus (HIV) or hepatitis B virus (HBsAg positive), treatment with any investigational drug within 30 d of the randomization visit in this study, evidence of decompensated liver disease including history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy, diabetic and/or hypertensive subjects with clinically significant ocular examination findings (like retinopathy, cotton wool spots, optic nerve disorder, retinal hemorrhage, or any other clinically significant abnormality), pre-existing psychiatric conditions, clinical diagnosis of substance abuse of the specified drugs within the specified timeframes, any known pre-existing medical condition that could interfere with the subject’s participation in and completion of the study, evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). Further exclusion criteria included protocol-specified hematologic, biochemical, and serologic criteria: hemoglobin < 12 g/dL; neutrophils < 1500/mm³; platelets < 100000/mm³, direct bilirubin >1.5 × upper limit of normal (ULN), serum albumin < lower limit of normal (LLN), thyroid-stimulating hormone (TSH) > 1.2 × ULN or < 0.8 × LLN of laboratory, serum creatinine > ULN of the laboratory reference, protocol-specified serum glucose concentrations, prothrombin time/partial thromboplastin time (PT/PTT) values > 10% above laboratory reference range, anti-nuclear antibodies > 1:320.

In this single-assignment, unblinded study we treated menopausal women with previous treatment failure to a prior course of PEG-IFN/RBV. The primary objective of retreatment was to verify whether a sustained virological response (SVR) (HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be achieved with Boceprevir in menopausal women with chronic HCV genotype 1 with a previous failure of PEG IFN/Ribavirin. Secondary objective of this study was the evaluation of the percent of patients with negative HCV RNA at week 4 (rapid virological response, RVR), 8 (rapid virological response after BOC addition, RVR BOC), 12 (early virological response, EVR), or at the end-of-treatment (ETR) that reached SVR.

All patients received 4-wk lead-in with with PEG-IFN-α-2b at 1.5 μg/kg subcutaneously weekly, in combination with weight-based oral RBV at a total dose of 800 to 1400 mg per day according to body weight. In relapse and partial responder patients after 4 wk of lead-in, all patients received 32 wk of BOC 800 mg administered orally three times a day, in combination with PEG-IFN and RBV. These patients then received an additional 12 wk of PR only if HCV-RNA was positive by week 8 yet. In previous null-responders, after the lead-in phase, triple therapy with PEG-IFN/Ribavirin and Boceprevir was continued until week 48. All drugs were self-administered by the patients.

In all patients, if HCV RNA was detectable at week 12, treatment was stopped.

IL28B rs12979860 genotype was tested as already described[13].

Adverse events (AEs) were graded according to WHO grading system. The safety analyses included all subjects who receive at least one dose of study medication. Non severe hematological adverse events were managed by pharmacological dose reduction. In case of neutrophil count < 0.75 × 10⁹/L, granulocyte colony stimulating factor (GCS-F) was also used. In case of hemoglobin decrease < 10 g/dL, Ribavirin dose was reduced and/or erythropoietin administered.

Subjects having AEs were monitored with appropriate clinical assessments and laboratory tests, as determined by the investigator.

Analysis regarding the primary end-point included all patients who had received at least one dose of any study medication (intention-to-treat analysis). Our primary endpoint was attainment of sustained virological response, defined as undetectable circulating HCV RNA at week 24 of follow-up. Secondary end point was the identification of independent baseline and on-treatment SVR predictors.

To calculate sample size, we estimated to obtain at least a 20% increase in SVR vs historical controls with the same characteristic. Thus, with 80% power and a type 1 error set to 0.05, 49 subjects were required. A 15% excess of inclusions was allowed in order to compensate for withdrawals.

Dichotomous or continuous variables were compared with the Fisher exact test with mid-p correction or the nonparametric Mann-Whitney rank-sum test, respectively.

To assess the relationship between SVR and clinical and biochemical parameters, two multiple logistic regression models were used; the first assessed baseline variables only and the second assessed both baseline and on-treatment parameters. In the statistical model, the dependent variable was coded as 1 (present) vs 0 (absent). In all analyses, partial and null responders were considered together and referred to as non-responders. Variables associated with the dependent variable in univariate analyses (probability threshold, P < 0.10) were included in the multivariate regression model. The PASW Statistics 20 program (SPSS, Inc, Chicago, IL) was used for the analysis.

A total of 87 menopausal women with chronic Hepatitis C, genotype 1, with previous treatment failure to standard antiviral therapy, were evaluated (Figure 1). Baseline characteristics of the 56 enrolled patients are shown in Table 1. Thirty-eight women were from Northern Italy while 18 were from Southern Italy. There were no significant differences between them regarding previous response to antiviral therapy, percentage of patients with cirrhosis, IL28B genotype, basal BMI, duration of menopause, basal viral load. All patients completed follow up and were included in the analysis.

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Figure 1 Trend statement flow diagram. HCV: Hepatitis C virus; AE: Adverse event.

Mean age was 56.8 ± 6.1 years; mean menopausal duration was 11.4 ± 6.1 years (median 12.5 years). Mean BMI was 26.2 ± 4.0 (median 24.8). Four patients (7.1%) were previous null responders, 23 (41.1%) partial-responders and 29 (51.8%) relapsers. According to Metavir fibrosis score, 30/56 (54.0%) women had a score of 1 or 2, while 26/56 (46.0%) had a score of 3 or 4; of these, 21 (37.5%) had cirrhosis. Approximately 60% of patients had a high viral load (an HCV RNA level > 800000 IU per milliliter). Genotype 1b infection was predominant (52/56, 92.9%). IL28B rs12979860 genotype was available for 43 patients (9 CC, 26 TC, and 8 TT).

In the entire population, SVR was obtained in 25/56 (44.6%) patients. There was no significant difference between women of Northern and Southern origin in the SVR rate (44.7% vs 44.4%, respectively, P = 0.964).

After 4 wk of lead-in, none but two patients achieved RVR, while the HCV RNA drop of at least 1 log₁₀ from baseline (IFN sensitivity) was obtained in 62% of patients. After Boceprevir addition, RVR BOC, EVR and ETR were obtained in 32/56 (57.1%), 41/56 (73.2%), and 42 (75.0%) respectively. Of these, 53.8%, 52.0%, and 52.0%, respectively, achieved SVR.

Fourteen patients (25.0%) stopped therapy [6/14 (43%) for intolerance, 5/14 (36%) for HCV RNA detectability at week 12; 3/14 (21%) for viral breakthrough]. All experienced a virological relapse.

The rate of sustained virological response among patients with prior relapse or non-response was 55% and 41% respectively (P = 0.250). No significant correlation was present between SVR and high viral load (HCV RNA > 800.000 IU/mL: P = 0.597) or IL28 status (P = 0.333). Patients with IFN sensitivity had significantly higher SVR rates compared patients with IFN insensitivity (57.1% vs 26.3%, P = 0.030). Level of fibrosis did not negatively influence the SVR rate, which occurred in 44% of women with F0-F2 vs 54% of those with F3-F4 fibrosis (P = 0.488) nor was the presence of cirrhosis (presence of cirrhosis vs. absence: P = 0.485). Figure 2 depicts SVR rates according to the pattern of prior response, severity of fibrosis and baseline viral load.

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Figure 2 Percentage of patients with a sustained virologic response according to prior response to Peginterferon-α + Ribavirin treatment, level of fibrosis and viral load. HCV: Hepatitis C virus; SVR: Sustained virological response.

At univariate analysis for baseline predictors of SVR, none of the clinical and biochemical parameters but previous response to antiviral therapy (OR = 2.662, 95%CI: 0.957-6.881, P = 0.043) was related with SVR. When taking into consideration also “on treatment” factors, 1 log₁₀ HCV RNA decline at week 4 (3.733, 95%CI: 1.676-12.658, P = 0.034) and achievement of RVR BOC (7.347, 95%CI: 2.156-25.035, P = 0.001) were significantly related with SVR, although RVR BOC only (6.794, 95%CI: 1.596-21.644, P = 0.010) maintained significance at multivariate logistic regression analysis (Table 2).

Anaemia and neutropenia were managed with Erythropoietin and Granulokine supplementation, respectively: only six patients discontinued therapy.

The treatment was well tolerated, with low rates of severe adverse events. Fatigue and nausea were the most common adverse events. Hemoglobin levels decreased significantly at all-time points, without requiring the introduction of erythropoietin before week 6 (i.e., 2 wk following the addition of boceprevir). Conversely, the neutrophil count reduction required Granulokine supplementation already at week 2. Anemia was successfully managed with erythropoietin supplementation, as neutropenia with Granulokine supplementation. The supplementation of both Erythropoietin and Granulokine was necessary to preserve the full treatment doses. None of the patients experienced skin problems; dysgeusia was frequent, but no patient discontinued therapy due to this event (Table 3).

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. In menopausal women, the disease becomes much more rapidly progressing than during reproductive age, severe fibrosis develops, and response to antiviral therapy becomes low.

The therapeutic options for HCV are rapidly growing. New drugs will be, however, extremely expensive and the use of the best cost-effective options should be pursued in order to offer treatment to the largest number of patients.

The results support the concept that triple antiviral treatment with PEG IFN/Ribavarin and Boceprevir is able to obtain a striking improvement in the SVR rate of menopausal women with HCV with previous treatment failure.

The management of patients who do not achieve a viral response has always been challenging. The results of this study support the efficacy, safety and tolerability of PEG IFN/Ribavirin and Boceprevir in a high percentage of previous non responders to PEG IFN/Ribavirin thus offering immediate cure to patients otherwise likely to rapidly progress toward severe fibrosis.

SVR indicates sustained virological response, i.e., viral clearance for more than 24 wk after treatment.

In the manuscript the authors present data showing that the difficult to treat population of menopausal women display improved treatment results by the inclusion of boceprevir. The manuscript is clearly presented and generally well-written, although it should be edited once more by the authors before publishing. HCV triple therapy including either telaprevir or boceprevir is now the current standard of care therapy for HCV infection, though this will soon change to “next generation” antivirals. The population numbers of the current study are limited to 56, and would be strengthened by expanding the study to a larger population.