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Correspondence to: Professor G. B. Gaeta, Istituto Malattie Infettive, c/o Osp. Gesù e Maria, Via Cotugno, 1, 80135 Naples, Italy. E-mail: email@example.com
Background : Interferon-α plus ribavirin therapy for chronic hepatitis C is associated with adverse effects that lead to therapy discontinuation in up to 27% of patients in randomized controlled trials.
Aim : To examine the causes and predictive factors for therapy discontinuation in patients treated in current clinical practice.
Methods : We retrospectively enrolled 441 consecutive patients, scheduled to receive interferon-α + ribavirin for chronic hepatitis C, in five centres. Patients had been treated with 3 or 6 MU interferon-α three times a week plus ribavirin, 800–1200 mg daily, for 6 or 12 months.
Results : One hundred and eight [24.5%; confidence interval (CI), 20.5–28.8%] patients failed to finish combination therapy because of adverse events. The discontinuation rate was higher during the first 6 months of treatment; anaemia was an important cause (36.1% of discontinuations); unexplained lipothymia resulted in discontinuation in 11 patients. Female gender [hazard ratio (HR) = 1.85; CI, 1.17–2.92], an interferon-α dose > 15 MU/week (HR = 1.79; CI, 1.12–2.86) and no previous interferon-α treatment (HR = 1.63; CI, 1.04–2.57) were independent factors associated with discontinuation. The simultaneous presence of these factors identified patients at high risk for discontinuation [odds ratio (OR) = 10; CI, 3.98–25.13].
Conclusions : The study identified some predictive factorsfor adverse event-related discontinuation, which may improve the safety profile and effectiveness of interferon-α + ribavirin combination therapy in chronic hepatitis C.
The combination of interferon-α (IFN) plus ribavirin (RBV) is recommended as the therapy of choice for patients with chronic hepatitis C who have never been treated with IFN (naive patients) or who have relapsed after effective treatment with IFN alone.1,2 These recommendations have emerged from some large randomized controlled trials which have shown that a stable response can be achieved in up to 40% of naive patients treated with combination therapy, i.e. almost double the percentage achieved with IFN alone. The efficacy of combination therapy is even greater in relapsed patients.3–5
These studies have also shown that premature discontinuation of the drugs due to adverse events was necessary in up to 27% of naive patients receiving 12 months of treatment.4 An analysis of the individual data of the patients enrolled in six trials showed that none of the patients who discontinued therapy achieved a sustained response.6
Randomized controlled trials of efficacy are performed on patients selected using strict criteria, largely in tertiary referral centres. In the normal clinical setting, a greater variety of patients may be treated, usually following general guidelines comprising a range of treatment options. In addition to the overall efficacy, this ‘in the field’ use may also influence the occurrence of adverse events, a problem that may be of great importance in geographical areas where chronic hepatitis C has a high prevalence and the majority of patients are treated outside randomized controlled trials.7,8
The aims of this study were to examine the adverse events leading to drug discontinuation in a series ofconsecutive patients treated with IFN + RBV in thedaily practice of five Italian centres, and to analyse the factors associated with discontinuation of treatment.
Materials and methods
This study retrospectively enrolled all consecutive patients (age > 18 years), not included in randomized controlled trials, who were scheduled to receive IFN + RBV therapy for chronic hepatitis C between 1 September 1999 and 1 September 2000. Six centres attended the meeting to define the study design and the requirements for participation in the study. The basic requirements were that the diagnosis of chronic hepatitis C had been established by the presence of anti-hepatitis C virus antibodies and hepatitis C virus RNA in the serum, and that the basal evaluation had included the determination of the haemoglobin level, differential white blood cell count, platelet count, thyroid stimulating hormone level and autoantibodies (antinuclear and anti-liver–kidney microsomes). Moreover, clinical and laboratory records had to be available at 1 month after the start of therapy and then at no more than 2-month intervals, and had to include the haemoglobin level, white blood cell count and platelet count. All centres adopted the World Health Organization classification of adverse events, and, if an adverse event occurred, it was managed according to the manufacturers' instructions for IFN and RBV. Only patients with hepatitis B virus and/or human immunodeficiency virus co-infection were excluded.
Five centres agreed to participate in the study. The patients had been treated with IFN plus RBV at doses in the range 9–18 MU IFN per week and 800–1200 mg RBV per day for 6 or 12 months. The data for each patient were collected on a case report form. The study design was approved by the local ethics committees.
Quality control of the data was performed by verifying the consistency (i.e. claimed outcomes were matched with the reported values and events) and possible input errors (entered data were checked by two operators). When inconsistencies were found, they were discussed with the single investigator.
Premature discontinuation of IFN + RBV therapy because of an adverse event was the end-point; patients who stopped therapy because of a lack of response were not considered as premature discontinuations. The discontinuation rate was calculated using Kaplan–Meier curves and possible differences were tested using the log rank test. Possible predictors for therapy discontinuation included 10 variables: age, gender, previous IFN therapy, IFN and RBV dose, basal alanine aminotransferase, haemoglobin, platelet and white blood cell levels, and presence of cirrhosis. Student's t-test was used to compare continuous variables and the chi-squared test was used to compare categorical variables. Hazard ratios (HR) and 95% confidence intervals (CI) for the association of each variable with therapy discontinuation were computed. To assess the factorsindependently associated with therapy discontinuation, Cox proportional hazard regression analysis wasperformed.9
Data analysis was carried out using SPSS software (SPSS Inc., Chicago, IL, USA).
A total of 441 patients scheduled to receive IFN plus RBV combination therapy (117 naive patients and 324 previously treated with IFN, of whom 208 were IFN relapsers and 106 were IFN non-responders) were enrolled in the study. The basal clinical and laboratory characteristics of the patients are reported in Table 1. The median body weight (calculated for the 171 patients for whom the body weight was available) was 72 kg (range, 50–94 kg); it was 63.5 kg for females (n = 48) and 76 kg for males (n = 123). There was no difference between centres with regard to the basal characteristics of the patients. The discontinuation rates were similar amongst IFN relapsers and non-responders (19.2% vs. 22.6%, respectively); these patients were grouped together for subsequent analysis and were referred to as ‘previously IFN treated’.
The flow diagram of the study is shown in Figure 1. Of the 441 patients who entered the study, 108 (24.5%; CI, 20.5–28.8%) failed to complete combination therapy due to adverse effects: 56 (12.7%) discontinued both drugs, 50 (11.3%) discontinued RBV only and two (0.45%) were lost for unknown reasons; 78 (17.7%) continued after dose reduction of one or both drugs and 255 (57.8%) continued with the full dosage until the end of treatment or until a lack of response was assessed. There were no differences between the patients who discontinued RBV alone and those who discontinued both drugs with regard to age, gender, IFN dose, RBV dose, basal haemoglobin level, white blood cell count, platelet count or alanine aminotransferase level; only cirrhosis was more frequent amongst patients who discontinued both drugs (25.8% vs. 2.1%; P = 0.001). The patients who discontinued one or both drugs were grouped together for subsequent analysis. Overall, discontinuation was recorded in 37.6% of naive patients and in 20.3% of those previously treated with IFN.
The causes which led to treatment discontinuation are listed in Table 2. Anaemia was by far the most frequent cause of discontinuation (36.1%, i.e. it occurred in 8.8% of all treated patients), followed by gastrointestinal symptoms (19.4%) and pruritus or rash (12.9%); amongst the typical adverse events of IFN, discontinuation due to depression, leucopenia or flu-like syndrome occurred in 5.6%, 4.6% and 3.7% of cases, respectively. For 11 patients, recurrent lipothymia was the only cause of discontinuation, and in none was it associated with anaemia or any detectable cause.
Table 2. Adverse events (not mutually exclusive) in the 108 patients who discontinued therapy
Amongst the patients who did not discontinue treatment, mild side-effects or adverse reactions were recorded, which did not differ from those reported in randomized controlled trials in type and frequency (flu-like syndrome, 52%; gastrointestinal symptoms, 19%; mild anaemia, 15%; pruritus–rash, 7%; cough–dyspnoea, 6%; anxiety–irritability, 4%). There was no difference in the incidence rates or types of adverse events between the centres.
Figure 2 shows the discontinuation rate for anaemia (broken line) and for the other adverse events (full line).Seventy per cent of the cases of anaemia occurred within the first 4 weeks of therapy; no cases occurredafter the sixth month of therapy. The other events occurred throughout the treatment period ( P < 0.0001). The haemoglobin values that dictated discontinuation ranged from 7.3 to 10.1 g/dL.
The clinical and laboratory variables potentially associated with the discontinuation of therapy due to any adverse event were analysed by univariate analysis (Table 3). Female gender, no previous IFN treatment, a higher IFN dose, a lower basal white blood cell or platelet count and a lower basal haemoglobin concentration were associated with drug discontinuation. With multivariate analysis, only female gender, no previous IFN treatment and a higher IFN dose were independently associated with therapy discontinuation (Table 4). The same factors were independently associated with therapy discontinuation during the first 6 months of therapy (data not shown).
Table 3. Baseline features by univariate analysis in patients who finished combination therapy and those who did not
Finished therapy (n = 333)
Lost to combination therapy (n = 108)
Hazard ratio (95% CI)
ALT, alanine aminotransferase; IFN, interferon-α; WBC, white blood cell.
Table 4. Multivariate analysis of the factors associated with premature discontinuation of IFN + RBV therapy
IFN, interferon-α; RBV, ribavirin; WBC, white blood cell.
No previous IFN
IFN dose > 15 MU/week
WBC/mm3 (× 103)
Platelets/mm3 (× 103)
Therapy discontinuation was recorded in 14.3% of the 189 patients with no risk factors (Table 5). The simultaneous presence of three independent factors was recorded in 24 patients, 15 of whom (62.5%) discontinued therapy [odds ratio (OR) = 10; CI, 3.98–25.13].
Table 5. Therapy discontinuation due to adverse events according to the number of discontinuation factors
Number of discontinuation factors present (no. of patients)
Lost to combination therapy
Odds ratio (95% CI)
One factor (150)
Two factors (78)
Three factors (24)
This study examined the reasons for the premature discontinuation of IFN plus RBV therapy in patients treated for chronic hepatitis C in routine practice, and the factors associated with withdrawal from therapy.
This retrospective study may have some limitations, particularly with regard to the detection of thefrequency of certain outcomes. The minimal requirements for a centre to participate in the study were established to ensure the quality of the diagnosis and of the collection of the data, in order to minimize possible biases (see ‘Materials and methods’ section). All consecutive patients scheduled to receive IFN + RBV therapy were included in the database, with the exclusion of patients with hepatitis B virus or human immunodeficiency virus co-infection. It can therefore be assumed that our study population reflects the current profile of patients treated for chronic hepatitis C in daily practice. This patient population may differ from that enrolled in randomized controlled trials, as subjects participating in randomized controlled trials are carefully selected so that compliance with treatment can be maximized. Some of these differences may involve measurable variables (for example, in our series, there were fewer patients with a history of drug use or transfusion than in randomized controlled trials), whereas other differences may involve factors that are difficult to assess, such as emotional factors. In routine practice, less rigorous conditions prevail, i.e. a more heterogeneous patient population is treated and the drug regimen may be more easily adapted to the needs of the individual patients.10,11 Thus, provided that the criteria for internal validity are met, the external validity of randomized controlled trials needs to be verified in different populations.
In our series, 24.5% of patients discontinued therapy due to adverse events and 17.7% reduced the dose of either drug. In our analysis, we considered the discontinuation of combination therapy as the primary end-point, i.e. a clear cut-off event which is relevant to the efficacy of therapy.6
Severe adverse events have been reported more often in patients receiving combination therapy than in those treated with IFN alone. In a large retrospective multicentre survey,12 which included 11 241 patients treated with IFN alone at standard doses for either hepatitis B or C, life-threatening effects occurred in 1 per 1000 cases and severe adverse events in 1 per 100 cases. A meta-analysis of randomized controlled trials of IFN in chronic hepatitis C showed that the overall incidence of adverse events was higher in patients receiving 5 MU or more three times a week than in those receiving 3 MU three times a week.13 The simultaneous administrationof RBV added to the toxicity caused by IFN. Randomized controlled trials comparing the efficacy of IFN + RBV vs. IFN alone in naive patients invariably showed that the number of patients discontinuing therapy was higher in those receiving a combination of IFN + RBV,3,4,14 and that patients treated for 12 months showed a higher adverse effect rate than patients receiving a 6-month course. Our data are consistent with this observation. In addition, the rate of discontinuations was higher during the first 6 months of treatment, particularly when anaemia was involved.
Amongst the adverse events recorded in our study, the occurrence of recurrent lipothymia in 11 patients cannot be explained, as it was not related to anaemia or to any other detectable cause. In none of the cases did lipothymia recur during the 6-month period after stopping treatment, which suggests a relationship with the treatment received.
Anaemia was by far the most typical adverse event due to RBV. Although in vivo studies have shown that RBV may induce metabolic changes and oxidative damage of erythrocytes,15,16 these parameters are of no clinical use, and the occurrence of RBV-induced severe haemolysis is still considered to be unpredictable.
In pivotal industry trials, strict criteria for RBV discontinuation (usually haemoglobin < 8.5 g/dL) have been pre-established. In our analysis, 40% of patients who discontinued therapy had haemoglobin values below this limit, whilst, in the remaining cases, therapy discontinuation was dictated by haemoglobin values in the range 8.5–10.1 g/dL. Clearly, individual tolerance to anaemia had a decisive role in inducing therapy discontinuation. Most patients had active lives, and a drastic reduction in haemoglobin values, i.e. the amount and rate of decline, was poorly tolerated. In view of this, the haemoglobin cut-off levels for therapy discontinuation proposed for randomized controlled trials are unacceptable in clinical practice.
The identification of simple clinical factors associated with the premature discontinuation of treatment may be the key to the further improvement of treatment strategies. In randomized controlled trials, successful efforts have been made to identify parameters associated with a sustained response to therapy. As a consequence, optimization of the dose and duration of the treatment regimen with IFN plus RBV has been achieved on the basis of response predictive factors,17 and is now part of treatment guidelines. In general, adverse events have received less attention in randomized controlled trials, in which they have simply been listed as such. However, a rate of more than 20% premature discontinuations should generate an effort to improve tolerability, which may in turn lead to a further enhancement of the response rate, as the early discontinuation of therapy causes a reduction in efficacy.6 Our study showed that female gender, naive status and a higher dose of IFN were independent risk factors for the premature discontinuation of therapy.
How should a patient at risk for therapy discontinuation be managed? The decision not to treat a single patient on the basis of the presence of risk factors is not practicable. An obvious option is stricter surveillance, particularly during the first 3-6 months of therapy, when the majority of discontinuations occur. Timely treatment of serious side-effects in patients who are responding to therapy might be considered. For example, as anaemia is a frequent cause of discontinuation, the use of erythropoietin might allow the continuation of successful therapy.18 It has been calculated that the direct cost of this approach comprises 1% of the cost of combination therapy.19 The use of antioxidant vitamins may be a preventive strategy, which needs to be validated.
Tailoring the drug dose to the individual patient may be a possible alternative for risk avoidance. To date, the relatively well-tolerated dose of 3 MU IFN three times a week has been the standard for combination therapy with RBV.1–4 The use of low-dose RBV requires the evaluation of the advantages in terms of safety. Indeed, a recent study showed that the RBV dose did not influence the decrease in the haemoglobin level,20 which was instead related to the amount of IFN received. In our study, the number of patients receiving RBV at < 1000 mg/day was too small to assess the possible advantage of low-dose treatment, whereas the IFN dose was associated with the discontinuation of therapy. Tailoring the IFN and RBV doses on the basis of body weight may maximize the efficacy and tolerability. In our series, the discontinuation rate tended to be higher in patients with a lower body weight (26% vs. 20%, respectively, in patients weighing less or more than 72 kg; not significant).
Recently, pegylated IFNs, given as monotherapy, have shown an efficacy comparable to that achieved with conventional IFNs plus RBV.21–23 Pegylated IFNs might be the best alternative for those patients at high risk for intolerance to combination therapy, or the best rescue strategy for those who have had to suspend combination treatment.
We expect RBV to be part of anti-viral therapy for chronic hepatitis C in the pegylated IFN era, as the combination of pegylated IFNs + RBV may achieve significantly higher efficacy rates than conventional IFN + RBV or pegylated IFNs alone.24,25 Thus, the identification of subgroups of patients who are at risk of premature discontinuation of combination therapy remains important in order to improve the safety profile and the effectiveness of therapy.
This study was supported by the Ministero della Sanità, project ‘Sviluppo di strategie diagnostiche e terapeutiche innovative nella epatite cronica C’ and in part by the Ministero della Università e Ricerca Scientifica (MURST), Rome, Italy.
We thank Professor Ciro Gallo for constructive discussions on the data analysis and Professor Giuseppe Giusti for his comments on the manuscript.