The recommended therapy for chronic hepatitis C (CHC) is the combination of ribavirin and pegylated interferon alfa, which elicits a sustained virological response (SVR) in >50% of cases [1-4]. However, >75% of patients receiving this therapy experience one or more side effects. The most frequent adverse events are flu-like syndrome with headache and fatigue, neuropsychiatric manifestations such as depression and anxiety, and hematological side effects such as anemia, neutropenia and/or thrombocytopenia [1-3].
These adverse events result in treatment discontinuation in 4% to 19% of patients and in dose reductions of interferon and/or ribavirin in 19% to 38% of patients, depending on the dose and duration of treatment [3]. This reflects the dose-effect and duration effect of each drug: a reduction of treatment exposure significantly reduces the rate of SVR. Thus, patients who were given <80% of the proposed dose of each drug for a duration <80% of the expected duration (according to viral genotype and early viral kinetics) have a marked decrease in SVR compared to ‘adherent’ patients [5]. Early adherence, namely in the first 12 weeks of therapy, appears to be essential for optimal SVR: reducing the dose to <60% of the prescribed dose, for both ribavirin and interferon, results in a marked decrease in the rate of SVR [6]. Finally, in trials of patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) [7-8], the difference in SVR between the perprotocol and the intent-to-treat groups underscores the importance of therapeutic adherence to the recommended doses and duration of treatment. While the primary goal of antiviral therapies is to achieve an SVR, in HCV-infected naïve patients, prediction, early detection, and specific treatment of adverse effects that may preclude an SVR appear to be crucial to optimize the response to therapy.
PATHOPHYSIOLOGY
During combination therapy, anemia stems mainly from ribavirin-associated hemolysis resulting from accumulation of ribavirin metabolites in erythrocytes. Neutropenia and thrombocytopenia are related to the myelosuppressive properties of interferon. Interferon-associated myelosuppression is synergistic with ribavirin for erythrocytes: interferon reduces the reticulocytosis induced by the ribavirin-related hemolytic anemia [9].
Ribavirin-related hemolytic anemia is observed in 15% of patients [1-3]. It induces fatigue, lowers the quality of life, and may necessitate a reduction of dosages, and thus efficacy. The incidence of anemia is dose-dependent: it is higher in patients treated with high (1000-1200 mg) doses compared to low doses (800 mg); it is also higher in situations that enhance myelosuppression or peripheric destruction of erythrocytes—female gender, low body weight, HIV coinfection, combination treatment with zidovudine, renal failure, all of which intrinsically reduce erythropoietin production, or cirrhosis (hypersplenism).
Neutropenia and thrombocytopenia are related to the direct central myelosuppressive effect of interferon, but ribavirin tends to stabilize the reduction in platelet count compared to treatment with interferon alone. Finally, fibrogenesis itself reduces the intrahepatic production of thrombopoietin: thrombocytopenia may occur during the progression of fibrosis in the absence of myelosuppressive therapy and of cirrhosis. The hypersplenism of cirrhosis may largely contribute to both neutropenia and thrombocytopenia through the splenic destruction of granulocytes and platelets, a process not always associated with morphological splenomegaly; their counts can be lowered further if cell production in the bone marrow is also reduced, by whatever mechanism (interferon, chronic alcohol consumption resulting in myelosuppression of the mega-karyocytic lineage, vitamin deficiency or myelosuppressive drugs).
HEMATOLOGICAL GROWTH FACTORS IN DAILY PRACTICE
Hematological growth factors (HGFs) such as erythropoietin (EPO) or granulocyte colony stimulating factors (G-CSFs)—and, in the future, agonists of the thrombopoietin receptor, which have been evaluated in phase II trials—may be used to treat the haematological side effects of pegylated interferon alfa–ribavirin [10-13].
A French study involving approx. 6630 patients being treated by 274 hepatogastroenterologists reported frequent use of HGFs during treatment of CHC: 9% of the patients were given EPO and 4% G-CSF [14]. The main indications for EPO were ‘at risk’ patients (cirrhotics, dialysis patients), 34%; pre-existing anemia, 19%; hemoglobin decline (2-5 g/dL), 12%; and symptomatic anemia, 7%. The main indication for G-CSF was significant neutropenia (400 to 750/mm3) in 65% of those receiving the drug [14].
Erythropoietins
Benefits
It is now well established, especially from the results of controlled studies, that administration of EPO during combined therapy of HCV limits the reduction of hemoglobin levels. This amelioration of ribavirinassociated anemia not only allows administration of a full course of the antiviral drugs (or at least a smaller reduction of the dosage) to pursue an SVR, but also significantly improves the physical well-being of the patient during treatment [10,15,16].
However, if it is clear that EPO improves the physical and psychic tolerance of the patient for therapy [14-16], the real antiviral benefit is more controversial, requiring balancing the significant cost of HGF, the HGF-associated side effects reported in 19% of patients [14], and the limited evidence of a higher SVR rate. Nevertheless, pragmatic work suggests an antiviral benefit. Our own clinical experience of HGF over 2 years is as follows: 33 of 135 patients (24.4%) treated with the pegylated combination required HGF for anemia and/or neutropenia; 65% were cirrhotics, 15% HIV-coinfected, and 85% had a hematological risk factor (as detailed above). HGF allowed the continuation of effective dosages in most patients, and the rates of early virological response, end-of-treatment virological response, and SVR (35%) were not different between the patients who required HGF and those who did not [17]. According to the same pragmatic principle, 15% of patients in the AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT; comparing the standard to the pegylated combination in HIV/HCV coinfection) [7] were given HGF according to the physician’s judgment: again, the rate of SVR was similar between patients who required HGF and those who did not. This demonstration of the noninferiority of SVR in patients given HGF to avoid a dose-reduction compared to patients who did not require HGF has to be considered in the context of the deleterious impact on SVR of dose-reduction or treatment discontinuation in pivotal trials: in patients with an early virological response, as defined by a decrease of at least 2 log10 copies/mL of the baseline viral load, the rate of SVR in patients given >80% of the prescribed doses (75%) was significantly higher than that of patients given <80% of the doses (48%); the SVR rates were 67% in the dose-reduction group and 12% in the discontinuation group. All these studies suggest a clinical and virological benefit from the use of EPO for treating anemia associated with pegylated-interferon alfa–ribavirin combination therapy.
A recent study comparing two doses of ribavirin (13.3 vs. 15.2 mg/kg/d) with or without systematic use of EPO in 150 genotype-1-infected naïve patients concluded that: (i) systematic use of EPO at the beginning of a treatment course with a given dose of ribavirin (13.3 mg/kg/d) did not increase the rate of SVR (29% vs. 19%); and (ii) a higher dose of ribavirin (15.2 mg/kg/d) was associated with a significantly lower risk of relapse (8% vs. 38%), resulting in a higher rate of SVR (29% vs. 49%) [18]. Thus, even if EPO does not modify the SVR rate, it does allow the dose-effect of ribavirin to be maintained. Finally, the best demonstration of virological benefit derived from the use of EPO is a recent study of US veterans: in univariate and multivariate analyses of SVR, EPO was an independent factor for SVR [19].
However, HGFs are costly. A US cost-effectiveness study was performed using a Markov model during combination therapy [20]. Seven clinical situations were identified (SVR, chronic hepatitis, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and death) and the authors compared the impact of dose reductions of ribavirin and the use of HGF on both treatment cost and quality of life [20]. For all viral genotypes, the use of EPO was found to be cost-effective.
Side effects associated with EPO
There are unresolved questions concerning the adverse events associated with EPO substitution and the recommendations on EPO doses and threshold to begin therapy. Side effects such as arterial hypertension and headache have to be managed, but we have not observed such events in hepatitis C patients. A bigger concern is the risk of erythroblastopenia, which was first reported in dialysis patients after long exposure to epoetin alfa [21-22]. Some cases have now been reported in the treatment of hepatitis C, but we do not know their prevalence, and the immunomodulatory properties of interferon may indeed increase the risk of immunization. Such a risk has to be weighed against the expected benefits by clear-cut indications (recommendations are lacking) and the shortest treatments. If erythroblastopenia has not been described with epoetin beta or darbepoetin, it is probably because epoetin alfa is the first EPO to be widely used in dialysis patients. Finally, the major concern is an increased risk of cancers triggered by the hypervascularization induced by a better oxygen supply and higher hemoglobin levels, which has been discussed for breast and neck cancers [22]. In a pretumoral situation such as cirrhosis, we must be cautious in using EPO, including performing prospective follow-ups of cirrhotics thus treated.
Monitoring and threshold
Another concern is the threshold of hemoglobin that justifies either the introduction or discontinuation of EPO substitution; it is necessary to make some consensual recommendations. It will depend probably more on the clinical background (e.g., fatigue, chest pain) and reduction kinetics of hemoglobin under antiviral therapy (and increase under EPO therapy) than on absolute values.
In our experience, administration of EPO is effective in maintaining the level of hemoglobin at >11.5 g/dL, which should allow an ‘acceptable’ quality of life [17]. The dosage depends on the EPO that is used: 10,000-30,000 units per week subcutaneously for epoetin beta (Neo-RecormonTM), 40,000 units per week subcutaneously for epoetin alfa (EprexTM), or 150-300 μg per week subcutaneously for darbepoetin (AranespTM). Algorithms for doses and duration are not consensual—we propose an algorithm based on our clinical experience (Figure 1). It is necessary to identify patients with a higher risk of developing anemia during therapy (e.g., cirrhotics, HIV-coinfected patients and those treated with zidovudine) and to test each week the hemoglobin level under therapy in those patients—a decrease >0.4 g/dL per week indicates the need for EPO [17]. The aim is to avoid a decline below 11.5 g/dL, and in all cases below 10 g/dL, to maintain effective doses of ribavirin and to reduce adverse events such as fatigue, dyspnea, and chest pain associated with anemia in patients with coronary disease. When patients receiving EPO attain hemoglobin levels of approx. 12 g/dL in women and 13 g/dL in men, the EPO should be discontinued (Figure 1). A complete pretreatment (before both antiviral and EPO) blood evaluation has to be performed to exclude causes of anemia other than ribavirin-associated hemolytic anemia. Indeed, vitamin deficiency or hyposideremia prevent a response to EPO therapy, as observed in 5% to 10% of patients, and therefore must be corrected first.
 | Figure 1. Algorithm of EPO use for ribavirin-associated anemia during pegylated and ribavirin combination therapy of chronic hepatitis C. |
Granulocyte growth factors (G-CSFs)
Clinical and biochemical data are more scant for G-CSF compared to EPO. The intrinsic antiviral properties of G-CSF have never been confirmed in clinical trials [23]. There are few data concerning the benefit of G-CSF during treatment of hepatitis C. There is a real, albeit rare, risk of sepsis associated with the neutropenia induced by interferon therapy. Bronchopulmonary infections are clearly more frequent in neutropenic patients, whereas severe forms of sepsis (which are more frequent under pegylated as opposed to standard interferon in daily practice, but not in pivotal trials) are rarely seen: this suggests more functional rather than quantitative disturbances. The use of G-CSF (filgrastim, 300 or 480 μg/mL/week or lenograstim, 30 or 48 MUI/week) induces significant improvement of neutropenia, which allows effective dosages of interferon to be maintained [10,24]. Attention has to be paid to the timing of neutrophil testing after interferon injection so as to avoid under- or overestimation of neutropenia—the blood test should be performed 3 to 4 days after injection, and G-CSF should be given only if the neutrophil count is below 750 or 500/mm3 (see Figure 2). G-CSF therapy is associated with side effects, including enhancement of flu-like syndrome and bone pain. Algorithms for doses and duration are not consensual—we propose an algorithm based on our clinical experience (Figure 2). Injections of EPO and G-CSF as well as those of interferon may be performed on the same day of the week.
 | Figure 2. Algorithm of G-CSF use for interferon-associated neutropenia during pegylated and ribavirin combination therapy of chronic hepatitis C. PMN: polymorphonuclear neutrophils. |
Platelet factors
Agonists of the thrombopoietin receptors are under evaluation for both thrombopenic purpura and hypersplenism- associated thrombopenia of cirrhosis. In cirrhotic patients under antiviral therapy, such agents have been tested in patients with pretreatment platelet counts of ~70,000/mm3, which concerns probably <5% of treated patients (13%). The first trials have shown a marked efficacy of the treatments, producing platelet counts >250,000/mm3 in most patients. Ophthalmologic disturbances have been reported in animal models, and high serum levels of the drug indicate a need for drug monitoring and prospective long-term studies.
CONCLUSION
The correction of anemia by EPO and of neutropenia by G-CSF permits efficacious doses of ribavirin and interferon, respectively, to be maintained in the treatment of CHC. This appears to be crucial, especially in the first 12 weeks of therapy when the likelihood of success of antiviral treatment is highest (positive predictive values of 90% and 70%, and negative predictive values of 90% and 100% at 4 and 12 weeks, respectively). In patients with an early (at 12 weeks) or rapid (at 4 weeks) virologic response, promoted by the maintenance of good doses of ribavirin and interferon, antiviral treatment and also HGF should be continued along with regular blood evaluations to maximize the chances of SVR. Studies now suggest that maintenance of good doses of ribavirin and interferon in mono-infected and also coinfected patients produces a similar rate of SVR between those who need HGF and those who do not, in contrast to patients without HGF therapy and for whom treatment is reduced or discontinued.
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