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EPO for Anemia During IFN/RBV Therapy for HCV
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"Epoetin alfa treatment for acute anaemia during interferon plus ribavirin combination therapy for chronic hepatitis C"
Journal of Viral Hepatitis
Volume 11 Issue 3 Page 191 - May 2004
N. Bräu
Department of Medicine, Division of Infectious Diseases, Veterans Affairs Medical Center, Bronx
Summary. Infection with the hepatitis C virus (HCV) remains chronic in 75% of infected individuals, in whom it can cause liver inflammation and progressive fibrosis leading to cirrhosis in 20% of patients. A sustained viral response (SVR) to HCV therapy, i.e. undetectable plasma HCV RNA 6 months after the end of treatment, leads to permanent eradication of the virus in 98.3% of patients. The current treatment of choice is combination therapy with pegylated interferon alfa (PEG-IFN alfa), 2a or 2b, and ribavirin (RBV), which achieves an SVR in 54-56% of patients. In patients with HCV genotype 1, RBV doses of 1000-1200 mg/day are associated with a higher SVR than 800 mg/day (51 vs 40%). However, RBV also causes dose-dependent reversible haemolytic anaemia that, in combination with the myelosuppressive effects of PEG-IFN, results in a mean drop in haemoglobin (Hb) level of 3.7 g/dL within 4 weeks. Conventionally, this acute anaemia has been managed with RBV dose reductions. However, this may result in a decreased SVR rate. Alternatively, this anaemia can be managed with administration of epoetin alfa at 40 000 IU once weekly. In a randomized placebo-controlled trial, treatment with epoetin alfa has been shown to raise Hb levels and maintain RBV doses. Furthermore, the increase in Hb level was associated with improved quality of life. Anaemia in patients treated with interferon plus RBV combination therapy can be managed effectively and safely with once weekly epoetin alfa without sacrificing optimal dosing of RBV.
Natural history of chronic hepatitis C
Infection with the hepatitis C virus (HCV) is typically acquired parenterally through injecting drug use or (rarely now) through contaminated transfusions of blood or blood products. Infection with HCV remains chronic in about 75% of patients [1,2,3]. Although chronic hepatitis C is typically asymptomatic, it causes various degrees of liver inflammation and fibrosis, and over time (20 years on average), it can lead to liver cirrhosis in about 20% of patients. A higher histological score of necroinflammation is associated with faster progression to cirrhosis [4]. Complications of HCV-cirrhosis are liver decompensation, which occurs in 18% of patients after 5 years or hepatocellular carcinoma (HCC) with a 5-year risk of 7%. Mortality associated with compensated HCV-induced liver cirrhosis is 9% at 5 years, but once symptoms of liver decompensation occur, the 5-year mortality increases to 50% [5]. The incidence of HCC in HCV cirrhosis is 14% after 10 years in Europe [5], but for unknown reasons, the 10-year incidence of HCC is much higher in Japan, where rates of 25-53% have been reported [6,7]. Alcohol consumption, especially in large quantities, and coinfection with the human immunodeficiency virus (HIV) have been associated with faster progression to HCV-induced liver cirrhosis and with faster progression to liver decompensation [8-14]. In HIV/HCV-coinfection, progression to cirrhosis is accelerated further in the setting of advanced immunodeficiency with low CD4+ cells.
Treatment for chronic hepatitis C
The primary goal of anti-HCV therapy is the permanent eradication of the virus or a sustained viral response (SVR). An SVR is defined as undetectable plasma HCV RNA 6 months after the end of therapy, which typically lasts 6-12 months. This leads to a long-term viral cure in 98.3% of patients [15]. Following an SVR, resolution of necroinflammation and regression of fibrosis, up to complete resolution, is seen over time [16,17]. Reversal of cirrhosis has been described in 49% of patients [18]. While an SVR is the optimal outcome of HCV treatment, there are benefits to interferon (IFN)-based therapy even in the absence of viral clearance, in that liver inflammation decreases and the rate of fibrosis progression is slowed down [19,20]. In one randomized controlled Japanese trial that studied patients with compensated HCV-related cirrhosis, IFN monotherapy compared with no treatment was associated with decreased rates of progression to liver decompensation, HCC, or death after a mean follow-up period of 8.7 years [21]. However, no such difference in progression to decompensation, HCC, or death was observed in a similar 3-year randomized study from France [22].
In 1986, the first pilot study reported treatment success of subcutaneous IFN alfa-2b against what was then known as non-A-non-B hepatitis [23]. Since then, great progress has been made in the treatment of chronic hepatitis C. The rate of sustained response has improved from 8% with 6 months of IFN alfa-2b monotherapy to 22% with 18 months of IFN monotherapy [24]. A significant improvement in treatment response came with the introduction of oral ribavirin (RBV), which, combined with IFN, led to SVR rates of 38-43% [25,26]. Pegylation of IFN alfa led to a further increase in treatment response. The SVR rate is now 54-56% for combination of pegylated interferon alfa (PEG-IFN alfa 2b or 2a) and RBV [27,28]. In June 2002, a consensus conference sponsored by the US National Institutes of Health accepted the combination of PEG-IFN alfa and RBV as therapy of choice for the initial treatment of chronic hepatitis C [29].
Pegylated interferon alfa consists of a high-molecular weight polyethylene glycol (PEG) moiety that is attached to the IFN alfa protein. This resulting increase in the molecular size prolongs the absorption and elimination half-life and allows once weekly injections (compared to three times weekly with standard IFN) with sustained IFN levels throughout the week. PEG-IFN alfa 2b (PEG-Intron®) has a 12 kDa linear PEG molecule attached to IFN by an ester bond, and in PEG-IFN alfa 2a (Pegasys®) a branched 40-kDa PEG molecule is attached to IFN by an amide bond. In combination with the same dose of RBV (800 mg/day), both PEG-IFNs have similar SVR rates (2b, 42%vs 2a, 40% in genotype 1; and 2b, 82%vs 2a, 73% in genotypes 2 and 3) [27,30]. The most significant factor predicting SVR is the HCV genotype. HCV genotype 1 is the most frequent genotype (74% in the US [1], 56% in Europe and Canada [25]) and responds less well to therapy with an SVR rate of 42% [27] to 51% [30] in combination therapy with PEG-IFN and RBV. HCV genotypes 2 and 3 are less common (23% in the US, 35% in Europe) [1,25] but have a high SVR rate of 76% [27,28] with PEG-IFN and RBV.
The side effects of IFN (standard or pegylated) include initial transient influenza-like symptoms (e.g. fever, myalgia, arthralgia, lack of appetite), neuropsychiatric symptoms e.g. mood swings, insomnia, depression, suicide attempts, and pancytopenia with varying degrees of anaemia, neutropenia and thrombocytopenia. Rare side effects are mild alopecia and thyroiditis that may lead to permanent hypothyroidism. With the exception of the latter, all side effects are reversible upon discontinuation of IFN. RBV has been shown to have serious teratogenic effects in pregnant laboratory animals, and therefore all patients (female or male) must practice effective birth control during and 6 months after RBV therapy. RBV also causes reversible dose-dependent haemolytic anaemia. In one placebo-controlled study of RBV monotherapy for chronic hepatitis C, reversible haemolytic anaemia was seen in 32% of RBV-treated patients compared with 3% of placebo patients (P < 0.001), and the haemolytic anaemia was associated with a rise in serum uric acid and bilirubin levels [31]. Less common toxicities of RBV are cough with asthma-like presentation, rash, severe migraine headaches [32], and gastrointestinal symptoms, all of which resolve when RBV is discontinued [25-28].
Anaemia during HCV combination therapy
Interferon has long been known to cause cytopenia, including mild anaemia. With the addition of RBV to IFN therapy, it was noted that the degree of anaemia in combination therapy was much more pronounced than with IFN alone (Fig. 2) [25]. In two large randomized trials of IFN and RBV, haemoglobin (Hb) levels dropped by a mean of 2.9 g/dL [25] and 3.1 g/dL [26] with a maximum drop of 7.0 g/dL. The lowest point of Hb levels occurred within 4 weeks. The Hb concentration dropped below 10 g/dL in 7% [25] and 8% [26] of patients, at which time the RBV dose was decreased from 1000-1200 mg/day (weight cut-off 75 kg) to 600 mg/day. McHutchison and coworkers found that the SVR rate was no different between the RBV-dose reduced subgroup and patients who maintained the full dose [26]. As a result, RBV dose reductions became the standard of care (SOC) to manage anaemia during HCV combination therapy (Rebetron® Product Information 2000). PEG-IFN not only has higher SVR rates than standard IFN, but it also has a more pronounced bone marrow suppressive effect [33,34]. In combination therapy of PEG-IFN-2a and RBV, the mean drop in Hb was 3.7 g/dL, and 22% of patients required a RBV dose reduction due to an Hb level drop below 10 g/dL or for symptomatic anaemia [28].
Ribavirin concentrates in red blood cells at 60-fold higher concentration than in plasma due to irreversible intracellular phosphorylation to RBV-triphosphate that traps RBV within the red blood cells. The mechanism of haemolytic anaemia is believed to be due to depletion of intracellular adenosine triphosphate (ATP) levels through high levels of RBV that competes for phosphorylation enzymes. Low intracellular levels of ATP lead to impaired antioxidant defence mechanisms. This in turn induces red blood cell oxidative membrane damage with resulting premature removal of red blood cells by the reticular-endothelial system [35].
While it was initially thought that HCV-therapy-induced anaemia is mostly due to haemolytic anaemia from RBV, it has now become apparent that the anaemia is a combination of RBV-induced haemolysis with acute reduction of red blood cells and bone marrow suppression from IFN that leads to impaired ability to make up for the loss of red blood cells. In one randomized study, HCV-infected patients receiving RBV monotherapy had a much higher level of reticulocytes than patients on combination therapy with RBV and IFN (230 vs 80/mm3) [35]. In another randomized controlled trial of hepatitis C therapy, treatment with 24 weeks of IFN alfa-2b and RBV was followed by either RBV monotherapy or no treatment. After discontinuation of IFN alfa 2b at 6 months, anaemia improved both in the RBV arm and the no-treatment arm, albeit at a slower pace in the RBV group.[36] In consideration of this combined effect on Hb levels of haemolysis from RBV and bone marrow suppression from IFN, there are two measures that can be taken to correct the anaemia: (1) dose reductions of RBV to decrease haemolysis and (2) treatment with recombinant human erythropoietin (rHuEPO, epoetin alfa) to stimulate the suppressed erythroid precursors in the bone marrow.
Ribavirin dose reduction
Given the findings by McHutchison and coworkers of no difference in SVR between patients with dose-reduced (600 mg/day) vs full-dose (1000-1200 mg/day) RBV, dose reductions became the SOC for managing anaemia during HCV therapy. However, the study was not powered to show equivalency between the two subgroups, and subsequent studies showed that higher RBV doses do indeed lead to higher rates of SVR when combined with IFN. In a pooled subanalysis of all studies evaluating IFN plus RBV, higher plasma levels of RBV at treatment week 4 (steady-state phase) were associated with higher SVR rates. The SVR rate ranged from 31% for RBV levels 1000 ng/dL to 62% for levels >4000 ng/dL [37]. An independent linear correlation between mg/kg RBV dose and SVR was observed in a retrospective analysis of a randomized controlled trial, looking at the group that received PEG-IFN2b at 1.5 g/kg once weekly plus RBV at 800 mg/day. Since the RBV dose was fixed at 800 mg/day, heavier individuals with lower mg/kg RBV doses had lower SVR rates than lighter patients with higher mg/kg doses [27]. In a further subanalysis of the same trial using PEG-IFN alfa-2b plus RBV, McHutchison and coworkers analysed the influence of medication adherence on SVR rate. They found that patients who received at least 80% of the PEG-IFN alfa-2b dose and 80% of the RBV dose had a better SVR rate than patients who received less than 80% of the dose of either medication (63 vs 52%, P = 0.04). Each group received medication for at least 80% of the 48-week course. This difference was only seen in genotype 1 (SVR, 51 vs 34%, P = 0.011) but not in genotypes 2 and 3 (SVR, 90 vs 89%, P = 0.96) [38]. The strongest support for the hypothesis that higher RBV doses contribute to higher SVR rates was provided by a large randomized controlled trial (n = 1284) by Hadziyannis and colleagues. Patients with chronic hepatitis C were randomized into four groups: a RBV dose of 800 mg/day or 1000-1200 mg/day for either 24 or 48 weeks of treatment, each group in combination with PEG-IFN alfa 2a at 180 g once weekly. In patients with HCV genotype 1, the rate of SVR after 48 weeks of therapy was significantly higher in the 1000-1200 mg/day group than in the 800 mg/day group (51 vs 40%, P = 0.012). By contrast, in genotype 2 or 3, no difference was seen in the SVR rate (78% for both doses after 24 weeks) [30]. A second large randomized controlled trial with PEG-IFN alfa 2b that compares RBV at a fixed dose of 800 mg/day with weight-based dosing from 800-1400 mg/day is ongoing [39]. Because lower RBV doses yield a lower treatment response in genotype 1, the concept of RBV dose reduction for the management of anaemia is now being reconsidered.
Epoetin alfa treatment
In an uncontrolled pilot study, Talal and colleagues found that 18 of 56 (32%) HCV-infected patients treated with IFN and RBV combination therapy developed anaemia (Hb <10 or >2 g/dL Hgb drop from baseline). The Hb concentration dropped from a baseline Hb value of 14.3 g/dL to 10.6 g/dL, with an average Hb reduction of 26%. These 18 patients were given epoetin alfa at 40 000 IU weekly. The RBV dose was lowered in eight of these patients before the initiation of epoetin alfa therapy and in five patients concurrently with epoetin alfa therapy. At the end of HCV therapy, the mean Hb level increased to 12.7 g/dL, which was similar to the 13.0 g/dL level in patients without anaemia and who did not receive epoetin alfa treatment (P = NS). On average, epoetin alfa recovered 72% of the previous decrease in Hb concentration. The relative roles of RBV dose reduction and epoetin alfa therapy in the observed increase in Hb level could not be differentiated due to the lack of a control group in this pilot study [40].
A randomized controlled study by Dieterich and coworkers evaluated 64 HCV-infected patients whose Hb value dropped below 12.0 g/dL during combination therapy. Patients received either epoetin alfa at 40 000 IU once weekly or SOC, i.e. RBV dose reductions or in extreme cases blood transfusions. Hb levels and RBV dose changes were measured during a 16-week period. In the epoetin alfa arm, the Hb level rose by a mean of +2.8 g/dL compared to +0.4 g/dL in the SOC arm (P < 0.001) and mean RBV dose changes were 34 mg/day with epoetin alfa and 146 mg/day with SOC (P = 0.060). At treatment week 16, the mean Hb level was 14.2 g/dL in the epoetin alfa arm vs 11.2 g/dL in the SOC arm (P < 0.001), and the mean RBV doses were 895 and 707 mg/day, respectively (P = 0.038). Patients treated with epoetin alfa maintained their RBV dose at 800 mg/day or higher in 83% of cases compared to 54% of patients with SOC (P = 0.022) [41].
A second randomized controlled trial conducted by Afdhal and colleagues evaluated 186 HCV-infected patients whose Hb value dropped to 12.0 g/dL while on combination therapy with IFN alfa (standard or pegylated) and RBV. Patients were randomized to receive either epoetin alfa at 40 000 IU once weekly or matching placebo for 8 weeks. After the 8-week double-blind period, patients on placebo were allowed to switch over to open-label epoetin alfa. The primary endpoint was RBV dose success, defined as an RBV dose at week 8 that was greater than or equal the RBV dose at randomization. RBV dose success was achieved in 88% of patients on epoetin alfa compared to 60% of patients receiving placebo (P < 0.001). The mean RBV doses at week 8 were 944 mg/day in the epoetin alfa group and 855 mg/day in the placebo group (P < 0.001). The mean Hb levels at week 8 were 13.0 g/dL (epoetin alfa) and 10.8 g/dL (placebo, P < 0.001), and mean Hb changes from baseline were +2.2 g/dL (epoetin alfa) and 0.0 g/dL (placebo). Quality of life, measured by a linear analog scale and the standardized Medical Outcomes Survey short form 36 (SF-36, version 2.0), improved significantly from baseline in the epoetin alfa group compared to the placebo group (P < 0.001 to P = 0.003) [42].
Clinical implications for the management of hcv therapy-induced anaemia
With the knowledge that lower RBV doses lead to lower SVR rates, there is a growing reluctance among HCV-treating clinicians to reduce RBV doses. Increasingly, clinicians are instead using epoetin alfa to manage anaemia during HCV combination therapy. Clinical trials have shown that in the setting of HCV therapy-induced anaemia, administration of epoetin alfa at 40 000 IU once weekly increases the Hb concentration, maintains the RBV dose, and improves quality of life. It should be noted, though, that to date no prospective study has demonstrated a direct relationship between the use of epoetin alfa and increased SVR rates. In addition, epoetin alfa is not currently approved by the US Food and Drug Administration or the European Medicines Evaluation Agency for use in HCV-therapy-induced anaemia. However, a consensus is growing that epoetin alfa is useful in maintaining the RBV dose, particularly when the patient is symptomatic (fatigue, dyspnoea, etc.) during an acute drop in Hb level (typically of 3.0 g/dL or more) and some intervention is needed to alleviate the anaemia. Because of the rapid onset of treatment-related anaemia within the first 4 weeks, Hb levels should be monitored weekly or biweekly during that interval of HCV combination therapy for prompt intervention when significant anaemia occurs.
Devine and colleagues performed a cost analysis of managing RBV-induced haemolytic anaemia by RBV dose reductions (without the use of epoetin alfa), taking into account increased physician visits and laboratory tests, and possible transfusions. The attributable direct cost of managing clinically significant anaemia was US$170 per patient (range US$68-692), the difference between the direct cost of managing such anaemia of US$303 per patient and the cost of routine monitoring of patients with nonclinically significant anaemia of US$133. This study did not take into account the influence of RBV dose reductions on SVR rate because at the time the relationship had not yet been established [43]. A new cost-benefit analysis is needed that takes into account the cost of epoetin alfa along with likely viral response rates with either RBV dose reductions or use of epoetin alfa for clinically significant anaemia. The inability of achieving an SVR is associated with costs of retreatment or possible progression of liver disease. A dialogue between clinicians and medical insurance providers will be helpful to determine conditions under which epoetin alfa can be used to manage anaemia during combination therapy for chronic hepatitis C.
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