Fifty-three patients (58%) underwent a full course of HCV therapy according to the study protocol. Of the remaining 39 patients, HCV treatment was discontinued in 8 (9%) patients because of severe anemia, 3 (3%) because severe neutropenia, and 12 (13%) because of other severe side effects. Nine patients (10%) were discontinued because of violation of the study protocol while 6 (7%) withdrew consent.
Effect of Management Strategies on Hematological Parameters
Because anemia most often occurs secondary to RBV and neutropenia secondary to PEG-IFN alfa, they were considered independent processes and were analyzed separately even if they both occurred in the same patient.
At baseline, median hemoglobin levels were comparable among patients who were assigned to receive either dose reduction or growth factor supplementation: growth factor supplementation group: 14.0 g/dL (IQR: 12.8, 15.3), RBV dose reduction group: 14.1 g/dL (IQR: 13.3, 15.2) (P > 0.05). Among all patients, hemoglobin levels decreased ∼25% from baseline after initiation of PEG-IFN/RBV in both groups, resulting in median (IQR) nadir hemoglobin levels of 10.4 (9.6, 12.1) g/dL and 10.6 (10.2, 12.2) g/dL, respectively.
A total of 43 patients developed anemia, 24 (51%) of whom were randomized to receive growth factor supplementation versus 19 (42%) randomized to receive RBV dose reduction (P = 0.41). Among anemic patients, median baseline hemoglobin levels were comparable among those who received either growth factor supplementation or RBV dose reduction: 13.4 g/dL (IQR: 12.7, 14.4) versus 13.9 g/dL (IQR: 12.9, 14.7), respectively (P = 0.54). Their hemoglobin levels decreased before intervention to median (IQR) nadir hemoglobin levels of 9.8 (9.3, 10.4) g/dL and 10.1 (9.7, 10.4) g/dL, respectively (P = 0.32) (Fig. 2A).
Treatment week 5 was the median initiation time for treatment with rHuEPO or RBV reduction, IQR (3, 18) and (4, 8), respectively (Fig. 2B). After the intervention, median (IQR) hemoglobin levels peaked at 11.7 (10.6, 13.1) g/dL in anemic patients who received growth factor supplementation and at 11.9 (10.8, 13.6) g/dL in those who had RBV dose reduction (P = 0.46). The median (IQR) time on the interventions was 13 (7.0, 24.5) weeks and 25 (9.0, 41.0) weeks, respectively (P = 0.36). To mitigate variations in individual hemoglobin levels over time, we also evaluated mean hemoglobin levels postintervention while patients remained on PEG-IFN/RBV. The median (IQR) level of the mean hemoglobin values after initiation of intervention was 10.8 (9.9, 12.2) for the growth factor group and 11.3 (10.4, 11.9) for the RBV reduction group (P = 0.74).
Fifteen anemic patients (63%) in the growth factor arm completed a full course of HCV treatment versus 9 (47%) in the dose reduction arm (P = 0.37). More patients were discontinued from the study because of severe anemia in the growth factor arm compared with those in the dose reduction arm [6 (25%) versus 1 (5%)], although the difference was not statistically significant (P = 0.11).
Similar to the changes observed in hemoglobin levels, median baseline ANC levels were comparable among patients who were assigned to receive either growth factor supplementation or dose reduction: 2220 (IQR: 1634, 2622) × 103 cells/μL versus 2317 (IQR: 1786, 3192) × 103 cells/μL, respectively (P = 0.20). Taking all patients together, median ANC levels decreased ∼57% in both intervention groups, resulting in nadir ANC levels of 960 (IQR: 756, 1288) × 103 cells/μL and 1000 (IQR: 700, 1312) × 103 cells/μL, respectively (P = 0.93).
After PEG-IFN/RBV initiation, 10 (21%) patients randomized to growth factor supplementation became neutropenic versus 15 (33%) patients randomized to PEG-IFN alfa-2b dose reduction (P = 0.24). Among neutropenic patients, baseline median ANC levels were comparable among those who received either growth factor supplementation or PEG-IFN dose reduction: 1648 (IQR: 1350, 2478)× 103 cells/μL and 2045 (IQR: 1575, 2375) × 103 cells/μL, respectively (P = 0.62) (Fig. 3A). Their ANC levels decreased before intervention to median (IQR) nadir ANC levels of 700 (692, 775) × 103 cells/μL and 669 (521, 707) × 103 cells/μL, respectively (P = 0.25).
G-CSF or PEG-IFN reduction were initiated at a median (IQR) of week 10 (1, 19) or week 8 (4, 11), respectively (P = 0.50) (Fig. 3B). After the intervention, median (IQR) ANC levels peaked at 1942 (1028, 2609) × 103 cells/μL in neutropenic patients who received growth factor supplementation and at 974 (741, 2176) × 103 cells/μL in those who had PEG-IFN dose reduction (P = 0.20). The median (IQR) time on the intervention was 26.5 (8, 34.5) weeks and 20 (6, 26) weeks, respectively (P = 0.73). We also evaluated mean ANC levels post–G-CSF intervention while patients remained on a stable dose of PEG-IFN/RBV. The median (IQR) level of the mean ANC values after initiation of intervention was 1071 (926.9, 1886) × 103 cells/μL for the growth factor group and 862 (690.8, 1270) × 103 cells/μL for the PEG-IFN reduction group (P = 0.14).
Eight neutropenic patients (80%) in the growth factor arm completed a full course of HCV treatment versus 8 (53%) in the dose reduction arm (P = 0.21). Three patients who were discontinued from the study because of severe neutropenia were in the PEG-IFN reduction arm.
A full course of HCV therapy, as defined in the study protocol, was completed by 53 (58%) patients. Virologic outcome data were also available for an additional 4 patients, all of whom were discontinued from the treatment protocol because of side effects. SVR was defined as undetectable HCV RNA levels 6 months posttreatment cessation. Of 57 patients with known HCV treatment response, 19 (33%) achieved an SVR (21% by intention to treat). Of these 57 patients, 27 developed anemia and 16 developed neutropenia. Of 27 anemic patients, 16 received growth factor supplementation, and 11 had RBV dose reduction; of 16 neutropenic patients, 8 received growth factor supplementation and 8 had PEG-IFN reduction. Eleven of 43 (26%) patients who became anemic during PEG-IFN/RBV attained an SVR. SVR percentages were similar among anemic patients in the growth factor supplementation group and the RBV dose reduction group (29% versus 21%, respectively, P = 0.92) (Fig. 4). Seven of 25 (28%) patients who became neutropenic during PEG-IFN/RBV attained an SVR. SVR percentages were similar among neutropenic patients in the growth factor group and the PEG-IFN reduction group (40% versus 20%, respectively, P = 0.46) (Fig. 4).
SVR percentages were generally lower among the subgroups of patients traditionally regarded as more difficult to treat. As per intention to treat, SVR percentages were 16% (12 of 77) among genotype 1 patients, 8% (3 of 39) among African Americans, and 20% (3 of 15) among cirrhotics (Table 2). A total of 34 genotype 1–infected patients developed anemia: 19 were treated with dose reduction and 15 were treated with growth factor supplementation. SVR outcome in anemic genotype 1–infected patients was achieved in 4 (21%) of those who received growth factor supplementation and in 2 (13%) of those managed through dose reduction (P = 0.9). A total of 23 genotype 1–infected patients developed neutropenia: 14 were treated with dose reduction and 9 were treated with growth factor supplementation. SVR percentages were similar among neutropenic genotype 1–infected patients treated with either dose reduction [n = 3 (21%)] or G-CSF supplementation [n = 3 (33%), P = 0.65].
The current standard treatment for chronic HCV infection, PEG-IFN in combination with RBV, is frequently associated with hematologic abnormalities, especially in HIV/HCV-coinfected patients. Treatment-induced anemia and neutropenia are traditionally managed by dose reduction and more recently with growth factor supplementation. To compare these 2 management strategies, we performed a prospective, randomized preliminary study in HIV/HCV-coinfected patients treated with weight-based PEG-IFN alfa and weight-based RBV. Based on our results, these 2 strategies do not seem to differ in their ability for management of hematologic abnormalities in HIV/HCV-coinfected patients, although these conclusions may be affected by low power. Overall, SVR percentages were similar in patients who received dose reduction compared with those treated with growth factor supplementation. In addition, the proportion of patients who completed a full course of HCV therapy was comparable between the 2 strategies for management of anemia and neutropenia.
The main limitation of this study is the cessation of recruitment before full enrollment. Additional limitations include withdrawal from the study because of violation of the study protocol in 10% of the patients and consent withdrawal in 7%, which contributed to lower power to prove the a priori hypothesis. Therefore, our results should not be considered as a definitive statement of the management practice for hematologic abnormalities in HIV/HCV-coinfected patients treated with PEG-IFN/RBV.
Treatment of HIV/HCV-coinfected patients with PEG-IFN and RBV results in suboptimal therapeutic outcomes compared with HCV-monoinfected patients.3–7 In addition, coinfected patients are twice as likely to discontinue treatment prematurely in comparison with monoinfected patients, with hematological toxicities being cited as one of the most common causes for treatment discontinuation.3,21–23 The prevalence of anemia varies from 18% to 50% in patients with HIV without AIDS to 68% to 92% in patients with advanced AIDS.24 Antiviral medications can also contribute to anemia. RBV is directly toxic to red blood cells resulting in hemolysis,25,26 and AZT is a well-recognized cause of anemia in HIV infection. In our study, only 2 patients received AZT, both of whom developed anemia. We also observed a significant association between undetectable HIV RNA at baseline and development of anemia. One possible explanation for this finding is that those patients with undetectable HIV RNA may have been more adherent to their medications leading to increased RBV adherence and more anemia. Although higher RBV doses have increased antiviral activity,27,28 higher doses have also been associated with more profound hemoglobin declines during treatment.29 Similar to the situation with anemia, neutropenia occurs in ∼50% of patients with AIDS.30
Historically, dose reduction was the standard management strategy for hematological side effects of PEG-IFN and RBV. However, recent studies have shown that the response to therapy is strongly influenced by adherence to optimal medication doses.31 Treatment of anemia, besides improving adherence to combination antiviral therapy, may also improve patients' health-related quality of life.16 Therefore, the use of growth factors, such as G-CSF and rHuEPO to stimulate bone marrow production of leukocytes and erythrocytes, respectively, has been advocated to enhance patients' ability to tolerate optimal doses of PEG-IFN alfa and RBV.
Growth factors are not without limitations. rHuEPO can cause hypertension, pure red cell aplasia, injection site erythema, erythropoietin resistance, and venous thromboembolism.32,33 Additionally, several large randomized clinical trials have recently shown a potential detrimental effect of rHuEPO administration on tumor progression and survival in patients treated for oncologic conditions.34 Both G-CSF and rHuEPO can substantially increase total medication costs. Despite these limitations, a recent analysis suggested that the use of hematopoietic growth factors, especially darbepoetin, was a cost-effective intervention during PEG-IFN/RBV treatment of HCV-monoinfected patients.32,35 However, this analysis assumed that growth factor supplementation resulted in improved SVR rates, which has not yet been conclusively determined.36
To date, very few studies have compared growth factor supplementation and dose reduction for management of hematologic abnormalities in HCV-infected or in HIV/HCV-coinfected patients treated with PEG-IFN and RBV. A study performed in HCV-monoinfected patients found that the use of rHuEPO from the beginning of HCV treatment did not increase SVR rates.17 Although erythropoietin use significantly reduced the incidence of anemia and RBV dose reductions, it did not affect treatment responses. Another study demonstrated that erythropoiesis-stimulating agents significantly improved treatment outcome in those with early-onset anemia (≤8 weeks of therapy).37 In the AACTG-A5071 study, rHuEPO and G-CSF support was also associated with an improved clinical response to therapy in HIV/HCV-coinfected patients.38 Although we observed higher SVR percentages in those who received G-CSF (40% versus 20%), our sample size precluded the observation of a significant relationship. Twenty-one percent of our patients achieved an SVR, which is slightly lower than SVR percentages reported in other clinical trials in HIV/HCV-coinfected patients receiving PEG-IFN/RBV therapy.3–5,10,39 The inclusion of a relatively high proportion of patients who are traditionally regarded as difficult to treat [such as African American (43%), genotype 1 (84%), and cirrhotic individuals (17%)] likely contributed to the low overall SVR percentage in the current study. In addition, poor patient adherence coupled with high early discontinuation rates likely also contributed to a poor antiviral response.
In summary, in HIV/HCV-coinfected patients, the use of growth factors did not significantly enhance hemoglobin and ANC values compared with dose reduction, although this conclusion may be influenced by our low numbers of subjects. Our results on the timing and extent of hemoglobin and ANC decline and recovery before and after intervention with growth factors or dose reduction may be useful in the clinical management of HIV/HCV-coinfected patients and can also be used for planning larger trials.
We acknowledge Jay Kadam, MD, Kristina Jones, MD, Preeti Golia, MD, Sandra Flynn, RN, Michelle Pappas, and Ray Peterson for assistance with the conduct of the study. We also acknowledge Larry Heller for assisting in the study design and for helpful conversations.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
hepatitis C virus/HIV coinfection; anemia; neutropenia; recombinant human erythropoietin; granulocyte colony-stimulating factor