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 two 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 upon our results, these two strategies do not appear to differ in their ability for management of hematologic abnormalities in HIV/HCV co-infected 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 two strategies for management of anemia and neutropenia.
The main limitation of this study is the cessation of recruitment prior to full enrollment. Additional limitations include withdrawal from the study due to violation of the study protocol in 10% of the patients and consent withdrawal in 7%, which contributed to lower power to prove the apriori 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 to HCV monoinfected patients3–7
. 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 advanced AIDS patients24
. Antiviral medications can also contribute to anemia. RBV is directly toxic to red blood cells resulting in hemolysis,25, 26
and zidovudine is a well recognized cause of anemia in HIV infection. In our study, only two patients received zidovudine, 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 activity27, 28
, higher doses have also been associated with more profound hemoglobin declines during treatment29
. Similarly, neutropenia occurs in, approximately 50% of patients with AIDS30
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 doses31
. Treatment of anemia, besides improving adherence to combination antiviral therapy, may also improve patients’ health-related quality of life16
. 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 thromboembolism32, 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 conditions34
. 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 patients32, 35
. However, this analysis assumed that growth factor supplementation resulted in improved SVR rates, which has not yet been conclusively determined36
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 rates17
. Although EPO 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 co-infected patients38
. 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 co-infected patients receiving PEG-IFN/RBV therapy3–5, 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.