Abstract
Background
This study investigates whether dose modifications for adverse hematologic effects or the use of hematopoietic growth factors influenced the outcome of therapy for hepatitis C virus (HCV) infection in patients who were coinfected with HCV and human immunodeficiency virus (HIV) and who were participants in a randomized, controlled trial.
Methods
Subjects were randomized to receive ribavirin plus interferon-alfa-2a (IFN-alfa-2a) or pegylated IFN-alfa-2a for a total of 48 weeks. Doses were modified for a number of adverse effects (including hematologic toxicity), and hematopoietic growth factors were administered at the discretion of the physician. Associations of dose modifications or initiation of hematopoietic growth factor support with treatment outcomes were determined by standard statistical methods.
Results
One hundred thirty-three subjects were included in this study. Subjects treated with pegylated IFN-alfa-2a were more likely to have had dose modifications (dose reduction or discontinuation) than were those treated with IFN-alfa-2a. By multivariate analysis, treatment with pegylated IFN-alfa-2a is associated with higher sustained virologic and/or histologic response. Dose modifications for nonhematologic toxicity are independently associated with lower sustained virologic and/or histologic responses. Although hematologic toxicity was not directly associated with clinical outcome in this analysis, use of hematopoietic growth factors was associated with an increased sustained virologic and/or histologic response.
Conclusions
Dose modifications for anti-HCV therapy may adversely affect the outcome of treatment of HCV in individuals who are coinfected with HIV. The use of hematopoietic growth factor support may be associated with an improved clinical response to therapy.
Chronic hepatitis C virus (HCV) infection is common among individuals infected with HIV. In the United States, 15%–33% of people with HIV infection are coinfected with HCV [1–4], and up to 60% of people who acquired HIV infection via injection drug use have chronic HCV infection [4, 5]. As a result of patients’ increased longevity with the emergence of combination antiretroviral therapy, complications of HCV-related disease are becoming increasingly more important causes of morbidity and mortality in HIV-HCV–coinfected individuals [1, 6, 7]. Individuals with HIV infection have a higher HCV load [8–11], more rapid progression of fibrosis and cirrhosis [11–13], and a more rapid development of hepatocellular carcinoma [14], leading to increased mortality, compared with patients with HCV infection alone. The risk of cirrhosis or decompensated liver disease in patients with HIV-HCV coinfection is estimated to be 3 times that in patients infected with HCV alone [15].
The efficacy of IFN or pegylated IFN (plus ribavirin) as treatment for HCV infection has been established in HCV-monoinfected patients and those with HCV-HIV coinfection, with sustained virologic responses of 47%–66% [16–18] and 12%–44% [19–22], respectively. Response rates among patients infected with HCV genotype 1 are significantly lower than among those with non–genotype 1 HCV infection. Hematologic toxicity may be more pronounced in HIV-infected individuals than in those without HIV infection, especially for patients with underlying hematologic disorders.
People with chronic HIV infection are at risk for multiple hematologic abnormalities [23–25]. Chronic HCV infection can lead to leukopenia, anemia, and thrombocytopenia resulting from splenic sequestration in patients with cirrhosis and portal hypertension, as well as to anemia resulting from chronic inflammation and autoimmune hemolytic anemia [26]. Use of antiretrovirals and prophylactic medications, opportunistic infections, and malignancies, also contribute to cytopenia in people with HIV-HCV coinfection.
Both IFN and, to a greater degree, pegylated IFN can lead to bone marrow suppression [17, 18, 28]. Ribavirin is associated with a dose-dependent hemolytic anemia. Although combination therapy with IFN and ribavirin can occasionally lead to severe neutropenia and thrombocytopenia, an increase in infectious complications has not been noted, and spontaneous bleeding is rare [26, 27]. However, these adverse effects commonly lead health care providers to reduce the dose or discontinue therapy, which may negatively impact the outcome of therapy [29]. To date, the effect of dose modifications for hematologic toxicity on outcomes of therapy for HCV infection in individuals coinfected with HIV has not yet been described.
In randomized, controlled trials comparing IFN plus ribavirin with pegylated IFN plus ribavirin for the treatment of HIV-HCV–coinfected individuals, withdrawal from therapy occurred in up to 39% of subjects (12%–17% for adverse events) [19–21]. The rate of dose modification for hematologic toxicities varies. Most trials report the percentage of patients who require dose modification for anemia in the range of 8%–15%, 3%–12% for anemia, and only 2%–5% for thrombocytopenia [19–21].
The Adult AIDS Clinical Trials Group A5071 study was a prospective, phase II/III, open-label, randomized, controlled trial designed to compare the efficacy, safety, and tolerability of IFN-alfa-2a plus ribavirin versus pegylated IFN-alfa-2a plus ribavirin for chronic HCV infection as treatment for chronic HCV infection in individuals coinfected with HIV-1. As has previously been reported, adverse events led to premature withdrawal from treatment for 8 subjects in each arm (12% overall); all withdrawals occurred within the first 20 weeks of treatment. Grade 4 anemia occurred in 3 subjects and was managed with dose modifications. Of the subjects who developed grade 4 neutropenia, 2 discontinued treatment, and 4 underwent dose modifications, some of which involved the addition of a hematopoietic growth factor. Only 1 subject experienced grade 4 thrombocytopenia [22].
Because of the concern that overlapping hematologic complications of HIV and HCV coinfection and toxicity associated with IFN-alfa-2a and ribavirin therapy may have affected treatment outcomes, this analysis was undertaken to examine the effect of hematologic toxicity on the treatment outcome in the Adult AIDS Clinical Trials Group A5071 study.
METHODS
Subjects
Subject selection, study design, and statistical methods have been described elsewhere [22]. Subjects aged ≥18 years were eligible to participate if they had chronic HIV infection and chronic HCV infection (HCV RNA level, >600 IU/mL). The CD4+ T lymphocyte count was required to be >100 cells/mm3 for subjects who were receiving stable antiretroviral therapy and >300 cells/mm3 for those who were not receiving antiretroviral therapy. Entry criteria also specified that all subjects should have an absolute neutrophil count >1000 cells/mm3, a hemoglobin concentration ≥10.5 g/dL, and a platelet count ≥70,000 platelets/mm3.
Treatment interventions
Because the safety of HCV treatment in HIV-HCV–coinfected patients was not known, ribavirin treatment was started at a dosage of 600 mg/day. If the hemoglobin concentration remained ≥10.5 g/dL, the dosage was escalated to 800 mg/day by week 5 and then to 1000 mg/day by week 9; treatment stopped for any new onset of a hemoglobin concentration ≤10.5 g/dL, unless the dosage was 1000 mg/day and the hemoglobin concentration was ≥9.5 g/dL, in which case it was reduced to 600 mg/day. If the hemoglobin concentration improved to ≥10.5 g/dL at the next assessment of the hemoglobin concentration, ribavirin treatment was restarted at 600 mg/day. Hemoglobin measurements were repeated 2–4 weeks after any new or worsening anemia.
The starting dose of IFN-alfa-2a was 6 million U subcutaneously 3 times weekly for the first 12 weeks and 3 million U 3 times weekly for the remaining 36 weeks; pegylated IFN-alfa-2a was started at 180 μg subcutaneously weekly. IFN-alfa-2a and pegylated IFN-alfa-2a doses were delayed and/or adjusted if the neutrophil count decreased to <1000 cells/mm3 and if the platelet count decreased to <50,000 platelets/mm3; use of the drug was stopped if the platelet count decreased to <20,000 platelets/mm3. Treatment was also discontinued for subjects who experienced severe depression with suicidal ideation or acute psychosis requiring hospitalization. Erythropoietin and granulocyte–colony-stimulating factor (G-CSF) were administered at the discretion of the individual investigators. Other reasons for dose modifications or discontinuations included other toxicities and subject nonadherence to treatment or were otherwise not specified.
Assessments
Evaluations of symptoms and hematologic parameters were performed on weeks 2 and 4, then every 4 weeks until week 24, and then every 6 weeks until week 48. Assessments for efficacy and safety were made at 24 weeks. Subjects with a virologic response, defined as a viral load of <60 IU/mL, continued to receive treatment; those without a virologic response at week 24 underwent liver biopsy. Patients with histologic response (defined as a reduced hepatic activity index [30] by ≥2 points, compared with the pretreatment liver biopsy value) continued to receive treatment; those who did not have a histologic response or who did not undergo liver biopsy stopped receipt of the study drugs.
Statistical analysis
We used descriptive statistics to characterize the study population by treatment arm, by use of antiretroviral therapy, and among patients receiving antiretroviral therapy, by CD4+ T lymphocyte count. “Treatment modification” refers to any dose reduction or discontinuation. The χ2 test was used to compare the proportions of patients who required treatment modifications by treatment arm; in addition, we used Kaplan-Meier plots and the log rank test to compare the time to first modification by treatment arm. We conducted an exploratory analysis using the Lowess nonparametric smoother to assess whether the mean hemoglobin level, platelet count, and neutrophil count started to increase after treatment modifications, stratified by the reason for the modification; however, because numbers in each stratum were small, we did not attempt formal statistical inference. Finally, we used multivariate logistic models to assess the influence of adherence to treatment and treatment modifications on the likelihood of a sustained virologic response and/or histologic response. Because the numbers of end points were limited, we assessed these predictors in separate models, each controlling for treatment assignment. Our continuous measure of adherence, defined as the percentage of the planned cumulative dose actually received, takes account of protocol-mandated discontinuation of treatment at 24 weeks for nonresponders. Specifically, to avoid confusing cause and effect, adherence was computed for participants who stopped receiving treatment at 24 weeks because of nonresponse as the percentage of planned dose at 24 weeks, whereas for subjects allowed to continue to receive treatment after week 24, the adherence percentage was computed with respect to the planned cumulative dose at 48 weeks. The Kaplan-Meier, log rank, and Lowess analyses were performed using the freeware package R (R Foundation for Statistical Computing); all other analyses were performed using SAS software, version 8.2 (SAS Institute).
RESULTS
Description of the Study Subject Population
A total of 134 subjects were randomized to receive ribavirin plus either IFN-alfa-2a or pegylated IFN-alfa-2a. One subject was excluded after randomization, resulting in 67 subjects in the IFN-alfa-2a group and 66 subjects in the pegylated IFN-alfa-2a group. Baseline hematologic variables did not differ significantly by antiretroviral therapy group, CD4+ T lymphocyte count, or treatment group (table 1). Additionally, there were no significant associations between baseline hematologic values and hepatic activity index score or HCV genotype (data not shown).
Table 1.
Baseline characteristics of the study population.
| ART recipients |
|||||
|---|---|---|---|---|---|
| Characteristic | Patients who did not receive ART (n = 15) |
CD4+ T lymphocyte count, ≤200 cells/mm3 (n = 14) |
CD4+ T lymphocyte count, >200 cells/mm3 (n = 104) |
Ribavirin plus IFN-alfa-2a arm (n = 67) |
Ribavirin plus pegylated IFN-alfa-2a arm (n = 66) |
| CD4+ T lymphocyte count, cells/mm3 | 522 (174–856) | 154 (85–198) | 568 (211–1376) | 476 (85–1001) | 563 (142–1376) |
| Neutrophil count, cells/mm3 | 3033 (1032–5670) | 2246 (800–3800) | 3025 (682–8600) | 2834 (682–6800) | 3055 (800–8600) |
| Hemoglobinc oncentration, g/dL | 15.0 (12.8–17.2) | 14.2 (10.6–18.2) | 14.7 (11.6–17.8) | 14.7 (10.6–17.3) | 14.7 (11.6–18.2) |
| Platelet count, platelets/mm3 | 203 (105–352) | 181 (94–274) | 216 (99–437) | 212 (94–437) | 210 (99–417) |
NOTE. Dataa re mean (range). The protocol mandated that subjects who did not receive antiretroviral therapy (ART) had a CD4+ T lymphocyte count >300 cells/mm3, and those who did receive ART had a CD4+ T lymphocyte count >100 cells/mm3. However, 2 subjects who did not receive ART had values that were less than the mandated level (174 and 286 cells/mm3), as did 1 subject in the ART group (85 cells/mm3).
During the course of the study, there were minor changes in mean hemoglobin concentration, neutrophil count, and platelet count over time, the pattern of which did not differ significantly between treatment groups. Among subjects who had treatment modifications, there was no significant difference in mean levels for the hematologic variables among subgroups defined by the reason for dose modification or the initiation of hematopoietic growth factor (erythropoietin and/or G-CSF). There were mild decreases in the mean hemoglobin concentration and neutrophil count in the first weeks after randomization that stabilized and/or improved over time. The mean platelet count appears to have decreased mildly in the pegylated IFN-alfa-2a group but not in the IFN-alfa-2a group; however, the level remained within the normal reference range (figure 1). At baseline, no patient was using G-CSF, and 1 patient was using erythropoietin (a protocol violation).
Figure 1.
Changes in mean hematologic parameters over time. Changes in mean hemoglobin concentration, platelet count, and absolute neutrophil count over time since treatment modification based on the reason for modification or initiation did not vary significantly of hematopoietic among subgroups growth factor treatment. Patients may have appeared in >1 group.
Treatment Intervention
IFN-alfa-2a vs. pegylated IFN-alfa-2a
The proportion of dose reductions and discontinuations for IFN-alfa-2a, pegylated IFN-alfa-2a, and ribavirin and the reasons for treatment modification are shown in tables 2–4. Subjects in the pegylated IFN-alfa-2a group were more likely to have undergone a dose reduction for either ribavirin or pegylated IFN-alfa-2a and to have met the combined end point of dose reduction or discontinuation of either drug, compared with patients in the IFN-alfa-2a group (table 4). This difference began to become apparent within the first 12 weeks after randomization (figure 2). Reasons for treatment modifications did not vary significantly between the IFN-alfa-2a and pegylated IFN-alfa-2a groups (tables 2 and 3). Although neutropenia led to majority of reductions in the IFN-alfa-2a and pegylated IFN-alfa-2a doses, it did not lead to any discontinuations. Similarly, the majority of ribavirin dose reductions were associated with anemia, but only 1 patient discontinued ribavirin because of anemia.
Table 2.
Reasons for modification of the dose of IFN-alfa-2a, pegylated IFN-alfa-2a, and ribavirin
| Treatment modified, reason | IFN-alfa-2 recipient |
Pegylated IFN-alfa-2a recipient |
|---|---|---|
| IFN-alfa-2a or pegylated | ||
| IFN-alfa-2a modification | ||
| All patients | 9 | 19 |
| Neutropenia | 6 (67) | 19 (100) |
| Other toxicity | 2 (22) | 0 (0) |
| Clinical decision | 1 (11) | 0 (0) |
| Ribavirin modification | ||
| All patients | 3 | 12 |
| Anemia | 3 (100) | 9 (75) |
| Subject decision | 0 (0) | 2 (17) |
| Other | 0 (0) | 1 (8) |
| IFN-alfa-2b, or pegylated | ||
| IFN-alfa-2b, or ribavirin modification | ||
| All patients | 11 | 27 |
| Anemia | 2 (18) | 7 (26) |
| Neutropenia | 6 (55) | 18 (67) |
| Other toxicity | 2 (18) | 0 (0) |
| Clinical decision | 1 (9) | 0 (0) |
| Subject decision | 0 (0) | 1 (3.7) |
| Other | 0 (0) | 1 (3.7) |
NOTE. Data are no. (%) of patients.
Table 4.
Treatment interventions, by treatment assignment.
| No. (%) of patients |
|||
|---|---|---|---|
| Intervention, agent | IFN-alfa-2a arm (n = 67) |
Pegylated IFN-alfa-2a (n = 66) |
P |
| Dose reduction | |||
| IFN-alfa-2a or pegylated | |||
| IFN-alfa-2a | 9 (13.4) | 19 (28.8) | .030 |
| Ribavirin | 3 (4.5) | 12 (18.2) | .013 |
| Any | 11 (16.4) | 27 (40.9) | .002 |
| Discontinuation | |||
| IFN-alfa-2a or pegylated | |||
| IFN-alfa-2a | 12 (17.9) | 14 (21.2) | .631 |
| Ribavirin | 12 (17.9) | 13 (19.7) | .792 |
| Any | 12 (17.9) | 14 (21.2) | .631 |
| Any dose modification | |||
| IFN-alfa-2a or pegylated | |||
| IFN-alfa-2a | 19 (28.4) | 31 (47.0) | .027 |
| Ribavirin | 15 (22.4) | 24 (36.4) | .077 |
| Any | 21 (31.3) | 38 (57.6) | .002 |
Figure 2.
Percentage of subjects who underwent dose reductions and discontinuations of IFN-alfa-2a (IFN; solid line; n = 67), pegylated IFN-alfa-2a (PEG-IFN; dashed line; n = 66), and/or ribavirin, by treatment arm. P values were determined using the log rank test.
Table 3.
Reasons for discontinuation of IFN-alfa-2a, pegylated IFN-alfa-2a, and ribavirin.
| No. (%) of patients |
||
|---|---|---|
| Treatment discontinued, reason | IFN-alfa-2a recipients |
Pegylated IFN-alfa-2a recipients |
| IFN-alfa-2a or pegylated | ||
| IFN-alfa-2a discontinued | ||
| All patients | 12 | 14 |
| Anemia | 0 (0) | 1 (7) |
| Neurologic/psychiatric | 2 (17) | 2 (14) |
| Other toxicity | 2 (17) | 3 (21) |
| Clinical decision | 0 (0) | 2 (14) |
| Subject decision | 3 (25) | 5 (36) |
| Drug treatment not resumed | 1 (8) | 0 (0) |
| Noncompliance | 2 (17) | 0 (0) |
| Other | 2 (17) | 1 (7) |
| Ribavirin discontinued | ||
| All patients | 12 | 13 |
| Anemia | 0 (0) | 1 (8) |
| Neurologic/psychiatric | 1 (8) | 2 (15) |
| Other toxicity | 3 (25) | 3 (23) |
| Clinical decision | 0 (0) | 2 (15) |
| Subject decision | 3 (25) | 4 (31) |
| Drug treatment not resumed | 1 (8) | 0 (0) |
| Noncompliance | 2 (17) | 0 (0) |
| Other | 2 (17) | 1 (8) |
| IFN-alfa-2a, pegylated | ||
| IFN-alfa-2a, or ribavirin discontinued | ||
| All patients | 12 | 14 |
| Anemia | 0 (0) | 2 (14) |
| Neurologic/psychiatric | 2 (17) | 2 (14) |
| Other toxicity | 2 (17) | 3 (21) |
| Clinical decision | 0 (0) | 2 (14) |
| Subject decision | 3 (25) | 4 (29) |
| Drug treatment not resumed | 1 (8) | 0 (0) |
| Noncompliance | 2 (17) | 0 (0) |
| Other | 2 (17) | 1 (7) |
There were no differences in the treatment interventions when comparisons were made between subjects who received versus patients who did not receive antiretroviral therapy, between recipients of antiretroviral therapy regimens that contained zidovudine versus recipients of regimens that did not, between a CD4+ T lymphocyte count ≤200 cells/mm3 versus >200 cells/mm3, by HCV genotype, or by hepatic activity index score (data not shown).
Initiation of growth factor use
During the course of the study, 6 subjects in the IFN-alfa-2a group and 13 in the pegylated IFN-alfa-2a group used erythropoietin (P = .08); 10 in the IFN-alfa-2a group and 23 in the pegylated IFN-alfa-2a group used G-CSF (P = .008). The mean total drug dose delivered did not differ between subjects who received versus those who did not receive growth factor support for IFN-alfa-2a (1050 and 949 million IU of IFN-alfa-2a for patients who did and did not receive growth factor support, respectively; P = .38) or for pegylated IFN-alfa-2a (40,358 and 42,498 μg of pegylated IFN-alfa-2a, respectively; P = .65). There was a trend toward a higher mean total dose of delivered ribavirin in subjects who received growth factor support (234,247 vs. 201,416 mg of ribavirin; P = .067).
Treatment Interventions as Predictors of Outcome
Multivariable logistic modeling was used to assess whether treatment assignment, compliance, or treatment interventions (dose reduction and discontinuation and initiation of growth factor support) affected the outcomes of HCV therapy. In the first model, which included type of interferon (pegylated IFN-alfa-2a vs. IFN-alfa-2a) and adherence to IFN-alfa-2a and ribavirin treatment, randomization to the pegylated IFN-alfa-2a regimen versus IFN-alfa-2a regimen was associated with a more favorable outcome for both sustained virologic response (OR, 3.81; 95% CI, 1.45–10.01) and the combined end point of sustained virologic response or histologic response (OR, 2.79; 95% CI, 1.23–6.37). The finding of improved sustained virologic response rate in the group receiving pegylated IFN-alfa-2a was reported previously [22]. Adherence with IFN treatment was also found to be associated with the combined end point of sustained virologic response or histologic response (OR, 1.44; 95% CI, 1.06–1.94).
The second model includes dose modification for anemia, neutropenia, nonhematologic toxicity, initiation of hematopoietic growth factor (either erythropoietin or G-CSF), and other reason. Although no significant associations between treatment modifications (dose reduction or discontinuation), hematologic toxicity, and outcome were identified, modifications for nonhematologic toxicity (OR, 0.08; 95% CI, 0.01–0.67) and other, otherwise unspecified reasons (OR, 0.07; 95% CI, 0.01–0.59) were associated with a lower likelihood of sustained virologic response or histologic response.
The third model suggested that any dose modification was associated with a lower likelihood of sustained virologic response and/or histologic response (OR, 0.27; 95% CI, 0.11–0.69), independent of the type of IFN-alfa-2a and whether hematopoietic growth factor treatment was initiated. The initiation of erythropoietin or G-CSF therapy appears to be associated with an increase in the combined end point of sustained virologic response or histologic response (OR, 2.62; 95% CI, 1.04–6.58) (table 5)
Table 5.
Predictors of response to IFN-alfa-2a or pegylated IFN-alfa-2a therapy.
| Sustained virologic response |
Histologic responsea |
Sustained virologic response or histologic responsea |
||||
|---|---|---|---|---|---|---|
| Model | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P |
| Model 1 | ||||||
| Pegylated IFN-alfa-2a vs. IFN-alfa-2a | 3.81 (1.45–10.01) | .01 | 1.32 (0.57–3.09) | .52 | 2.79 (1.23–6.37) | .01 |
| Compliance with IFN therapyb | 1.38 (0.95–2.02) | .09 | 1.34 (0.90–1.98) | .15 | 1.44 (1.06–1.94) | .02 |
| Compliance with ribavirin therapyb | 1.14 (0.82–1.58) | .44 | 1.12 (0.83–1.52) | .45 | 1.22 (0.94–1.59) | .14 |
| Model 2 | ||||||
| Pegylated IFN-alfa-2a vs. IFN-alfa-2a | 2.71 (1.02–7.23) | .05 | 1.09 (0.45–2.65) | .85 | 1.84 (0.83–4.05) | .13 |
| Dose modification for anemia | 0.93 (0.24–3.63) | .91 | 0.77 (0.16–3.74) | .75 | 0.80 (0.23–2.73) | .72 |
| Dose modification for neutropenia | 0.50 (0.13–1.92) | .31 | 0.52 (0.13–2.11) | .36 | 0.60 (0.17–2.07) | .42 |
| Dose modification for nonhematologic toxicity | 0.25 (0.03–2.33) | .22 | 0.32 (0.03–3.70) | .36 | 0.08 (0.01–0.67) | .02 |
| Dose modification for other reason | 0.27 (0.03–2.23) | .23 | 1.51 (0.09–26.22) | .78 | 0.07 (0.01–0.59) | .01 |
| Commencement of EPO or G-CSF treatment | 2.48 (0.78–7.87) | .12 | 1.89 (0.57–6.21) | .30 | 1.90 (0.66–5.49) | .23 |
| Model 3 | ||||||
| Pegylated IFN-alfa-2a vs. IFN-alfa-2a | 2.97 (1.12–7.90) | .29 | 1.11 (0.46–2.69) | .82 | 2.02 (0.94–4.34) | .07 |
| Any modification | 0.35 (0.11–1.07) | .66 | 0.68 (0.20–2.29) | .54 | 0.27 (0.11–0.69) | .01 |
| Commencement of EPO or G-CSF therapy | 2.91 (1.00–8.51) | .51 | 1.51 (0.50–4.53) | .47 | 2.62 (1.04–6.58) | .04 |
NOTE. Multivariable logistic models assessing associations between potential predictors of outcomes and outcome (sustained virologic response, histologic response, and the combined end point) are shown. Predictors include treatment assignment (pegylated IFN-alfa-2a vs. IFN-alfa-2a), adherence to treatment (as a percentage of the drug dose received out of the maximum possible dose specified by the protocol), hematologict oxicity (anemia and neutropenia), nonhematologic toxicity, “other reason” not otherwise specified, and initiation of hematopoietic growth factor support (erythropoietin [EPO] or granulocyte–colony-stimulating factor [G-CSF]).
Data with missing biopsy information were excluded.
Per 10%.
DISCUSSION
This analysis of data from a randomized, controlled trial comparing IFN-alfa-2a plus ribavirin with pegylated IFN-alfa-2a plus ribavirin for the treatment of HCV infection in subjects coinfected with HIV suggests that dose modification is associated with a lower response to therapy. Even though dose modification is more common in subjects treated with pegylated IFN-alfa-2a than with IFN-alfa-2a, compared with the other clinical features analyzed, treatment with pegylated IFN-alfa-2a rather than IFN-alfa-2a was associated with a higher sustained virologic response and the combined outcome of sustained virologic response and/or histologic response—a finding that has been reported elsewhere [22].
This study showed that dose reductions for any reason were associated with suboptimal outcomes, including those dose reductions made for nonhematologic reasons. We failed to show a significant association between dose reductions for hematologic toxicities and worse outcome, although this may have resulted from insufficient power, because such analysis was not part of the original clinical trial design. Not only was the number of participants relatively small, but the number of subjects requiring dose reductions for hematologic toxicity may have been lowered by the use of hematopoietic growth factors. It is also possible that the use of growth factors by patients who had undergone dose reductions for hematologic toxicity allowed for subsequent dose escalation in these subjects, influencing this analysis towards the null hypothesis.
There does appear to be an association between the use of hematopoietic growth factor and a higher combined end point of sustained virologic response and/or histologic response (table 5). We did find a trend toward higher total ribavirin dose in subjects receiving growth factor support, compared with subjects who did not (P = .067), but there were no differences in total IFN-alfa-2a or pegylated IFN-alfa-2a doses, regardless of whether hematopoietic growth factors were administered. Because the use of hematopoietic growth factors was not explicitly specified by the study protocol, there may have been variability in their use by study centers or individual investigators that was not necessarily based on the degree of hematologic toxicity, and they may have been used too late in the course of treatment. These factors could contribute to the lack of significant association between IFN-alfa-2a or pegylated IFN-alfa-2a doses and ribavirin doses and the use of erythropoietin or G-CSF.
Adherence to therapy (or the amount of antiviral therapy delivered) has been shown to be an important factor in outcome of therapy for HCV infection. Studies have shown that there is a higher sustained virologic response in persons who receive >80% of the intended drug dose, compared with those who do not [29, 31].
A number of previous studies have shown that growth factors can be used to effectively manage hematologic toxicity due to anti-HCV therapy, although this approach has not been well studied in patients with HCV-HIV coinfection. A randomized, placebo-controlled trial of epoetin-alfa (40,000 U subcutaneously once per week) in HCV-infected patients who were treated with ribavirin plus either IFN-alfa-2a or pegylated IFN-alfa-2a and who became anemic revealed that mean hemoglobin levels increased with epoetin-alfa treatment, and ribavirin doses were maintained in 88% of patients treated with epoetin-alfa, compared with 60% in the placebo arm. In an open-label phase of the study, both mean ribavirin dose and mean hemoglobin level increased when patients’ regimens were switched to epoetin-alfa [32, 33]. A pilot study of darbepoetin-alfa (3 μ/kg every 2 weeks) in HCV-infected patients who were treated with pegylated IFN-alfa-2a and ribavirin revealed an increase in hemoglobin levels and 92% maintenance of the ribavirin dose after 6 weeks [34, 35]. A cost-effectiveness analysis showed that the use of growth factors for treatment-induced anemia in HCV infection may lead to a quality-of-life–adjusted cost of $16,443—a number that is generally felt to be acceptable [36].
A randomized trial of G-CSF (300 μg weekly) versus no G-CSF in 30 HCV-infected patients who were receiving IFN-alfa-2a therapy demonstrated a nonsignificant trend toward higher sustained virologic response in the G-CSF group (53% vs. 40%; P>.05) [37]. Another study of 39 patients treated with pegylated IFN-alfa-2a and ribavirin showed a significant improvement in neutrophil counts in 89% of neutropenic patients who received G-CSF [35]. To date, to our knowledge, no studies have examined the use of pegylated G-CSF in HCV-monoinfected patients or the use of any myeloid growth factors for patients with HIV-HCV coinfection undergoing treatment.
Although the data from this analysis suggest that dose modification for hematologic toxicity may not affect outcome, the findings are limited by the fact that our clinical trial was not specifically designed to answer this question. Multivariate analysis revealed that any dose modification appeared to be associated with a worse outcome and that hematopoietic growth factor support was associated with an improved outcome, suggesting that there is a benefit with improved adherence to therapy and that hematopoietic growth factors may be used to facilitate maximal drug dosing. It is possible that earlier implementation of hematopoietic growth factor treatment may have prevented hematologic toxicities and reduced dose reductions for both hematologic and nonhematologic dose reasons, because reductions made on the basis of clinician and/or subject decision could have been associated with symptoms of hematologic toxicity.
Because the rate of significant hematologic toxicity warranting dose modification is relatively uncommon during therapy—even for HCV-HIV–coinfected individuals—it will be important to study the outcomes in such individuals in larger clinical cohorts, to more accurately assess the effect of hematologic toxicities and use of growth factors on the outcome of HCV treatment. Because adherence to therapy is an important factor in optimal outcome of anti-HCV therapy, any dose reduction should be avoided. Until more definitive data are available, it makes sense to use hematopoietic growth factors to help prevent dose reductions.
Acknowledgments
We thank Janet Anderson and Tun Liu for provision of statistical data, the AIDS Clinical Trials Group, the site personnel, and the patients involved in this study.
Financial support. AIDS Clinical Trials Group (U01 AI27663) and Center for AIDS Research (P30 AI27763).
Footnotes
Potential conflicts of interest. M.G.P. has served as a consultant for F. Hoffman La Roche and has received honoraria from Gilead Sciences, F. Hoffman La Roche, and Schering Plough. P.A.V. has served on the advisory board for Pfizer, Gilead, Merck, BMS, Schering, and GSK; has served on the Endpoint Adjudication Committee for Schering; has received honoraria from Vertex, Gilead, and BMS; and has stock options from Immune Response. All other authors: no conflicts.
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