Incident infections during treatment with peginterferon and ribavirin for chronic hepatitis C virus infection are associated with on-treatment lymphocytopenia, female sex, and baseline depression, but not with on-treatment neutropenia.
Keywords: hepatitis C virus, lymphopenia, infections, neutropenia, interferon
Abstract
Background. Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy.
Methods. A total of 3070 treatment-naive, chronic hepatitis C genotype 1–infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2–6 weeks. Dose reduction was required for a neutrophil count <0.75 × 109 cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 109 cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0.
Results. A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 109 cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 109 cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection.
Conclusions. Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 109 cells/L).
Interferon alfa has been used to treat chronic hepatitis C virus (HCV) infection since the early 1990s and remains the backbone of many treatment regimens involving HCV protease inhibitors [1–3]. Interferon alfa, however, has many side effects, including cytopenias [1]. When patients are treated with one of the long-acting, pegylated formulations of interferon, pegylated interferon (peg-IFN) alfa-2a, or peg-IFN alfa-2b, in combination with ribavirin (RBV) for up to 48 weeks, the incidence of severe neutropenia, defined as an absolute neutrophil count (ANC) of <0.5 × 109 cells/L, ranges from 4% to 12% [4, 5]. Furthermore, more modest declines in ANC to <0.75 × 109 cells/L have been reported in up to 30% of patients [4, 5]. Due to concern for increased infection risk in the setting of neutropenia, the prescribing information for both approved peg-IFN products recommends peg-IFN dose reduction and discontinuation in patients with ANC <0.75 × 109 cells/L and <0.5 × 109 cells/L, respectively [4, 5]. These treatment modifications are not without consequence; they have been associated with a decreased likelihood of achieving sustained virologic response (SVR) [6–8].
In this context, the relationship of neutropenia and incident infection during treatment with peg-IFN-based HCV therapy has been extensively investigated. The risk of infection associated with severe neutropenia due to chemotherapy among cancer patients and recipients of hematopoietic cell transplants is well established; however, most studies have not demonstrated any increased infection risk among patients who develop neutropenia while receiving peg-IFN [6, 9–14]. Nevertheless, up to 23% of patients develop acute infections during HCV treatment [6, 10–14]. The risk factors for acute infection, particularly clinically severe infections, have not been fully established in these relatively small studies [6, 10–14]. Because of the large number of patients treated with peg-IFN (>3000) and the breadth of data collected, the Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study provides a unique opportunity to evaluate the incidence of and risk factors associated with acute infections among patients receiving HCV treatment with peg-IFN/RBV, with an emphasis on understanding the relationship between treatment-induced cytopenias and infection [15].
METHODS
Study Design
The IDEAL study has been described in detail elsewhere [15]. In brief, this was a phase 3, randomized, parallel-group, US multicenter study of peg-IFN alfa-2b 1.5 µg/kg/week or 1.0 µg/kg/week or peg-IFN alfa-2a 180 µg/week combined with ribavirin (RBV) for the treatment of chronic HCV infection. Persons aged 18–70 years weighing 40–125 kg were eligible if they had compensated liver disease due to HCV genotype 1 infection and were treatment naive. The primary endpoint was SVR, defined as an undetectable HCV RNA level 24 weeks after stopping therapy.
Setting and Participants
Demographic data, vital signs, height, weight, medical history, physical examination, medication use, tobacco use, and depression assessment via the Center for Epidemiologic Studies Depression (CES-D) scale were performed and/or collected at screening. Laboratory testing included complete blood count, chemistry panel, antinuclear antibodies, serum pregnancy test, HCV RNA level, and HCV genotype. Liver biopsy performed within 3 years of treatment was required. Patients were required to meet eligibility criteria consistent with standard HCV treatment guidelines: white blood cell (WBC) count ≥3.0 × 109 cells/L; ANC ≥1.5 × 109 cells/L; platelet count ≥80 × 109/L; hemoglobin (Hb) level ≥12 g/dL for women and ≥13 g/dL for men; normal serum creatinine and thyroid stimulating hormone; no known human immunodeficiency virus or hepatitis B virus infection; fasting glucose level 70–140 mg/dL (and if 116–140 mg/dL or if diabetic, HbA1C ≤8.5%); absence of moderate and severe psychiatric disorders and/or recent substance abuse; and absence of uncontrolled medical conditions such as obesity (weight >125 kg) and clinically significant heart disease. Patients with chronic obstructive pulmonary disease and/or immunologically mediated diseases (eg, inflammatory bowel disease or systemic lupus erythematosus) were excluded.
Data Collection
Patients were evaluated at weeks 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 after initiating therapy, and then at weeks 4, 12, and 24 after discontinuing therapy. Complete blood counts were performed during each of these visits, as were vital signs and blood chemistries. During each visit, patients were queried about signs and/or symptoms suggestive of adverse events (AEs). The CES-D scale was performed at baseline and at weeks 2, 4, 12, 24, 36, and 48.
Safety and Adverse Events
All AEs were recorded, and the severity was assessed by the investigator according to modified World Health Organization recommendations. Actions or outcomes (eg, hospitalization) resulting from AEs were recorded. Clinical assessments and/or laboratory evaluations were performed as appropriate until resolution or stabilization of any AE. When indicated, medication dose reductions were performed according to the product label for each agent. While receiving reduced medication doses, patients were evaluated every 2 weeks until the AE resolved or they stabilized. Treatment medications were discontinued permanently in the event of any life-threatening AE. Dose reductions were required for grade 3 leukopenia (WBC <1.5 × 109 cells/L), grade 3 neutropenia (ANC <0.75 × 109 cells/L), anemia (Hb <10 g/dL), or grade 3 thrombocytopenia (platelet count <50 × 109/L); permanent treatment discontinuation was required for grade 4 leukopenia (WBC <1.0 × 109/L), grade 4 neutropenia (ANC <0.5 × 109 cells/L), Hb <8.5 g/dL, or grade 4 thrombocytopenia (platelet count <25 × 109/L). Use of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor was prohibited. In conjunction with appropriate medication dose reductions, erythropoietin use was permitted for management of incident anemia at the discretion of the individual investigator. Treatment modification for lymphocytopenia was not recommended or required.
Infections were defined by the examining clinician as mild (resulting in awareness of the otherwise easily tolerated infection), moderate (resulting in discomfort interfering with usual activities and potentially warranting intervention), severe (precluding usual activities, significantly affecting clinical status, and warranting intervention), or life-threatening (major infection with hypotension). Patients who developed mild depression were monitored weekly for 4–8 weeks; no medication dosing changes were required. Patients who developed moderate depression were required to undergo dose reduction per the prescribing information for each agent, and weekly monitoring was instituted. Medications were discontinued for any patient with worsening or severe depression.
Statistical Analysis
Categorical variables were summarized using proportions, and continuous variables were summarized using means, medians, and standard deviations. A logistic regression model using a stepwise selection method with baseline demographic characteristics and on-treatment minimum hematologic parameters was used to identify variables independently associated with incident infections. P values for comparison are presented based on the χ2-test for categorical variables or the t test for continuous variables. Odds ratios (ORs) and 95% confidence intervals (CIs), with P values, were also reported using logistic regression. All P values reported are nominal P values and have not been adjusted for multiple comparisons. All statistical analyses were done using SAS software, version 9.3.
The study was approved by each center's institutional review board and was conducted in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. Each patient provided informed consent for participation in the study.
RESULTS
Incident Infections
Incident infection of any severity was reported in 1092 of 3070 (35.6%) patients treated with peg-IFN/RBV for up to 48 weeks. The majority of these patients sustained infections classified by their treating physician as mild (n = 511; 46.8% of 1092 patients with incident infections) or moderate (n = 520, 47.6%); 55 (5.0%) and 6 (0.5%) infections were classified as severe or life-threatening, respectively. No pathogen was identified for 443 of 581 (76.2%) patients who sustained 550 episodes of infection of at least moderate severity; most of these infections involved the respiratory tract. A pathogen was culture confirmed or clinically suspected in 200 patients (34.4%) who sustained 210 episodes of moderate, severe, and life-threatening infections. (The sum of these percentages equals >100% because some patients developed >1 infection.) Among the identified pathogens, influenza viruses, herpes viruses, Staphylococcus species, and Candida species were most commonly reported (Supplementary Table 1). The 6 life-threatening infections were Escherichia sepsis, blastomycosis, appendicitis, infective tenosynovitis, pneumonia, and sepsis.
Baseline Patient Characteristics and Incident Infections
Patients' baseline demographic and clinical characteristics according to severity of incident infection are shown in Table 1. When considering moderate, severe, and life-threatening infections, women were more likely than men to have ear infections (2.3 vs 1.2 infections per 100 person-years), lower respiratory tract and lung infections (6.5 vs 4.0), upper respiratory tract infections (12.7 vs 6.4), and urinary tract infections (4.8 vs 0.6) (Supplementary Table 2). The incidence of moderate, severe, and life-threatening infections did not differ significantly between patients treated with low-dose (17.3%) and standard-dose (18.0%) peg-IFN alfa-2b; the incidence was 21.4% among patients treated with peg-IFN alfa-2a. The incidence did not vary significantly according to patient age, histologic disease stage, or mean baseline neutrophil and lymphocyte counts.
Table 1.
Baseline Patient Characteristics by Infection Status
| Characteristic | No Infection (n = 1978) | Infection (n = 1092) |
P Value | ||
|---|---|---|---|---|---|
| Mild (Grade 1) (n = 511) | Moderate (Grade 2) (n = 505) | Severe or Life-Threatening (Grades 3–4) or Serious (n = 76)a | |||
| Sex | <.001 | ||||
| Male | 1264 (69.0%) | 281 (15.3%) | 246 (13.4%) | 42 (2.3%) | |
| Female | 714 (57.7%) | 230 (18.6%) | 259 (20.9%) | 34 (2.7%) | |
| Race | <.001 | ||||
| White | 1356 (61.9%) | 372 (17.0%) | 398 (18.2%) | 63 (2.9%) | |
| Black | 418 (73.3%) | 90 (15.8%) | 52 (9.1%) | 10 (1.8%) | |
| Asian | 35 (68.6%) | 9 (17.6%) | 6 (11.8%) | 1 (2.0%) | |
| Hispanic | 138 (64.8%) | 33 (15.5%) | 40 (18.8%) | 2 (0.9%) | |
| Other/Native American | 31 (66.0%) | 7 (14.9%) | 9 (19.1%) | 0 (0%) | |
| Baseline HCV-RNA level | .38 | ||||
| ≤600 000 IU/mL | 339 (61.4%) | 102 (18.5%) | 98 (17.8%) | 13 (2.4%) | |
| >600 000 IU/mL | 1639 (65.1%) | 409 (16.2%) | 407 (16.2%) | 63 (2.5%) | |
| Baseline Metavir fibrosis stage | .87 | ||||
| F0/F1/F2 | 1675 (64.5%) | 436 (16.8%) | 422 (16.3%) | 62 (2.4%) | |
| F3/F4 | 206 (62.8%) | 51 (15.5%) | 60 (18.3%) | 11 (3.4%) | |
| Missing | 97 (66.0%) | 24 (16.3%) | 23 (15.6%) | 3 (2.0%) | |
| Baseline steatosis | .86 | ||||
| Absent | 734 (65.7%) | 185 (16.6%) | 174 (15.6%) | 24 (2.1%) | |
| Present | 1147 (63.5%) | 302 (16.7%) | 308 (17.1%) | 49 (2.7%) | |
| Missing | 97 (66.0%) | 24 (16.3%) | 23 (15.6%) | 3 (2.0%) | |
| Baseline age | .38 | ||||
| ≤40 y | 296 (64.8%) | 75 (16.4%) | 75 (16.4%) | 11 (2.4%) | |
| 40–50 y | 921 (63.5%) | 232 (16.0%) | 256 (17.6%) | 42 (2.9%) | |
| >50 y | 761 (65.5%) | 204 (17.6%) | 174 (15.0%) | 23 (2.0%) | |
| Baseline weight, kg | .10 | ||||
| ≤65 | 249 (58.2%) | 75 (17.5%) | 93 (21.7%) | 11 (2.6%) | |
| 65 to <75 | 344 (65.8%) | 89 (17.0%) | 75 (14.3%) | 15 (2.9%) | |
| 75–85 | 491 (66.3%) | 118 (15.9%) | 118 (15.9%) | 14 (1.9%) | |
| >85 to 105 | 701 (65.4%) | 184 (17.2%) | 162 (15.1%) | 25 (2.3%) | |
| >105 | 193 (63.1%) | 45 (14.7%) | 57 (18.6%) | 11 (3.6%) | |
| Baseline glucose, 101 mg/dL | .046 | ||||
| <5.6 mmol/L | 1384 (63.2%) | 364 (16.6%) | 384 (17.5%) | 57 (2.6%) | |
| ≥5.6 mmol/L | 593 (67.5%) | 147 (16.7%) | 120 (13.7%) | 19 (2.2%) | |
| Medical history of diabetes | .15 | ||||
| Yes | 142 (68.9%) | 31 (15.0%) | 25 (12.1%) | 8 (3.9%) | |
| No | 1836 (64.1%) | 480 (16.8%) | 480 (16.8%) | 68 (2.4%) | |
| Baseline smoking statusb | .19 | ||||
| Current smoker | 723 (63.1%) | 179 (15.6%) | 207 (18.1%) | 36 (3.1%) | |
| Ex-smoker | 732 (65.3%) | 193 (17.2%) | 170 (15.2%) | 26 (2.3%) | |
| Nonsmoker | 486 (65.5%) | 130 (17.5%) | 112 (15.1%) | 14 (1.9%) | |
| Medical history of depressionc | <.001 | ||||
| No | 1560 (66.3%) | 390 (16.6%) | 348 (14.8%) | 56 (2.4%) | |
| Yes | 418 (58.4%) | 121 (16.9%) | 157 (21.9%) | 20 (2.8%) | |
| Mean baseline neutrophil count, ×109/Ld (SD) | 3.7 (1.4) | 3.8 (1.6) | 3.8 (1.4) | 3.9 (1.4) | N/A |
| Mean baseline lymphocyte count, ×109/Ld (SD) | 2.2 (0.7) | 2.2 (0.7) | 2.2 (0.7) | 2.2 (0.7) | N/A |
| Treatment regimene | .015 | ||||
| Peg-IFN alfa-2b 1.5 µg/kg/wk + RBV | 683 (67.0%) | 153 (15.0%) | 162 (15.9%) | 21 (2.1%) | |
| Peg-IFN alfa-2b 1.0 µg/kg/wk + RBV | 675 (66.4%) | 165 (16.2%) | 154 (15.2%) | 22 (2.2%) | |
| Peg-IFN alfa-2a + RBV | 620 (59.9%) | 193 (18.6%) | 189 (18.3%) | 33 (3.2%) | |
Data are presented as No. (%) unless otherwise indicated.
Abbreviations: HCV, hepatitis C virus; N/A, not applicable; peg-IFN, pegylated interferon; RBV, ribavirin; SD, standard deviation.
a This includes 15 patients with grade 2 infections deemed serious, 55 patients with grade 3 infections (29 of which were serious), and 6 patients with grade 4 infections (all of which were serious). Serious infections were defined as those resulting in death, persistent or significant disability/incapacity, or congenital anomaly or birth defect, those that were life-threatening, and/or those that required inpatient or prolonged hospitalization.
b Information missing for 2 patients.
c Depression was defined as depression (n = 702), postpartum depression (n = 6), major depression (n = 4), bipolar disorder (n = 4), affective disorder (n = 3), suicide attempt (n = 3), dysthymic disorder (n = 2), and menopausal depression (n = 1).
d Information missing for 25 patients.
e P values are from Pearson χ2 testing for 2-way tables involving the differences between the observed and expected frequencies, where the expected frequencies are computed under the null hypothesis of independence. Not adjusted for multiplicity.
On-Treatment Neutrophil and Lymphocyte Counts and Incident Infections
The mean maximum decline from baseline and the mean nadir ANC and absolute lymphocyte count (ALC) for all patients with at least 1 on-treatment complete blood cell profile are shown in Table 2. The incidence of infection varied according to the nadir on-treatment ANC (Table 3). A total of 648 patients (21%) treated with peg-IFN had an ANC <0.75 × 109 cells/L; of these patients, 12 (0.4%) developed a severe or life-threatening infection, and only 1 had sepsis that was considered to be treatment related (Figure 1A). Severe and life-threatening infections were observed at a similar frequency in each ANC category, including those with ANC >1.0 × 109 cells/L (incidence, 2.2%) and those with ANC <1.0 × 109 cells/L (incidence, 1.7%). The incidence of infection also varied according to the nadir on-treatment absolute lymphocyte count (Table 4). Of the 107 with a nadir ALC <0.5 × 109 cells/L, only 34 also had a nadir ANC <0.75 × 109/L (Table 5 and Figure 1B and 1C). For subjects who had post-baseline ALC and ANC values and a known date of infection, subjects were significantly more likely to have progressively lower ALCs in advance of infections of increasing severity (P = .01; Supplementary Table 3). No such relationship was demonstrated for ANCs in advance of infections.
Table 2.
Mean On-Treatment Nadir and Maximum Declines in Neutrophil and Lymphocyte Counts by Treatment Group
| Nadir/Decline | Peg-IFN alfa-2a + RBV | Peg-IFN alfa-2b 1.5 µg/kg/wk + RBV | Peg-IFN alfa-2b 1.0 µg/kg/wk + RBV | Total |
|---|---|---|---|---|
| Maximum decline in ANC, ×109/L, mean (SD) | 2.70 (1.41) | 2.50 (1.24)* | 2.43 (1.17)* | 2.54 (1.28) |
| Nadir ANC, ×109/L, mean (SD) | 1.09 (0.55) | 1.18 (0.62)* | 1.29 (0.63)* | 1.19 (0.61) |
| Maximum decline in ALC, ×109/L, mean (SD) | 1.38 (0.61) | 1.34 (0.60)** | 1.25 (0.58)* | 1.32 (0.60) |
| Nadir ALC, ×109/L, mean (SD) | 0.85 (0.39) | 0.89 (0.46)*** | 0.95 (0.45)* | 0.90 (0.44) |
Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; peg-IFN, pegylated interferon; RBV, ribavirin; SD, standard deviation.
*P < .001 vs peg-IFN alfa-2a + RBV.
**P = .15.
***P = .08.
Table 3.
Incidence of Infection by Nadir On-Treatment Neutrophil Counts (P < .001)a
| Nadir On-Treatment Neutrophil Count, ×109/L | Total No. of Patients | No Infection | Mild Infection | Moderate Infection | Severe Infection | Life-Threatening Infection |
|---|---|---|---|---|---|---|
| Grade 0: >1.5 | 652 | 475 (73) | 83 (13) | 85 (13) | 8 (1) | 1 (0.2) |
| Grade 1: 1.0 to 1.5 | 1064 | 666 (63) | 187 (18) | 182 (17) | 28 (3) | 1 (0.1) |
| Grade 2: 0.75 to <1.0 | 678 | 403 (59) | 130 (19) | 134 (20) | 9 (1) | 2 (0.3) |
| Grade 3: 0.5 to <0.75 | 538 | 337 (63) | 98 (18) | 93 (17) | 9 (2) | 1 (0.2) |
| Grade 4: <0.5 | 110 | 69 (63) | 13 (12) | 26 (24) | 1 (1) | 1 (0.9) |
Data are presented as No. (%).
a P value is from the Pearson χ2 test for 2-way tables involving the differences between the observed and expected frequencies, where the expected frequencies are computed under the null hypothesis of independence. Not adjusted for multiplicity.
Figure 1.
A, Infections among 648 patients with nadir absolute neutrophil count (ANC) <0.75 × 109 cells/L. B, Infections among 403 patients with nadir absolute lymphocyte count (ALC) <0.5 × 109 cells/L. C, Infections among 135 patients with nadir ANC <0.75 × 109 cells/L and nadir ALC <0.5 × 109 cells/L.
Table 4.
Incidence of Infection by Nadir On-Treatment Lymphocyte Counts (P < .001)a
| Nadir On-Treatment Lymphocyte Count, ×109/L | Total No. of Patients | No Infection | Mild Infection | Moderate Infection | Severe Infection | Life-Threatening Infection |
|---|---|---|---|---|---|---|
| Grade 0: >1.0 | 980 | 705 (72) | 146 (15) | 115 (12) | 13 (1) | 1 (0.1) |
| Grade 1: 0.8 to 1.0 | 615 | 384 (62) | 110 (18) | 110 (18) | 10 (2) | 1 (0.2) |
| Grade 2: 0.5 to <0.8 | 1044 | 636 (61) | 184 (18) | 204 (20) | 19 (2) | 1 (0.1) |
| Grade 3: 0.2 to <0.5 | 394 | 220 (56) | 69 (18) | 90 (23) | 12 (3) | 3 (0.8) |
| Grade 4: <0.2 | 9 | 5 (56) | 2 (22) | 1 (11) | 1 (11) | 0 |
Data are presented as No (%) unless otherwise indicated.
a P value is from the Pearson χ2 test for 2-way tables involving the differences between the observed and expected frequencies, where the expected frequencies are computed under the null hypothesis of independence. Not adjusted for multiplicity.
Table 5.
Number of Patients With Moderate, Severe, and Life-Threatening Infections by Absolute Neutropenia and Absolute Lymphocytopenia
| Infection Severity | ANC × 109 cells/L | ALC × 109 cells/L |
||
|---|---|---|---|---|
| <0.75 | ≥0.75 | All | ||
| Moderate | <0.5 | 28 (5.4) | 63 (12.1) | 91 (17.5) |
| ≥0.5 | 91 (17.5) | 338 (65.0) | 429 (82.5) | |
| All | 119 (22.9) | 401 (77.1) | 520 (100) | |
| Severe | <0.5 | 4 (7.3) | 9 (16.4) | 13 (23.6) |
| ≥0.5 | 6 (10.9) | 36 (65.4) | 42 (76.4) | |
| All | 10 (18.2) | 45 (81.8) | 55 (100) | |
| Life-threatening | <0.5 | 2 (33.3) | 1 (16.7) | 3 (50.0) |
| ≥0.5 | 0 (0) | 3 (50.0) | 3 (50.0) | |
| All | 2 (33.3) | 4 (66.7) | 6 (100) | |
Data are presented as No. (%).
Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count.
Risk Factors for Moderate, Severe, and Life-Threatening Infections
In univariate analysis, baseline factors associated with a higher risk of incident infection of moderate or greater severity included female sex, white race, low or high body weight, fasting glucose level, history of depression, treatment with peg-IFN alfa-2a, and lower nadir on-treatment ANC and ALC. Using a logistic regression model, female sex (adjusted OR [AOR], 1.61; 95% CI, 1.33–1.97), history of depression (AOR, 0.68; 95% CI, .55–.83), and nadir on-treatment ALC (AOR, 0.48; 95% CI, .37–.64) were independently associated with moderate to life-threatening (grades 2–4) infections (P < .001; Table 6). As expected based on the study protocol, peg-IFN dose modifications were common among subjects who sustained grade 3–4 neutropenia, regardless of incident infections (Supplementary Table 4). Whereas subjects who had grade 3–4 lymphocytopenia and either no or mild infections were more likely to have peg-IFN dose modifications than were subjects with grade 0–2 lymphocytopenia, no such trends were apparent among subjects who developed infections of at least moderate severity (Supplementary Table 5).
Table 6.
Risk of Infection by Logistic Regression Model
| Variable | Odds Ratio | 95% CI | P Value |
|---|---|---|---|
| Treatment | |||
| Peg-IFN alfa-2b 1.5 µg/kg/wk vs peg-IFN alfa-2a | 0.84 | .67–1.04 | .37 |
| Peg-IFN alfa-2b 1.0 µg/kg/wk vs peg-IFN alfa-2a | 0.84 | .67–1.04 | .37 |
| Sex (female vs male) | 1.61 | 1.33–1.97 | <.001 |
| Metavir fibrosis score (F0/1/2 vs F3/4) | 1.17 | .91–1.50 | .22 |
| Baseline weight, kg | 0.91 | .70–1.20 | .56 |
| Baseline glucose level, 101 mg/dL | 0.83 | .67–1.03 | .10 |
| History of depression (no vs yes) | 0.68 | .55–.83 | <.001 |
| Baseline HCV RNA (≤600 000 vs >600 000 IU/mL) | 1.00 | 1.00–1.00 | .32 |
| Age | 0.99 | .98–1.00 | .10 |
| Nadir on-treatment absolute neutrophil count | 1.00 | .83–1.21 | .98 |
| Nadir on-treatment absolute lymphocyte count | 0.48 | .37–.64 | <.001 |
| Nadir on-treatment hemoglobin level | 0.96 | .89–1.03 | .25 |
Abbreviations: CI, confidence interval; HCV, hepatitis C virus; peg-IFN, pegylated interferon.
The relationship of the nadir ALC and sex and history of depression are shown in Figure 2. After adjustment for other covariates, peg-IFN type (alfa-2a or alfa-2b) and nadir ANC were not associated with incident moderate, severe, or life-threatening infections.
Figure 2.
Plot of logistic regression model by nadir on-treatment lymphocyte count and predicted probability of infection by sex. The individual marks (+, •, ◊, ○) represent predicted probabilities of incident infection among women and men with and without depression modeled as a function of on-treatment nadir absolute lymphocyte count (ALC) (logistic regression). The solid lines represent the smooth functions of the predicted probabilities by sex and baseline depression. The histogram displays observed infection rates for disjoint intervals of nadir on-treatment ALC. The single bars on the x-axis display the distribution of nadir ALCs.
DISCUSSION
In this large, prospective cohort of HCV genotype 1–infected patients treated with peg-IFN alfa plus RBV, we did not detect an independent association between incident infection and neutropenia. Further, we identified novel factors—namely, treatment-related lymphocytopenia and female sex—associated with incident infections. These findings have important implications for the management of patients during HCV treatment that includes peg-IFN alfa.
First, although neutropenia was common, with 648 (21%) of patients experiencing an ANC <0.75 × 109 cells/L, the majority of clinically significant infections were not temporally associated with neutropenia. Furthermore, after adjustment for other factors, including lymphocytopenia and sex, nadir on-treatment ANC was not associated with such infections. These observations support previously published studies that did not demonstrate an association between neutropenia and incident infection [6, 10, 12–14]. When also considering the lack of association between peg-IFN dose reductions and reduced rates of incident infection [6, 13], these data suggest that IFN-related neutropenia is not strongly associated with infection risk. Despite these findings, in our study and those previously reported, the dose of peg-IFN alfa was reduced in patients with ANCs below a defined level, typically 0.75 × 109 cells/L; the safety of lower ANC thresholds for peg-IFN dose reduction was not evaluated. To date, one study, VIRAHEP-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C), incorporated a strategy of continuing full-dose peg-IFN alfa-2a in patients with ANC >0.5 × 109 cells/L and did not report a higher than expected rate of infections [16]. Although this study supports the use of a lower ANC threshold for peg-IFN dose reduction, additional studies are needed to confirm this revised approach to treatment-related neutropenia.
Second, independent of neutropenia, we identified a strong relationship between treatment-induced lymphocytopenia and incident infection. In prior HCV treatment studies with IFN alfa, lymphocytopenia was consistently observed. In clinical studies of peg-IFN alfa-2a for treatment of HCV infection described in the US prescribing information, for example, lymphocytopenia of any grade was reported in 81% and 91% of patients treated with monotherapy and combination therapy with RBV, respectively; severe lymphocytopenia (<0.5 × 109 cells/L) was observed in 5% and 14% of those treated with monotherapy and combination therapy with RBV, respectively [4]. Although RBV appeared to contribute to the lymphocytopenia in these studies, we were not able to assess the impact, if any, of RBV on incident lymphocytopenia in our study because all patients took RBV. While 1 case of a patient developing reactivation pulmonary tuberculosis in the setting of peg-IFN and RBV-associated lymphocytopenia has been reported, the clinical significance of HCV treatment-induced lymphocytopenia has not been previously described in a large patient cohort [17]. Our data suggest that lymphocytopenia may be an important marker of increased risk for moderate, severe, or life-threatening infections. Although our data do not permit assessment of causation and therefore cannot compel a recommendation for peg-IFN dose reduction for lymphocytopenia, our finding suggests that clinicians should monitor the ALC (in addition to ANC) carefully during treatment. Future studies of peg-IFN, as well as those of RBV plus direct-acting antivirals in the absence of peg-IFN, should assess the incidence of lymphocytopenia and the relationship, if any, of on-treatment lymphocytopenia and incident infection. Another question worthy of study is whether increased monitoring of patients at a higher risk of infection, such as those with cirrhosis, is warranted.
Third, we found a 61% increased risk of infection among women, predominantly as a result of an increased frequency of upper respiratory and genitourinary tract infections, as well as fungal or Candida infections. The relationship between sex and infection was independent of lymphocytopenia. The underlying mechanism for this observed increased risk is not known, although an increased incidence of urinary tract and Candida infections (eg, vulvovaginal candidiasis) among women is not unexpected; as such, these sex discordances may not be directly related to HCV treatment. The increased incidence of clinically diagnosed upper respiratory tract infections (URTIs) is more difficult to characterize as we are unable to determine the criteria by which such infections were diagnosed; clinical diagnoses were at the provider's discretion. Women may be more likely to present to medical attention with URTIs of at least moderate severity, such that sex differences in clinical presentation led to bias in ascertainment and classification of URTIs by treating clinicians. Although additional studies are needed, clinicians should be aware of the increased infection incidence in women treated with peg-IFN/RBV.
Last, we found an increased incidence of infection in patients with a clinical history of baseline depression. Interestingly, the risk of infection did not correlate with baseline CES-D score or occurrence of depression during treatment. This finding may be explained by differences in reporting of infectious symptoms between patients with a history of depression compared to those without such a history; it may, however, also point to the interplay between depression or psychological stress, innate immune function, and IFN [18–20]. Of interest, whereas leukopenia is not a common side effect of antidepressant medications, some agents, such as bupropion, have been associated with leukopenia.
Our study has several limitations. First, as noted above, most infections were diagnosed by individual clinicians on the basis of clinical presentation. In general, detailed microbiological and other related data were not reported. The possibility that some reported infections were noninfectious or were misclassified by pathogen and/or organ system cannot be excluded. These limitations, however, are present in most studies of outpatient infections; in practice, respiratory and other infections are routinely diagnosed on clinical grounds alone. A related limitation is that infection severity was also judged by individual clinicians; what one clinician may have judged as mild, another may have assessed as moderate. This limitation seems less likely, however, to have affected assessments of severe or life-threatening infections. We also did not capture information on therapeutic management of diagnosed infections. Second, because the treatment protocol mandated peg-IFN dose reductions for incident neutropenia, we were unable to fully characterize the association between infection and declines in ANC and ALC; these peg-IFN dose reductions led to increases in ANC and ALC. This limits the ability to understand the effect of prolonged ANC suppression. Third, laboratory data were not always collected contemporaneously with incident infections; we therefore cannot be certain, for example, about a temporal relationship between lymphocytopenia and diagnosed infection. Where these data were available, however, there was a relationship between lower nadir ALC and incident infections of greater severity.
In summary, moderate, severe, or life-threatening infections were common in HCV-infected adults treated with peg-IFN/RBV for up to 48 weeks, occurring in 19% of patients. In this cohort of 3070 patients, infectious complications were associated with reductions in the ALC rather than the ANC. This observation has important implications for the management of patients treated with peg-IFN/RBV alone or in combination with other agents. Although further research is needed to confirm this observation, clinicians should carefully monitor the ALC in addition to the ANC for patients receiving HCV therapy with peg-IFN and/or RBV.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online (http://cid.oxfordjournals.org). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Notes
Acknowledgments. We thank Dr Victoria Enwemadu of Merck for her help in managing the publication process, and Dr Seth Thompson of Merck for assistance with statistical analyses.
Disclaimer. The study sponsor collected and managed the data used in this work, performed the statistical analyses, and reviewed and approved the manuscript. The current analysis, however, was investigator-initiated, and the study sponsor had no role in the design and conduct of the study, analysis and interpretation of the data, or preparation of the manuscript.
Financial support. This work was supported by grants from Schering-Plough Research Institute, now Merck Research Laboratories.
Potential conflicts of interest. M. T. M. has provided expert testimony unrelated to HCV infection. N. B. has served on the advisory board for Janssen; has received research funding from Bristol-Myers Squibb, Vertex, and Gilead; and is a member of the speakers' bureaus for Vertex and Onyx. F. P. has received research funding from Abbvie, Achillon Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, Globelmmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, and ZymoGenetics; has served as an advisor to Abbvie, Achillon Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Globelmmune, Merck, Santaris Pharmaceuticals, Tibotec/Janssen, Theravance, and Vertex Pharmaceuticals; and is a member of the speakers' bureaus for Gilead, Kadmon, Merck, Onyx/Bayer, Salix, and Vertex. E. J. L. has received research funding from Merck; has served as consultant to Abbott Laboratories, Achillon Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, BioCryst, Biotica, Enanta, Globelmmune, Idenix Pharmaceuticals, Inhibitex Pharmaceuticals, Janssen, Merck, Novartis, Pharmasset, Santaris Pharmaceuticals, Tibotec, Theravance, and Vertex Pharmaceuticals; has received research funding from Abbott Laboratories, Achillon Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Globelmmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Pharmasset, Presidio, Roche, Santaris Pharmaceuticals, Schering-Plough, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics; and is a member of the speakers' bureaus for Gilead, Kadmon, Merck, and Vertex. M. L. S. has received research funding from Abbott, Achillion, Bristol-Myers Squibb, Gilead, Merck, and the Virginia Commonwealth University Medical Center; has served as consultant to Bristol-Myers Squibb, Gilead, Janssen, Merck, and Vertex; and is a member of the speakers' bureaus for Genentech, Gilead, Merck, and Vertex. J. G. M. is an employee of and owns stock or stock options in Gilead Sciences. A. J. M. has received research funding from Abbott, Achillon Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Globelmmune, Medtronic, Merck, Pfizer, Roche, Scynexis Pharmaceuticals, and Vertex Pharmaceuticals, and has served as a consultant for Achillon Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Merck, Profectus BioSciences, Salix, Scynexis Pharmaceuticals, and Vertex Pharmaceuticals. G. W. G. has received research funding from Schering-Plough. L. M. N. has received research support from Abbvie, Bristol-Myers Squibb, Gilead, Pharmasset, Roche/Genentech, and Schering-Plough/Merck; has served as a consultant to Schering-Plough/Merck; and is a member of the speakers' bureau for Schering-Plough/Merck. W. M. L. has received research support from Anadys Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb, Cumberland, Gilead, GlaxoSmithKline, Merck, Roche, and Siemens, and has served as a consultant to Lilly and Novartis. E. S. has served as a consultant for Gilead and Merck, and has received research funding from Abbott, Anadys Pharmaceuticals, Beckman Coulter, Bristol-Myers Squibb, Discovery Life Sciences, Gilead, Medtronics, Merck, Novelos Therapeutics, Orsure Technologies, Roche Molecular, and Vertex Pharmaceuticals. J. L. is an employee of Merck. S. N. has served as a consultant to Schering-Plough, is a former employee of Schering-Plough, is a current employee of Bristol-Myers Squibb, and owns stock or stock options in Schering-Plough/Merck and Bristol-Myers Squibb. C. A. B. is a former employee of Merck/Schering-Plough; is a current employee of Novartis, owns stock and stock options in Merck; and owns stock in Novartis. L. D. P. is a former employee of Schering-Plough and owns stock or stock options in Schering-Plough. M. S. S. has received research funding from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Vertex Pharmaceuticals, and has served as a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Vertex Pharmaceuticals.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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