Journal of Virology & Antiviral ResearchISSN: 2324-8955

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Research Article, J Virol Antivir Res Vol: 3 Issue: 4

A Randomized Clinical Trial of Pegylated Interferon for Acute Hepatitis C Virus Infection in Active Injection Drug Users

Erica Coppel1, Meighan Krows1, Misty Saracino1, Linda Cook2, Ka Wing Sullivan2, Jason Veitengruber3, Holly Hagan5, Hanne Thiede4, Anna Wald1,2,5,6 and Chia C Wang1*
1Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, USA
2Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Institute, USA
3Department of Psychiatry, University of Washington, USA
4Public Health, Seattle and King County, USA
5Department of Epidemiology, University of Washington, USA
6Department of Laboratory Medicine, University of Washington, USA
Corresponding author : Chia Wang
Virginia Mason Medical Center, 909 University Street, G2-ID, Seattle, WA 98101-2772, USA
Tel: (206) 625-7373 x 6675; Fax: (206) 223-6814
E-mail: [email protected]
Received: May 26, 2014 Accepted: November 04, 2014 Published: November 10, 2014
Citation: Coppel E, Krows M, Saracino M, Cook L, Sullivan KW, et al. (2014) BA Randomized Clinical Trial of Pegylated Interferon for Acute Hepatitis C Virus Infection in Active Injection Drug Users. J Virol Antivir Res 3:3. doi:10.4172/2324-8955.1000132

Abstract

Background: Treatment of acute HCV is more effective than treatment of chronic HCV, but physicians are often reluctant to treat people who inject drugs (PWID).


Methods: HIV seronegative PWID with acute hepatitis C infection were randomized to receive 24 weeks of pegylated interferon (Peg-IFN) or to observation. Serum HCV RNA was measured every 4 weeks. After 24 weeks, control subjects with persistent viremia were offered treatment with Peg-IFN and ribavirin. The primary endpoint of the trial was likelihood of achieving a sustained virologic response (SVR).Secondary endpoints included time to viral clearance, treatment adherence and incidence of depression.


Results: 24 patients were randomized to treatment vs. control; 1 was lost to follow-up before the baseline visit. Of the 9 patients who received >1 injection of Peg-IFN, 55% had an SVR; three became re-infected. Among controls, 14% cleared virus, 79% became chronically infected. Treated participants were more likely to clear HCV than controls (HR (95% CI) =15.34 (3.08-76.40), p=0.001).Additionally, for the univariate analysis, participants with more recent PWID (5.00 (1.23 – 20.00)), a baseline viremia< 5 log IU/mL (3.57 (0.94 – 14.28)), and an ALT level ≤ to 450 IU/mL (6.67 (0.83 – 50.00)) were more likely to clear virus. Sixty-seven percent of participants received at least 80% of scheduled injections and the incidence of severe depression was low.


Conclusions: We found that treatment of HCV in active PWID was effective and safe, though re-infections occurred. Adherence rates in this cohort were excellent, supporting the idea that this difficult-to-treat population benefits from medically supervised injections.

Keywords: Depression; Diagnosis; Injection drug use; Hepatitis C; Adherence

Keywords

Depression; Diagnosis; Injection drug use; Hepatitis C; Adherence

Introduction

Patient population and recruitment
Participants with acute HCV were recruited from Seattle area site of the multi-site Third Collaborative Intravenous Drug Users Study/ Drug Users Intervention Trial (DU-IT) from September 2003 to December 2005 [1-3]. In the DU-IT trial, actively using PWID were seen every 6 months to measure the effect of a behavioral intervention designed to promote safe drug use. One of the DU-IT study outcomes included HCV seroconversion; thus, the presence of HCV antibody was measured every 6 months, allowing us to identify PWID who had been infected with HCV in the preceding 6-12 months. Study recruitment was initiated on September 4, 2003 and recruitment and follow-up were completed on August 16, 2007. Subjects were eligible if they had acute HCV (defined as a documented HCV antibody seroconversion within the past year); had detectable HCV viremia, were at least 15 years of age; had no significant chronic or unstable medical conditions (including hematologic, metabolic, autoimmune, hepatic, HIV, or hepatitis B infection, or thyroid disease); had no severe psychiatric illness; and were not pregnant or nursing. All participants were active PWID, defined as drug use within the last six months. The Institutional Review Board at the University of Washington approved study procedures as well as a waiver of required parental consent for individuals ages 15, 16, and 17 and all participants signed informed consent prior to enrollment.
Study procedures
Eligible patients were sequentially randomized 1:1 to 24 weeks of treatment with Peg-IFN therapy or observation (control group). Investigators and participants were not blinded due to the logistical difficulties involved with a placebo injection. Control group patients were offered standard of care treatment with 48 weeks of Peg-IFN and ribavirin at the end of the 24-week study period. Treatment group visits occurred weekly until week 24 and then monthly up to week 48. During the first 24 weeks, weekly subcutaneous injections of Peg- IFN were administered and patients were assessed for adverse events at each visit. A complete blood count (CBC), serum chemistries, and HCV RNA were measured at week 2 and then monthly. The control group was seen monthly for 24 weeks, with symptom assessment and blood draws including CBC, serum chemistries, and HCV RNA. We provided a modest reimbursement ($10) per visit, and study coordinators made reminder phone calls to maximize visit attendance. Study personnel included an Infectious Diseases physician, a psychiatrist, and study coordinators.
Psychiatric evaluation
At weeks 2, 4, and then monthly, participants completed a Beck Depression Inventory (BDI) at screening. Mild depression was defined as a score 11-20, moderate 21-30, and severe >30. If a patient’s baseline BDI score was >20, they were evaluated by a psychiatrist. If the patient was already taking antidepressant medication, the dosing was adjusted accordingly. If not, treatment with an antidepressant was initiated by the psychiatrist, and patients were then reevaluated after 8 weeks to determine if the BDI score improved to <21. If the psychiatrist felt that the patient could safely start on Peg-IFN therapy, the patient was eligible for randomization. During the study, all subjects were monitored every four weeks using the BDI-II Fast Screen. If severe clinical depression (BDI score >30) was identified, subjects started antidepressants and discontinued study drug until evaluated by a psychiatrist. Moderate depression (BDI Score 21 – 30) identified during treatment led to a 50% decrease in interferon dosing and antidepressants until evaluated.
Laboratory methods
Serologic assays for HIV and HCV were performed using the Genetic Systems HIV-1/HIV-2 Peptide EIA assay (Bio-Rad Laboratories, Redmond, WA) and the Abbott HCV EIA 2.0 diagnostic kit (Chicago, IL). Testing for hepatitis B surface antigen was performed using the Abbott Auzyme™ assay (Chicago, IL). HCV RNA viral load was measured using the HCV RNA VERSANT 3.0 branched DNA assay (Bayer Diagnostics, Tarrytown, NY) with a lower limit of detection of 615 IU/mL. Samples negative by the bDNA assay were tested using the VERSANT HCV Qualitative transcription mediated amplification RNA assay (Bayer Diagnostics), with a lower limit of detection of 50 IU/ml. Serum samples were considered undetectable for HCV RNA if they were negative by the VERSANT HCV Qualitative RNA assay.
Genotype was determined at baseline using the INNO-LiPA HCV II (Bayer Diagnostics) or the Abbott Real Time PCR assay (Abbott Diagnostics, Abbott Park, IL). Samples from participants who developed recurrent viremia with the same genotype(s) at baseline were examined further using nucleotide sequencing [4-6]. Core sequences for patients with the same genotype in initial and follow-up samples were directly aligned and the number of mis-matched bases counted. Individuals were considered re-infected if more than 10% (35 of 350 bp) of the sequence did not match; otherwise they were considered relapsed [4].
Study outcomes and statistical analyses
Evaluation of HCV treatment response included all patients who received at least one injection of Peg-IFN. The primary endpoint was SVR, defined as having undetectable virus 24 weeks after the last Peg- IFN injection; non-response was defined as the presence of detectable virus of the same viral strain at the end of 24 weeks of treatment. A secondary endpoint was time to viral clearance. Adverse event and adherence rates were also assessed. Reinfection was defined as having detectable viremia after initial viral clearance, if the relapsed virus was a different genotype or a different strain of the same genotype by sequence analysis, when compared to the baseline strain.
Proportions of patients by category were compared by chi square. Kaplan-Meier curves and log-rank tests were used to compare time to clearance by treatment arm. Cox proportional hazard models were constructed to compare the hazard of viral clearance by treatment and the influence of the following variables: sex, age (≤28 or >28), race (white/non-white), genotype (1, 2 or 3), BDI score (≥20 or <20) alcohol use (not currently drinking/consuming at least one drink per week), diagnosis with depression/bipolar disorder (Yes/No), recent drug use (used day of enrollment/used within the past week or longer), frequency of drug use (daily/weekly or less), duration of drug use (≤6 years or >6 years), baseline ALT (>450 U/mLor≤450 U/mL), and baseline HCV RNA (≥5 log IU/mL or <5 log IU/mL).A multivariate model for predictors of HCV clearance was created using the backward stepwise approach, considering factors that were associated at the p<0.2 significance level in the univariate analysis.
BDI scores were compared by study arm using the Wilcoxon rank-sum test, with a score > 20 indicating moderate/severe depression. The Wilcoxon signed-rank test was used to compare the baseline BDI score to the 24 week follow-up BDI score. Adherence rates were measured by dividing the number of actual doses received by the number of scheduled doses. All analyses were performed using the statistical package STATA 10 (Stata Corporation, College Station, TX). Statistical significance was defined as a 2-sided p<0.05. Adverse events and reinfection rates were reported descriptively.

Results

Demographic characteristics
During the recruitment period, 37 injection drug users with acute HCV infection were screened; 13 patients were excluded and 24 were randomized (treatment (n=10), control (n=14)). The primary reason for exclusion was failure to meet the case definition of acute HCV. Of those randomized; one treatment patient did not return for his first Peg-IFN dose and was excluded from further analyses. Demographic and clinical characteristics, including psychiatric history, were balanced between the treatment and control groups (Table 1).
Table 1: Demographic and Clinical Characteristics of the Study population by andomization one patient were lost to follow-up after completing her 24 weeks of treatment.
Effect of treatment on HCV clearance
Of the 9 patients who received at least one injection of Peg-IFN, 5 (55%) had an SVR, 3 (33%) progressed to chronic HCV, and 1 (11%) died from an overdose. Among the 14 participants in the control group, 2 (14%) spontaneously cleared the virus, 11 (79%) became chronically infected, and 1 (7%) was lost to follow-up (Figure 1).
Figure 1: Study CONSTORT Flow Chart.
In univariate analysis, the likelihood of viral clearance was significantly greater in the treatment group (HR 15.34 (3.08-76.40), p<0.001), among those that had more recent PWID (HR 5.00 (1.23- 20.00), p=0.02), and trending towards significance for subjects with a baseline HCV RNA < 5 log IU/mL (HR 3.57 (0.94-14.28), p=0.06), as well as an ALT level ≤ 450 IU/mL (HR 6.67 (0.83-50.00), p=0.08). There was no significant association with age, race, sex, baseline BDI score, genotype, adherence, diagnosis of depression/bipolar disorder, frequency of drug use, alcohol use, or duration of infection prior to treatment initiation with time to HCV clearance (Table 2).
Table 2: Risk of SVR in univariate and multivariate Cox proportional hazards analysis among PWID treated with Peg-IFN.
In the final model, treatment (HR 61.65 (5.54-685.78), p< 0.001) and baseline HCV RNA< 5 log IU/mL (HR 14.28 (1.72-100.00), p=0.01) were significantly associated with viral clearance.
Adherence to the treatment
In treated patients who received at least one Peg-IFN injection (n=9), 86% of scheduled injections were administered (range 71% - 100%).The most common reason for missed appointments was incarceration. No other demographic factors were identified that influenced adherence, though analysis was limited by small sample size. The SVR rate among those with >80% adherence was 62.5% compared to 37.5% SVR among those with <80% adherence.
Depression and other adverse effects during treatment
Among the 23 patients in the analysis, 11 (48%) had no depression, 2 (9%) had mild depression, 7 (30%) had moderate depression, and 3 (13%) indicated severe depression at baseline. At the end of the 24-week treatment/observation period, 14 (61%) were categorized as having no depression, 1 (4%) reported mild depression and 3 (13%) were moderately depressed. BDI scores at the 24-week follow-up were significantly lower than the baseline depression scores (p=0.007); however, this difference appeared to be restricted to individuals on the control arm of the study (p=0.03 for control arm, p=0.18 for treatment arm).
Based on depression symptom severity and psychiatric consultation, 6 (26%) of patients started antidepressant medication at baseline; 3 in the treatment and three in the control group. Two additional patients (9%) were receiving antidepressants prior to study entry. BDI scores declined in all patients who started antidepressants. No patients initiated antidepressants during treatment.
One patient died 2 weeks after initiating HCV treatment from a suspected drug overdose. The patient did not report suicidal thoughts, had a normal BDI score, and reported to be feeling well at his last clinic visit. The patient had a history of two prior accidental overdoses. Another patient was taken off treatment at week 11 after being voluntarily admitted for suicidal ideation. The patient had a history of at least three reported suicide attempts. The patient’s week 11 BDI score was 10, which was substantially lower from his Initial score of 21.Subsequently, the patient denied suicidality but claimed that he was seeking a hospital bed as a respite from homelessness. He was not restarted on therapy but remained in follow-up; he developed recurrent viremia and chronic HCV infection. The Data Safety and Monitoring Board reviewed the factors associated with both of these events. Because neither event was associated with worsening of BDI scores on Peg-IFN, and because factors other than worsening depression may have contributed to the drug overdose, in the first case, and the reported suicidal ideation, in the second case, it was not concluded that study participation contributed to these occurrences.
Reinfection with Hepatitis C
Among the 9 patients who received at least one injection of Peg- IFN, 5 developed recurrent viremia after demonstrating undetectable serum viral loads at least once. Two patients (Patients 1 and 2) developed recurrent viremia with different genotypes from baseline, and thus were determined to have become reinfected. Three patients (Patients 3, 4, and 5) developed recurrent viremia with the same genotype. Of these, Patient 3 was determined to have been reinfected by a different strain of HCV, while patients 4 and 5 were considered to have relapsed with the same viral infection.Thus, 3 (30%) treated patients who successfully cleared viremia became reinfected; none of the control participants who spontaneously cleared virus became reinfected during the follow-up period. At the end of the study, including the reinfections, 5 of the treatment group versus 2 of the control group had viral clearance (Figure 2a and 2b).
Figure 2: (A) Kaplan-Meier curve of time to viral clearance and proportion of participants that cleared virus by treatment group ;(B) Kaplan-Meier curve of time to viral clearance and proportion of participants that cleared virus by baseline HCV RNA level.

Discussion

In our randomized controlled trial of treatment of acute HCV in active PWID, most treated patients achieved SVR; while most untreated controls went on to develop chronic HCV. However, reinfections lowered the overall response rate among treated PWIDs. Despite the high prevalence of psychiatric disorders at baseline, Peg-IFN treatment did not appear to exacerbate depression in this study. Surprisingly, the study participants were adherent to therapy, with most completing more than 85% of scheduled injections. Although this study is limited by the small sample size, particularly for conducting multivariate analysis, we found that treatment was associated with achieving SVR in this challenging population. The viral clearance rate among our participants is comparable to that noted in prior natural history studies in which the primary mode of infection was blood transfusions [9,10]. Regardless of the different patient populations, the spontaneous clearance rates were remarkably similar; 14% in this study compared with 14-29% in the large natural history trials. Despite some factors that may have theoretically predicted a high spontaneous viral clearance rate, such as young age and short duration of infection, few of our untreated patients cleared virus [11]. Thus, deferring treatment of acute HCV in PWID is likely to lead to chronic infection.
Few studies have described rates of reinfection after successful treatment of PWID. In this study, despite the small number of study participants, the fact that one-third had evidence of reinfection during the relatively short study period is discouraging, especially since the participants were also enrolled in a public health intervention study providing education about safe injection behaviors (DU-IT) [3]. In a recent Canadian study, only 1 reinfection was observed among 23 active PWID who achieved SVR [12]. However, ours was a challenging patient population; ~50% of participants injected drugs daily. When considering treatment for individuals with ongoing injection risks, the high efficacy of acute therapy for HCV needs to be balanced against substantial risk of re-infection.
Despite ongoing drug use, a high baseline prevalence of depression, frequent incarceration, and homelessness, the adherence rate in this study was high and the incidence of severe depression was low. In a Swiss study, 6 of 14 actively using PWID with acute HCV prematurely discontinued Peg-IFN, primarily due to psychiatric side effects [13]. In contrast, in our study, 86% of scheduled injections were administered and most missed clinic visits resulted from incarceration. This high adherence rate may have been due to the fact that we created a highly supportive clinic setting for our patients. We provided a modest reimbursement to compensate patients for time and travel, reminder phone calls, and study staff who were skilled at establishing rapport with this patient population.
Due to the limited efficacy of behavioral interventions, antiviral therapy is the key in reducing the prevalence of chronic HCV [12]. Due to the high cost of DAAs, widespread availability may be limited for several years to come in low- and middle-income populations in the United States and throughout much of the world. Therefore, interferon-based regimens may still play an important role in the treatment of acute HCV. Because Peg-IFN can be administered once weekly in an observed setting, administration can be adapted to other clinical arenas, such as methadone clinics [13-15]. Our results suggest that this difficult-to-treat population benefits from medically supervised injections, as well as integrated psychiatric care and drug treatment programs. Treatment of HCV in PWID may be most successful in clinical settings designed to serve this specific patient population, rather than in specialty clinics in which the majority of patients are not actively using injection drugs.

Statement of Interests

Declaration of funding interests: (i) This study was funded in part by the National Institute on Drug Abuse (NIDA), R21 DA016066-01; K24 AI 071113.

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