| |
Twelve-Week Treatment of Acute Hepatitis C Virus with Pegylated Interferon-a-2b in Injection Drug Users is Effective
|
| |
| |
Clinical Infectious Diseases Sept 1 2007;45:583-588
Francesco G. De Rosa,1 Olivia Bargiacchi,1 Sabrina Audagnotto,1 Silvia Garazzino,1 Giuseppe Cariti,1 Guido Calleri,2 Olga Lesioba,3 Stefania Belloro,2 Riccardo Raiteri,1 and Giovanni Di Perri1
1Department of Infectious Diseases, University of Turin, and 2Medical Department of Infectious Diseases and 3Department of Psychiatry, Amedeo di Savoia Hospital, Turin, Italy
In conclusion, we report the effectiveness and the high compliance rate of a 12-week regimen of pegylated IFN therapy in IDUs with AHC. The opportunity to provide a highly effective, short-term treatment should prompt us to reinforce the surveillance of AHC in IDUs.
Injection drug use is the leading risk factor for infection with hepatitis C virus, and interferon (IFN) treatment in this context is associated with a poor rate of adherence. In this article, we review our experience with injection drug users with acute hepatitis C who are treated with pegylated IFN--2b for 12 weeks. Acute hepatitis C was diagnosed according to standardized criteria, and patients were treated with a median dosage of IFN-a-2b of 1.33 g/kg per week. A sustained virological response was achieved in 17 (74%) of 23 patients. A sustained virological response was achieved in 14 (87%) of 16 patients treated with a dosage of >1.33 ug/kg per week and in 3 (43%) of 7 patients treated with a lower dosage. Sustained virological response was significantly associated only with a pegylated IFN--2b dosage >1.33 ug/kg per week (P = .022). A 12-week regimen of pegylated IFN to treat injection drug users with hepatitis C has a compliance that is much higher than that reported with a 24-week regimen. Adverse effects are minimal if patients are carefully selected.
The natural history of hepatitis C virus (HCV) is not completely understood, and the rate of chronic HCV infection worldwide is believed to be 50%-80% [1]. Spontaneous clearance of acute HCV infection may be as high as 50% in patients with jaundice, and lower rates have been recorded in asymptomatic patients [2-4]. In the past few years, a number of reports gave evidence of an extremely favorable outcome of acute hepatitis C (AHC) when patients were treated with IFN-based therapy, with a sustained virologic response (SVR) >94% associated with a 24-week treatment regimen of IFN and pegylated IFN--2b [5-7]. Although the identification of acutely infected subjects with HCV infection is rather difficult, mainly because of the high rate of asymptomatic infection, the knowledge of such high cure rates should encourage doctors to improve their efforts for early recognition of AHC in high-risk subjects.
Injection drug use is the leading risk factor for HCV infection. In Italy, the prevalence of injection drug users (IDUs) has been estimated to be 6 of 1000 adults, with an HCV infection prevalence of about 80% [8, 9]. Only a program of active surveillance may offer the possibility of increasing the recognition of patients with AHC because of the high rate of asymptomatic infection. In IDUs, treatment of AHC is difficult because of the poor rate of acceptance and/or adherence to the treatment, as recently detailed in a study in which a 24-week course of pegylated IFN-a-2b was administered to IDUs [10]. In this perspective, studies aiming at proposing a lower duration of pegylated IFN treatment coupled with early treatment, without waiting for a spontaneous clearance of HCV infection, may have the highest chance of being accepted by IDUs, who are often excluded from clinical trials. In this article, we report the results of an open-label, nonrandomized study of the 12-week treatment with pegylated IFN-a-2b of 23 IDUs with AHC.
MATERIALS AND METHODS
Patients included in this study are part of a prospective, open-label, nonrandomized study conducted at the outpatient clinic of the Amedeo di Savoia Hospital in Turin, Italy, which is a regional reference center for infectious diseases and part of a provincial network of outpatient facilities for IDUs. Because IDUs are consistently represented in our series of patients with AHC, they were analyzed separately from non-IDUs for the aims of this study.
AHC was diagnosed using the following criteria: an abnormal alanine aminotransferase (ALT) level and a detectable plasma HCV RNA level, together with either documented seroconversion or history of injection drug abuse within the preceding 6 months [5]. Patients with acute hepatitis caused by other viruses were excluded. HIV-positive patients were included in the study if the CD4+ T lymphocyte count was >400 cells/uL in patients naive to antiretroviral therapy.
As part of the outpatient services for IDUs, newly recruited patients undergo serological screening for bloodborne infections (i.e., HIV, hepatitis B virus, and HCV) and, depending on the individual profile, are offered vaccination and/or are invited to refer to our infectious diseases clinic for specific counselling and treatment. Patients found to have AHC who met the inclusion criteria and were accepted to receive specific anti-HCV treatment were administered pegylated IFN-a-2b subcutaneously at a dosage varying from 1.0 to 1.6 g/kg per week. Treatment dosage varied owing to the availability of vials containing only 100-ug and 80-ug doses of pegylated IFN. Treatment was administered under direct observation and was initiated as soon as laboratory baseline evaluation results were available, without waiting for spontaneous resolution. Clinical and laboratory evaluations were performed at baseline and at weeks 4, 8, 12, and 36. For selected patients, there were available data at the first, second, and third week of treatment. Baseline plasma HCV RNA levels were analyzed by branched-DNA (bDNA) assay with a lower limit of detection of 615 IU/mL (bDNA Assay, version 3.0;Versant, Bayer) and, in the instance of a negative bDNA test result (i.e., an undetectable HCV RNA level), by qualitative RT-PCR with a lower limit detection of 50 IU/mL (Cobas Amplicor HCV test, version 2.0; Roche). Plasma HCV RNA levels were studied using qualitative RT-PCR during treatment. Genotypes were studied by Line Probe Assay (HCV Genotype Assay LiPA; Versant, Bayer).
All patients underwent psychiatric evaluation before treatment. The protocol was approved by the local ethics committee, and all patients provided informed written consent before study enrollment.
The primary end point was SVR, defined as the absence of a detectable plasma HCV RNA level by RT-PCR 24 weeks after the end of treatment. Statistical analysis was performed for an intent-to-treat population, defined as patients who were given at least 1 dose of pegylated IFN. Mann-Whitney U test was used for continuous variables, and contingency tables were used for categorical variables. All P values were 2-tailed, with a .05 value being statistically significant. The X2 test was used when applicable.
RESULTS
From February 2002 through December 2005, 23 IDUs with AHC (15 male patients and 8 female patients; mean age, 26.6 years; range, 17-44 years) were recruited. The main characteristics of the patients are detailed in table 1. Fifteen (65.2%) of 23 patients received a diagnosis on the basis of evidence of seroconversion (i.e., definite diagnosis), and 8 patients (34.8%) received a diagnosis on the basis of the presence of the risk factor represented by injection drug use (i.e., probable diagnosis). The mean duration of injection drug use in our patients was 27 months (median duration, 12 months; range, 2-92 months), and 14 patients (61%) became IDUs during the year preceding the diagnosis. Four patients (17.4%) had mild dyspeptic syndrome, and only 2 patients (8.7%) had jaundice. Nine (39%) of 23 IDUs were treated with methadone (mean dosage, 52 mg/day) and reported an alcohol intake >50 g/day. The median HCV RNA level at baseline (intended to be immediately before treatment) was 25,380 IU/mL (range, 280-2,884,500 IU/mL). Twelve patients (52.2%) were infected with genotype 1, 2 (8.7%) with genotype 2, 6 (26.1%) with genotype 3, and 3 (13%) with genotype 4. The median HCV loads were 7945 IU/mL (range, 280-2,884,500 IU/mL) and 326,910 IU/mL (range, 280-1,749,930 IU/mL) in patients infected with genotypes 1 and patients infected with genotypes other than 1, respectively (the difference was not statistically significant). The median ALT level at baseline was 365 IU/L (range, 43-1168 IU/L). Two patients had HIV infection, with a mean CD4+ T lymphocyte count of 563 cells/uL and an HIV load of 40,500 copies/mL (determined by real-time PCR).
Treatment was initiated after a median duration from the diagnosis of AHC of 13.5 days (range, 0-166 days). The median weekly administered dose of pegylated IFN was 1.33 ug/kg (range, 1.07- 1.6 ug/kg). All but 1 patient completed >80% of the 12-week treatment regimen (1 patient received only 2 doses and, thereafter, was lost to follow-up). One patient received 10 of 12 doses but completed all follow-up analyses.
The rates of negative RT-PCR results (i.e., an HCV RNA level <50 IU/mL) at week 4 of treatment, at the end of treatment, and 24 weeks after treatment for patients treated with the high (>1.33 g/kg) and low doses (<1.33 g/kg) of pegylated IFN are shown in figure 1. Overall, an SVR was achieved in 17 patients (74%); the rate of SVR was 83% (10 of 12) among patients infected with genotype 1, 100% (2 of 2) among patients infected with genotype 2, 83% (5 of 6) among patients infected with genotype 3, and 0% (0 of 3) among patients infected with genotype 4. Of note, 2 of 3 patients infected with genotype 4 had undetectable on-treatment HCV RNA levels (both were treated with the low-dose regimen), although 1 patient was precociously lost to follow-up.
Figure 1. The rate of undetectable hepatitis C virus (HCV) RNA levels as determined by RT-PCR, according to the variable dose of pegylated IFN-a-2b (PEG-IFN) administered. The columns show the percentage of negative RT-PCR results (i.e., an HCV RNA level <50 IU/mL) for all patients (n = 23) and for those treated with >1.33 g/kg per week (n = 16) and <1.33 ug/kg per week (n = 7) of PEG-IFN.
As shown in tables 2 and 3, the rate of SVR was higher in patients treated with the higher dose, independent of definite or probable diagnosis (table 2) and the genotype (table 3), except for in those infected with genotype 4, which was not associated with SVR. Among patients with a definite diagnosis (according to the presence of seroconversion), SVR was observed in 9 (82%) of 11 IDUs treated with higher doses and in only 1 (25%) of 4 of those treated with doses <1.33 g/kg. Among patients with a probable diagnosis, the percentage of SVR was 100% and 66% in those treated with the high and low doses, respectively (table 3). Both patients with HIV infection achieved SVR. Injection drug use was interrupted during treatment and follow-up in all patients except 1, who did not achieve SVR.
Statistical analysis showed that SVR was significantly associated only with the administration of pegylated IFN at a dosage of 1.33 g/kg per week (P = .022; X2 value, 5.218) (figure 2). There was no statistically significant association between SVR and ALT levels at baseline by continuous or categorical variable (i.e., an ALT level >500 IU/mL and an ALT level <500 IU/mL), nor was there an association between SVR and alcohol abuse, methadone treatment, genotype, or type of diagnosis (definite vs. probable). An undetectable HCV RNA level at week 4 was not associated with the achievement of SVR, probably because of the low detection limit of the RT-PCR. In a previous study, SVR was significantly associated with an undetectable bDNA level at week 4 of therapy [15].
Figure 2. The rates of nonresponse (NR) and sustained virological response (SVR), according to the mean dosage of pegylated IFN-a-2b (PEG-IFN) administered. The error bars represent the standard deviation.
DISCUSSION
Treatment of HCV infection during the acute phase rather than during the chronic phase of infection leads to a better response rate, and response rates varying from 74%-98% have been achieved with standard or pegylated IFN-a-2b administered for 12 and 24 weeks [5, 11-13]. In a German multicenter trial, SVR was achieved in 74% of patients treated with pegylated IFN-a-2b at a dosage of 1.5 g/kg per week for 24 weeks, with a poor adherence rate that contrasts with the excellent compliance reported when IFN--2b was administered for the same duration in another study [5, 12]. The efficacy of a 12-week regimen to treat AHC was reported in other studies, including one of ours, in which SVR was significantly associated with higher doses of pegylated IFN in a population of patients treated without waiting for spontaneous clearance of the virus [11, 14].
Surprisingly, there are few data on IFN treatment of IDUs with AHC. In general, IDUs represent a scant proportion of patients (12%-20%) with AHC treated in the various studies published that use the 24-week treatment regimen [5, 12, 13]. Importantly, a poor rate of adherence of IDUs to a 24-week regimen of pegylated IFN-a-2b was reported in a Swiss study; among the 18 IDUs considered for treatment, 7 patients refused, and among those who initiated treatment, only 5 (45%) completed >80% of the treatment regimen [10]. Treatment was discontinued in 6 patients because of severe depression, violent behavior, and severe intolerance [10].
In this study, we demonstrated that IDUs achieved the same rate of SVR as that we published in previous studies, with an excellent compliance and no significant adverse effects, even in the presence of methadone treatment and significant alcohol consumption (measured before the beginning of treatment) [11, 14, 15]. Although our results are biased by the variable dose of pegylated IFN administered, we confirm that SVR is significantly associated with the high dose of pegylated IFN, independent of definite or probable diagnosis and viral genotype, with the possible exception of genotype 4 [11, 14, 15]. Among the 16 patients treated with the high-dose regimen, the rate of SVR was 100% among those infected with genotype 1, 100% among those infected with genotype 2, 83% among those infected with genotype 3, and 0% among those infected with genotype 4. Our results are clearly better than those achieved in the Swiss study [10], even if the overall SVR rate may appear lower, compared with that in other uncontrolled studies in which patients were treated longer with a high-dose regimen and in which IDUs were poorly represented [5, 6].
Furthermore, from a clinical point of view, IDUs are interested in short-term treatment, and they are not willing to wait for the spontaneous clearance of HCV infection. In our series, all but 1 patient received >80% of the scheduled doses, and treatment was well tolerated, even in patients receiving methadone treatment and specific therapy for psychiatric comorbidities. Reasons for such a high success rate are a stable multidisciplinary team, including a psychiatrist; free access to the outpatient clinic; and early treatment, which helps keep IDUs in contact with health care providers. Because the majority of IDUs are aware of the problem of chronic hepatitis C, most of them are also aware of the combination therapy with ribavirin needed and the longer duration of treatment, especially in the case of chronic infection with genotype 1. If the price that has to be paid for treatment of patients with AHC should at least be comparable to that paid for by patients who are treated needlessly, we underscore that, among IDUs, we achieved a rate of SVR equal to that achieved in the German Competence Network for Viral Hepatitis Study (the study population of which was only 22% IDUs), with a 12-week sparing regimen and with a rate of adherence to treatment close to 100%, clearly above that reported in the aforementioned study [12, 16]. Furthermore, the HEP-NET study was characterized by 1 suicide attributed to IFN therapy, probably because of the multicenter design of the study. We are not proposing that our regimen is a gold standard, because we are aware that IDUs are not handled the same way in all centers. We report our results from a unique center and emphasize how IDUs are handled in our regional referral system.
The design of the studies published to date that compare a 12-week regimen with a 24-week regimen is not going to resolve the issue of early- versus late-treatment strategies, especially if the studies include different percentages of IDUs [17]. These studies simply show that SVR is significantly associated with a high dose of pegylated IFN administered during early treatment in the 12-week course, whereas SVR is significantly affected by the lower compliance rate associated with the late-treatment strategy of the 24-week regimen [12]. Another piece of the puzzle comes from another study, in which a late-treatment strategy was associated with an SVR rate of 67.6%, 82.4%, and 91.2%, with 8-, 12-, and 24-week courses of pegylated IFN therapy, respectively [18]. It is very interesting to underscore that, in our study, in which the patients were treated without waiting for the spontaneous clearance of the infection, the difference between the results achieved with a high or low dose was greater after week 4 of treatment, indicating that the antiviral activity of IFN is probably more important for the achievement of SVR than is the immunomodulating activity (figure 1).
In a previous study involving 19 patients (14 of whom were IDUs), we reported that undetectable plasma HCV RNA levels determined by RT-PCR were observed 2.5 weeks after the beginning of treatment, but, to date, we are not sure whether this period may be shortened when using the high-dose pegylated IFN regimen, which is clearly more effective, at least in IDUs, after week 4 of treatment; these findings mirror the results of the Kamal study, in which pegylated IFN was administered for 8, 12, or 24 weeks [15, 18]. On the basis of these considerations, we believe that the benefits of early treatment with high-dose pegylated IFN are greater than those achieved with late treatment, especially in IDUs, and we are not totally persuaded by the possible effectiveness of a shorter duration of treatment (i.e., 4 and 8 weeks).
There are several limitations to the results of this open-label, nonrandomized study, including the early-treatment strategy, the variable dose of pegylated IFN administered, and the referral bias. Early treatment may overestimate the response rate, because spontaneous clearance of HCV infection may occur, especially in patients with symptoms and jaundice; in our study, there were few symptomatic patients. Various doses of pegylated IFN were administered because of the availability of vials containing only 80 g and 100 g of the drug. The referral bias may be more important for the high success rate achieved in IDUs, because our patients were referred by a regional network involving specific services for the outpatient care of IDUs; we cannot exclude that some patients with clear and unambiguous clinical criteria contraindicating IFN treatment were not referred to our center. Notwithstanding these limitations, the early-treatment strategy is of utmost importance in keeping IDUs in contact with health care services and is associated with a higher compliance rate when the 12-week regimen is administered. Treatment of IDUs with AHC is a very special situation, in which a late intervention may be erroneously mistaken for a decision to avoid treatment. In our experience, the benefits of early treatment of IDUs are much higher than the costs of treating IDUs who will spontaneously clear HCV infection. As it has been observed in the context of chronic hepatitis, IDUs have the same chance of being cured as non-IDUs, and there is no clinical evidence suggesting that treatment should not be administered [19].
In conclusion, we report the effectiveness and the high compliance rate of a 12-week regimen of pegylated IFN therapy in IDUs with AHC. The opportunity to provide a highly effective, short-term treatment should prompt us to reinforce the surveillance of AHC in IDUs. Although complementary actions should also be undertaken to guarantee the best long-term outcome of this therapeutic intervention (e.g., counseling and avoidance of injection practices because of risk for reinfection), attention should also be paid to the additional benefits of a successful medical intervention during the first months of drug addiction. The successful treatment of AHC might represent for new IDUs a positive complementary incentive for recovering from their newly developed noxious habit.
|
|
| |
| |
|
|
|
