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HIV/Hepatitis C Virus−Coinfected Virologic Responders to Pegylated Interferon and Ribavirin Therapy More Frequently Incur Interferon-Related Adverse Events Than Nonresponders Do

Osinusi, Anu MD*; Rasimas, Joseph J MD, PhD; Bishop, Rachel MD; Proschan, Michael PhD§; McLaughlin, Mary RN*; Murphy, Alison BA*; Cortez, Karoll J MD; Polis, Michael A MD, MPH*; Masur, Henry MD; Rosenstein, Donald MD; Kottilil, Shyam MD, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2010 - Volume 53 - Issue 3 - p 357-363
doi: 10.1097/QAI.0b013e3181c7a29d
Clinical Science
Free

Background: This study aimed to assess the relationship between interferon (IFN)-related adverse effects and Hepatitis C virus (HCV) virologic response in HIV/HCV-coinfected individuals treated with pegylated interferon and ribavirin.

Methods: We conducted 2 prospective, open-label trials treating HIV/HCV-coinfected individuals with pegylated interferon alpha-2b or alpha-2a and ribavirin for 48 weeks. Safety laboratories, HCV RNA, psychiatric, and ophthalmologic evaluations were performed at baseline and monthly until week 72.

Results: Responders were defined as those with HCV RNA decline of ≥2-log drop from baseline and nonresponders were those who did not. Remarkably, of the 27 patients (50%) who developed psychiatric toxicities, 26 patients were responders, although only 1 of 14 virologic nonresponders experienced psychiatric toxicity. Other adverse effects, such as anemia and ophthalmologic toxicities, were also more frequent in responders compared with nonresponders. Decline in CD4+ T-cell counts strongly correlated with HCV viral decline.

Conclusions: Our study demonstrates coupling of antiviral effect and occurrence of adverse events in HIV/HCV-coinfected patients. These patients with IFN-related adverse effects need a multidisciplinary treatment approach, hence, they are more likely to achieve sustained virologic response. Future studies are needed to evaluate the factors that predict the development of IFN-α-dependent adverse events before therapy.

From the *Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD; †National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; ‡National Eye Institute, National Institutes of Health, Bethesda, MD; §Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and ‖Critical Care Medicine Department, Clinical Research Center, National Institutes of Health; and CCMD, CC/National Institutes of Health, Bethesda, MD.

Received for publication April 17, 2009; accepted September 23, 2009.

Supported in whole by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, and the National Eye Institute).

The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

None of the authors have any conflicts of interest to report.

Both authors A.O. and J.J.R. contributed equally to the article.

Correspondence to: Dr. Shyam Kottilil, MD, PhD, Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building10, Room. 11N204, Bethesda, MD 20892 (e-mail: skottilil@niaid.nih.gov).

Coinfection with Hepatitis C virus (HCV) occurs in approximately one third of HIV-1-infected patients in the United States.1 It has been shown that liver disease is more rapidly progressive in coinfected patients with liver fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure occurring earlier than in HCV monoinfected patients.2,3 Introduction of antiretroviral therapy has resulted in decline of HIV-related mortality; however, HCV-related liver disease has become a leading cause of hospitalization and death.3,4

The efficacy of pegylated interferon (peg-IFN) plus ribavirin as treatment for HCV infection in coinfected patients has been shown to be much lower than HCV monoinfected patients, particularly in those infected with genotype 1.5 HIV/HCV-coinfected patients are also characterized by high rates of drug use and neurocognitive and psychiatric disorders rendering them potentially even more susceptible to the neuropsychiatric adverse events of interferon therapy.6,7 Likewise, chronic HIV infection, use of antiretrovirals, prophylactic medications, and malignancies may contribute to various cytopenias and make individuals more susceptible to hematologic toxicity from peg-IFN and ribavirin therapy.8,9 It is also well established that maintenance of recommended doses of peg-IFN and ribavirin throughout treatment is crucial to the achievement of a successful outcome.10,11 Many studies have suggested that there may be higher rates of toxicities in HIV/HCV-coinfected patients,12-15 however, none have explored the possibility that there might be differences in IFN-α-related adverse events in responders compared with nonresponders. Because both antiviral response and adverse effects are mediated by IFN-α signaling of host cells,16 it would seem plausible that antiviral response and occurrence of severe adverse events are related to one another. In this regard, we investigated the relationship between IFN-α-related adverse effects and HCV virologic response in HIV/HCV-coinfected individuals on therapy.

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METHODS

Study Design

Two-pilot, prospective, single-center, open-label trials were performed at the National Institute of Allergy and Infectious Diseases, National Institutes of Health from 2001 to 2008. Fifty-five HIV/HCV-coinfected patients were treated with ribavirin daily (Rebetol, [Schering-Plough, Kenilworth, NJ] at 1000 mg dose <75 kg, 1200 mg dose for >75 kg) and peginterferon alpha-2b at 1.5 μg/kg subcutaneously weekly (Peg-Intron; Schering-Plough) or peg interferon alpha-2a (Pegasys; Roche Laboratories, Palo Alto, CA) for 48 weeks and followed up for up to 24 weeks after completion of treatment. Treatment responders were defined as HCV viral RNA levels below level of detection (<615 IU/mL) or HCV RNA levels declining to greater than a 2-log drop from baseline by week 12. The responders include patients who achieved sustained virologic response (SVR) and relapsers. Nonresponders were individuals who never achieved greater than a 2-log decline in HCV RNA level by week 12. All patients gave written informed consent approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board before enrollment in the studies.

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Study Subjects Selection

HIV/HCV-coinfected patients were eligible if they had a CD4 count >100 cells per cubic millimeter, absolute neutrophil count >1000 cells per cubic millimeter, hemoglobin >10 g/dL, HCV viral load >2000 copies per milliliter, histologic evidence of chronic HCV infection. Exclusion criteria were advanced cirrhosis, severe liver decompensation, active and severe psychiatric disorders, active substance abuse or dependence (except nicotine), severe cardiopulmonary illness, renal disease, hemoglobinopathies, and retinopathies.

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Laboratory Evaluations

Safety laboratory tests and immune profiles including CD4+ T-cell counts were obtained at baseline and frequently during the entire study. G-CSF was initiated at 300 ug per week if absolute neutrophil count (ANC) dropped below 750 cells per cubic millimeter and titrated up based on response to maintain ANC >1000 cells per cubic millimeter. Erythropoetin was started at 40 ug per week when hemoglobin dropped below 10 g/dL and titrated to maintain hemoglobin above this level.

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Psychiatric Evaluations

All patients underwent routine psychiatric interviews conducted by Board-certified psychiatrists from the National Institute of Mental Health. Patients were assessed for current and past psychiatric and substance-abuse diagnoses. The majority of patients screened had a history of substance use. Patients who presented with active mood, anxiety, or psychotic symptoms were treated clinically before study enrollment. During the study, depression was evaluated by examination, by standard diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders [DSM] IV), and by the Beck Depression Inventory. Patients who received at least 4 weeks of IFN ribavirin treatment were classified into 2 groups, those with and without psychiatric toxicity after initiation of therapy based on the criteria. Study participation was discontinued for patients in whom severe psychiatric toxicity developed and could not be safely managed with ongoing IFN treatment.

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Ophthalmology Evaluation

All patients underwent ophthalmologic evaluations including visual acuity, visual field testing (automated perimetry using the Field Analyzer Model 750 SITA-fast program; Carl Zeiss Meditec, Dublin, CA), color vision exam (using the Ishihara Test for color deficiency, plates 2-17) and indirect ophthalmoscopy were performed at baseline, at least every 3 months or when clinically indicated. Patients who developed cotton wool spots (CWS), cataracts, or color vision abnormalities were monitored more frequently based on potential severity of lesions. Peg-IFN treatment was not stopped unless examination revealed more than 10 CWS in either eye or deteriorating visual fields, loss of central acuity, or any signs of optic neuropathy.

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Statistical Analysis

Patients were classified into 2 groups, treatment responders (which included patients who relapsed after 48 weeks of therapy, but had HCV viral levels <615 IU/mL up until 48 weeks) and treatment nonresponders. The IFN-related adverse events studied were anemia (or use of erythropoietin); neutropenia (or use of G-CSF); occurrence of psychiatric toxicities; and ophthalmologic toxicities. The T tests and nonparametric tests were used to compare continuous outcomes between responders and nonresponders, whereas χ2 methods and Fisher exact test were used to compare categorical outcomes. The relationship between HCV viral load and CD4+ T-cell counts was assessed in 2 ways. First, ordinary regression was used to summarize each patient's slope relating HCV log viral load to log CD4 count. These per-patient slopes were then plotted to assess whether there was a consistent pattern across patients. A more sophisticated mixed model approach was used to take into account that different patients had different amounts of data. The mixed model incorporated an average intercept and slope across all patients (fixed effects), together with patient-specific intercepts and slopes (random effects).

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RESULTS

Study Subjects

From 2001 to 2007, 55 HIV/HCV-coinfected patients enrolled in the treatment studies. Baseline demographic data for patients including responders and nonresponders are shown in Table 1. Both groups of patients received the same dose and statistically similar duration of therapy and were evaluated for pre-existing psychiatric and other conditions before therapy. The mean CD4 count was 558 (108-1273); median HIV RNA was less than 50 copies per millimiter. A total of 10 patients discontinued the study before 48 weeks, 4 (40%) of whom were responders. Five of these patients (50%) discontinued by week 2 (day 5 to week 2) for financial, social, and work issues that conflicted with the frequent demands of study participation. Five other patients discontinued between week 12 and 24. Three of these patients were responders, all of whom experienced psychiatric toxicity. One developed an acute psychotic episode requiring hospitalization, whereas the other 2 had alcohol and substance-abuse relapses that necessitated study discontinuation. The other 2 patients were nonresponders and opted to come off the study by week 20 due to nonresponse to IFN-α. The duration of treatment for nonresponders was not statistically different from that for responders (median 42 ± 13 weeks vs 48 ± 5.8 weeks; P > 0.05).

TABLE 1

TABLE 1

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Responders to Peginterferon-α and Ribavirin had Significantly Higher CD4+ T-Cell Decline Than Nonresponders

Two methods were used to determine whether CD4+ T-cell count was associated with virologic response to peg-IFN and ribavirin therapy. Ordinary regression was used to compute, for each patient, a slope relating HCV log viral load to log CD4 count. These per-patient slopes, depicted in Figure 1, showed remarkable consistency across patients. The great majority of slopes were positive, indicating that HCV viral load and CD4 count tracked together; as one decreased, so did the other, and similarly for increases. A disadvantage of this type of analysis is that it does not take into account that different patients have different amounts of data. Therefore, a mixed model analysis was also used. This more sophisticated analysis addresses the same questions-is there a consistent trend across patients, and what is that trend? The result was a highly statistically significant positive slope for the relationship between HCV log viral load and log CD4+ T-cell count (overall slope 1.12, P = 0.0001). This shows that CD4 counts tracked with HCV viral loads.

FIGURE 1

FIGURE 1

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IFN-α-Related Psychiatric Toxicities Were More Common in Responders Than Nonresponders

Twenty-seven of 55 patients (50%) had psychiatric toxicities as defined by the criteria listed in the Methods section. Although 26 of 41 peg-IFN treatment responders (63%) experienced psychiatric toxicities, only 1 in 14 nonresponders (7%) to peg-IFN developed such symptoms (P = 0.009; Fig. 2). The most common psychiatric adverse effects were anxiety, worsening depression, and other mood disturbances with associated sleep difficulties. Patients with a psychiatric history were no more likely to develop these symptoms than patients without a history of mental illness. Twenty-one of 27 patients (78%) with psychiatric toxicities required additions to or changes in psychiatric medications. The most commonly used antidepressants were mirtazapine (Remeron) and sertraline (Zoloft).

FIGURE 2

FIGURE 2

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IFN-α-Related Hematologic Toxicities: Neutropenia

Toxicity was defined as either an ANC level below 750 cells per cubic millimeter and/or use of G-CSF to maintain ANC levels on treatment. Median ANC values were similar in both groups of responders and nonresponders (P > 0.05) (Table 2). Twenty-four patients (43.6%) experienced ANC decline to below 750 cells per cubic millimeter requiring granulocyte colony stimulating factor (G-CSF) therapy. Seventeen (70.8%) of whom were responders, whereas seven [29%] were nonresponders (P > 0.05). Sixteen patients (66.6%) required dose escalations up to 480 μg and increased frequency up to thrice weekly, 12 (75%) of whom were responders (P > 0.05). Overall, 17 (41.5%) of responders compared with 7 (50%) of nonresponders developed neutropenia (P > 0.05). Only 1 patient of 24 with a baseline ANC >2500 cells per cubic millimeter required G-CSF, whereas 23 of 31 patients with a baseline ANC ≤2500 cells per cubic millimeter did require G-CSF.

TABLE 2

TABLE 2

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IFN-α-Related Hematologic Toxicities: Anemia

Toxicity was defined as either an hemoglobin (Hgb) level below 10 g/dL and/or use of erythropoetin to maintain Hgb levels on treatment. Twenty patients (36%) had at least 1 Hgb value less than 10 g/dL requiring erythropoetin. Fifteen (75%) were responders, whereas 5 (25%) were nonresponders (P > 0.05) (Table 2). Overall, 15 responders (36%) required erythropoetin compared with 5 nonresponders (36%) (P > 0.05). At initiation of therapy, 10 patients were on zidovudine-containing regimens and 3 (30%) were switched off due to concerns of anemia during treatment. The decline in Hgb was attributed to anti-HCV treatment; therefore, other causes of anemia were not investigated unless there was no response to erythropoetin and/or clinical history was suggestive of further investigation. A total of 32 patients (58.2%) received either or both growth factors, whereas 9 required both factors of whom 7 were responders (77.8%).

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IFN-α-Related Ophthalmologic Toxicities

A total of 38 of 55 patients (69%) had abnormal ocular findings, of whom, 21 (38%) were judged to be IFN-α related. Seventeen responders (42%) had ophthalmologic toxicity compared with 4 nonresponders (29%). (P > 0.05). There were 3 patients with serious ophthalmopathy (2 with color vision changes and 1 with a sight-threatening CWS involving the macula) of whom, 1 had to be taken off study medications due to the severity of the event. All 3 patients had HCV viral load less than 615 IU/mL at the time of the adverse event. The major ophthalmologic adverse events attributable to IFN-α were color vision changes (2), bilateral cataracts (2), and CWS (17). Ocular pathologies that were not attributable to IFN-α are described in Table 3.

TABLE 3

TABLE 3

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IFN-α-Related Multiple Adverse Events

A total of 28 patients (55%) had more than 1 of the above listed classes of toxicities, namely psychiatric, ophthalmologic, anemia, and neutropenia. Twenty-three of these patients (56%) were responders compared with 5 of nonresponders (36%) (P > 0.05). A total of 10 patients had up to 3 classes of toxicities of whom 8 (80%) were responders. A total of 50 patients experienced at least 1 major class of IFN-α-related adverse effects as shown. The major IFN-α-related toxicities seen in this study population are summarized in Table 4.

TABLE 4

TABLE 4

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DISCUSSION

This study demonstrates that serious adverse events associated with IFN-α therapy are seen more commonly with patients who respond virologically. Specifically, the CD4+ T-cell decline and psychiatric adverse effects are seen in virologic responders more frequently than in nonresponders to IFN-α treatment. Frequent monitoring of CD4+ T-cell counts and completion of 48 weeks of anti-HCV treatment for all patients including nonresponders were critical in establishing the relationship between virologic response and development of serious adverse events due to IFN-α therapy.

Combination therapy for HCV with peg-IFN and ribavirin is associated with peripheral CD4+ T-cell decline.17 Although there is a consistent decline in the absolute CD4+ T-cell counts, there is no significant change in the CD4+ T-cell percentage, and hence the mechanism and clinical relevance of this drop in CD4+ T-cell count decline is unclear.17 Interestingly, many patients with viral breakthroughs did have CD4+ T-cell declines, whereas they were responding with lower HCV viral loads initially, but had higher CD4+ T-cell counts, whereas they experienced breakthrough to combination therapy, suggesting a direct effect of IFN signaling on the bone marrow resulting in a decreased release of cells.

Consistent with prior reports of dose-limiting toxicity seen with HCV/HIV-coinfected individuals,5 we observed frequent psychiatric symptoms in patients treated with IFN. The principal challenge in characterizing this IFN-related toxicity is the assignment of psychiatric symptoms observed to the effects of medication as opposed to pre-existing mental conditions. In an effort to avoid type I error in suggesting causality, we established stringent criteria for emergent neuropsychiatric toxicity. An etiologic attribution of mental disturbance to IFN was determined on the basis of direct multidisciplinary evaluation of study subjects, including assessment by the psychiatrist who had seen them before IFN treatment.

Consistent with prior studies,18 50% of patients enrolled experienced specific IFN-related psychiatric toxicities-an important finding in light of the fact that HIV/HCV-coinfected patients are known to have high rates of pre-existing substance abuse, neurocognitive and psychiatric disorders.6 However, in contrast to prior studies,18-20 we observed a strong relationship between viral response and treatment emergent psychiatric toxicity (63% of responders, compared with only 7% of nonresponders) and not to baseline psychiatric morbidity.

Although our results stand in contrast to previous findings regarding the relationship between baseline mental health and risk of psychiatric toxicity from IFN, a correlation between emergent psychiatric symptoms with virologic response in IFN-α-treated subjects has been reported.21 The therapeutic goal of administering IFN for hepatitis C is to induce a global immunologic expansion in the service of activating cellular processes that will aid the body in clearing HCV. That activation is dependent upon a cascade of immunoendocrine interactions that are, in part, mediated by cytokines and other small molecules that can freely traverse the blood-brain barrier.22 Roles for such compounds in mediating neuropsychiatric symptoms have been hypothesized and investigated for a number of different disease states and their treatments, from cancer, to multiple sclerosis, to rheumatologic conditions.18-20,23,24 In the case of HCV, we suggest that when IFN is effective, 1 or more of the alterations in cytokine pools necessary for improved immune function may have corresponding negative effects on the brain. Although the profile of psychiatric symptomatology will vary on the basis of individual patients' genes, environments, and relational patterns, most manifest signs in the realm of mood disturbance, presumably due to effect of the IFN on neural systems related to emotion, memory, and motivated behavior. Those who do not display such symptoms in some form may fail to experience specific aspects of immune system modulation, which are not only crucial for viral clearance but also adversely affect mental functioning.

Even with the high frequency of psychiatric toxicity observed in this sample, it should be noted that only 3 patients (6% of all protocol subjects) had to discontinue the study due to psychiatric symptomatology, 2 of whom experienced substance-abuse relapse. This observation reinforces that through extensive multidisciplinary clinical management, active psychiatric assessments and interventions most individuals can complete 48 weeks of HCV treatment with IFN. Similar to what has been observed with gefitinib,25,26 the emergence of toxicity may, in this case, serve as an important predictor of positive treatment response.27 Furthermore, the presence of seemingly unrelated neuropsychiatric symptoms with IFN treatment for infectious hepatitis lends credence to hypothesized mechanisms of immune-mediated pathophysiology in mental illness.28 A novel approach in the management of HCV patients is developing molecular techniques to predict emergence of serious psychiatric adverse events during treatment with IFN-α.29,30 Such a tool for screening and monitoring HCV/HIV-coinfected individuals could help to optimize IFN-α treatment, enhance the SVR, and even elucidate genetic factors underlying the development of psychiatric symptoms.

Another significant dose-limiting adverse event observed with treatment with IFN-α is development of hematologic toxicities such as anemia and neutropenia.31 The need for G-CSF and erythroepoetin use in a majority of our patients to maintain their ANC counts and Hgb levels, respectively, within days after starting treatment in many cases made it difficult to study their relationship between virologic response. The anemia observed was largely attributable to the effects of ribavirin rather than a direct result of an effect of IFN-α. Moreover, about half of our patients also developed neutropenia, prompting treatment of all patients G-CSF, and a larger percentage of responders required dose escalations of G-CSF than nonresponders. Our results confirm that anemia and neutropenia are common and can occur early in HCV treatment with about 60% of our patients requiring growth factors. In HCV monoinfected patients, early virologic suppression and maintenance of full doses of peg-IFN and ribavirin throughout treatment have been associated with higher SVR rates particularly in patients with genotype 1 infection,10,11 which reiterates the need for use of hematopoietic factors in patients experiencing these side effects to avoid dose reductions.

Furthermore, more responders experienced ophthalmologic toxicity compared with nonresponders. In our study, the 2 patients who developed severe color vision, requiring study discontinuation, were both responding to IFN treatment and had HCV viral levels less than 615 IU/mL at the time of occurrence.32 Given these occasional dramatic ophthalmologic issues seen in responders, providers must follow patients closely for eye pathologies. The mechanisms of IFN-α-induced ophthalmic toxicities are not completely understood. IFN-α may cause immune complexes to be deposited in the retinal vessels leading to capillary infarction. There is also some evidence that IFN-α may raise levels of complement 5a, which may result in infarction and lead to toxicity to ganglion cells.33 Several of our patients also had ocular pathologies that were observed in patients regardless of their virologic response (such as CWS). It is plausible that a different mechanism that are not mediated via the IFN-α-IFN-α receptor interactions result in these toxicities (such as infarcts of retinal vessels), which is not related to the antiviral mechanism of action of IFN-α.

Several demographic factors can influence the occurrence of adverse events.5 In this regard, there were no statistical differences in the baseline characteristics (race, age, liver disease staging) and treatment characteristics (type of IFN-α, duration of therapy, ribavirin dosing) between the 2 groups. Clinically, these findings suggest anticipation of serious adverse events among virologic responders and pre-emptive therapy for symptoms to enable successful completion of therapy and enhance the opportunity for achieving a cure for HCV infection in this difficult-to-treat population. Biologically, virologic response equates with development of adverse events emphasizing a role for refractoriness of immune cells to IFN-α as a significant mechanism of treatment failure.

Finally, this study underscores the importance of thorough interdisciplinary baseline evaluation, frequent monitoring for adverse events, and prompt intervention, whenever symptoms threaten study completion. It also highlights the need for development of in vitro testing to predict and evaluate in vivo response to IFN-α. Such information would be prognostically informative and potentially invaluable in identifying virologic responders who need more frequent monitoring and supportive care during their long course of required therapy. Given the low rate of SVR and lack of new treatment options available now to cure HCV among HIV-coinfected patients, such an approach informed by clinical science is important to optimize therapeutic response in this population.

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Keywords:

adverse events; HCV; HIV; Peg-interferon alpha; psychiatric toxicity

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