The Supplementation of Acetyl- l -Carnitine Decreases Fatigue and Increases Quality of Life in Patients with Hepatitis C Treated with Pegylated Interferon-α 2b Plus Ribavirin

Abstract

The aim of this study was to evaluate whether supplementation of acetyl-l-carnitine (ALC) to pegylated-interferon-α 2b (Peg-IFN-α 2b) and ribavirin (RBV) improves the health-related quality of life during the treatment for chronic hepatitis C, thereby decreasing the risk of treatment discontinuation. Sixty patients with chronic hepatitis C underwent treatment with Peg-IFN-α 2b + RBV (group A; n=29) or Peg-IFN-α 2b + RBV + ALC (group B; n=31) for 12 months. At the end of the study, the comparison between group A and group B showed significant differences in aspartate aminotransferase (AST) (−80.9 versus −110.3; P<0.001), alanine aminotransferase (−111.6 versus −134.7; P<0.001), Viremia (−3.26 versus −3.82; P<0.05), mental health (0 versus 11; P<0.001), physical functioning (−1 versus 8; P<0.001), role-physical (1 versus 13; P<0.001), bodily pain (1 versus 12; P<0.001), general health (3 versus 12; P<0.001), vitality (3 versus 13; P<0.001), social functioning (3 versus 10; P<0.001), physical fatigue (2.1 versus −5.4; P<0.001), mental fatigue (−0.7 versus −2.7; P<0.001), and fatigue severity scale (−3.4 versus −12; P<0.001). ALC supplementation reduced both mental and physical fatigue, improved health-related quality of life, and, therefore, has the potential to increase patient adherence to the combination regimen. This, in turn, may increase the percentage of patients achieving a sustained virological response.

Introduction

H epatitis C (HCV) is the most prevalent viral liver disease in Western countries. It has been estimated that chronic HCV infection is responsible for ∼250,000–350,000 deaths per year (Chevaliez and Pawlotsky 2007). Approximately 100 million people worldwide are infected with HCV. Of these, nearly 70% have chronic hepatitis, and 15%–20% develop cirrhosis (Tripi and others 2003). The current standard in HCV treatment consists of combination regimens of pegylated interferon-α (Peg-INF-α) with ribavirin (RBV) (Montalto and others 1998a). Such treatment schemes are quite successful in patients with HCV genotypes 2 and 3 infection achieving HCV eradication rates of 75%–80%. However, they are much less effective in patients with genotype 1 infection with eradication rates ranging between 45% and 52% (Manns and others 2001; Hadziyannis and Koskinas 2004). Multiple studies have revealed that infection with HCV and IFN treatment significantly reduces quality of life, even in the absence of cirrhosis (Malaguarnera and others 1995; Bonkovsky and Woolley 1999; Foster 1999). Previous studies on HCV therapy have shown that such declines in health-related quality of life (HRQL) increase the risk of treatment discontinuation (Malaguarnera and others 2008b). In the patients treated with IFN plus RBV, various studies showed increased incidence and severity of fatigue and mood changes that interfere with physical and emotional well-being, work productivity, and activities of daily living (Bonkovsky and Woolley 1999; Foster 1999; Ware and others 1999). These changes in HRQL might adversely affect adherence and result in discontinuation of treatment (Di Fazio and others 2004). Therefore, the need for improvement of existing therapies and for development of new effective, safe, and tolerable drugs is a matter of great clinical relevance and importance (Malaguarnera and others 2001; Blonsky and Harrison 2008). Acetyl-l-carnitine (ALC) treatment has been reported to reduce physical and mental fatigue in the elderly and improves both the cognitive status and physical functions (Malaguarnera and others 2008a). ALC is an endogenous molecule synthesized in mitochondria by the enzyme ALC-transferase and is the predominant acylcarnitine in normal tissues. It is involved in the uptake of long-chain fatty acids into mitochondria and their β-oxidation. ALC mobilizes acetyl groups, stimulates phospholipids synthesis, increases acetylcoenzyme A and choline uptake and acetylcholine release. Therefore, ALC enhances oxidative energy metabolism and adenosine triphosphate production and counteracts oxidative and nitrosative stresses and apoptosis (Di Marzio and others 1999). The aim of the present study was to evaluate whether supplementation of ALC to Peg-IFN-α and RBV improves the quality of life during the treatment for chronic hepatitis C (CHC).

Materials and Methods

Study design

This 12 month, randomized, placebo-controlled trial was performed in accordance with the principles of the World Medical Association Declaration of Helsinki (1997) and was approved by the local Ethics Committee. It was conducted in the Department of Internal Medicine of Cannizzaro Hospital, University of Catania, Catania, Italy. All the patients provided written informed consent before participating in the study. Eligible patients were randomly assigned to 1 of the 2 study treatments in equal proportions by means of a computer-generated table of random numbers allocated in our central unit. They were divided into 2 groups (A and B), and they were stratified by HCV genotype (1 versus others) and viral load (≤600,000 versus >600,000 IU/mL). Group A received Peg-IFN-α 2b at dose 1.5 μg/kg per week plus daily oral RBV. The dose of RBV was adjusted to body weight: 800 mg for body weight below 60 kg, 1,000 mg when it was between 60 and 75 kg, and 1,200 mg when it was above 75 kg. Group B received Peg-IFN-α 2b and RBV at the same dosage, way, and duration plus ALC supplied in vials with 2 g ALC taken orally twice a day. Patients were evaluated before treatment, 6 and 12 months after the initiation of the therapy. A follow-up evaluation was performed 6 months after the end of the planned treatment. A medical interview and a physical examination were realized for all patients included in the study before starting therapy.

Patients

Between January 2003 and August 2007, a total of 60 patients with chronic hepatitis (29 women and 31 men) were consecutively enrolled in the study (Table 1). The patients underwent treatment with Peg-IFN-α 2b + RBV (group A; n=29) or Peg-IFN-α 2b + RBV + ALC (group B; n=31) for 12 months. All patients had to fulfill the following inclusion criteria: alanine aminotransferase (ALT) levels >1.5-fold higher than the upper limit of normal, the presence of anti-HCV antibodies in the serum, the HCV-RNA >1,000 copies/mL, and histological modifications in the liver biopsy. Exclusion criteria were positivity tests for serum hepatitis B surface antigen, positive test for serum HIV antibodies, negativity for HCV antibodies, alcoholic liver disease (daily alcohol consumptions >20 g/day), and diabetes. The presence of other causes of hepatopathy, decompensated cirrhosis, pregnancy, and formally known contraindications for Peg-IFN-α or RBV therapy such as hemoglobinopathies, cardiopathy, hemocromatosis, diabetes mellitus, autoimmune diseases, major depression or other severe psychiatric pathological conditions, every active illicit treatment, and any drug that might influence serum lipid levels within the last 12 months were considered causes for ruling out. Patients undergoing treatment were prospectively asked to complete questionnaires before, during, and after treatment and follow up. Patients were excluded from the questionnaire protocol if they were not able to read or speak Italian. Patients were prospectively enrolled in the trial examining health status [quantified by the Short Form (SF)-36] before, during, and after Peg-IFN-α + RBV + ALC treatment or Peg-IFN-α + RBV treatment.

Table 1.

Characteristics of the Subjects Included in the Study (Mean±Standard Deviation)

	Group A Peg-IFN-α + RBV (n=29)	Group B Peg-IFN-α + RBV + ALC (n=31)
Mean age (years)	44.6±5.1	46.2±5.2
Sex (M/F)	15/14	16/15
HCV exposure time (years)	6.22±3.8	6.46±3.6
BMI (kg/m²)	26.2±3.4	26.5±3.2
Route of transmission of HCV
Blood transfusion	9	13
Intravenous drug abuse	7	6
Occupational	1	2
Unknown	12	10
HCV genotype
1a	1	1
1b	24	25
2a	1	1
3a	3	4

There were not significant differences between groups.

ALC, acetyl-l-carnitine; BMI, body mass index; HCV, hepatitis C; Peg-IFN-α, pegylated-interferon-α 2b; RBV, ribavirin.

Laboratory

A complete routine chemistry including red cell count, hemoglobin, white cell count, platelets prothrombin time, fasting plasma glucose, insulin, C-reactive protein, blood urea nitrogen, serum creatinine, bilirubin, ALT, aspartate aminotransferase, alkaline phosphatase, γ-glutamil transpeptidase, and creatin phosphokinase levels was performed at every medical visit.

Virological findings

Anti-HCV antibodies were evaluated by using second-generation enzyme-linked immunosorbent assay (Ortho-Diagnostic Systems, Raritan, NJ), and positive samples were confirmed by immunoblotting (recombinant immunoblot assay [RIBA]; Chiron Corporation, Emeryville, CA). For hepatitis B virus serological markers, we used kits (Abbott Laboratories, Chicago, IL). The presence of antibodies (antinuclear, antimitochondrial, antismooth muscle, and anti-liver-kidney-microsome) was evaluated by indirect immunofluorescence. Serum HCV RNA levels have been measured by standardized quantitative polymerase chain reaction (PCR) assay with a lower limit of detection of <1,000 copies/mL, using the Amplicor quantitative PCR system (Roche Diagnostic System Inc., Branchburg, NJ). Serum samples negative for HCV RNA were re-tested using a more sensitive standardized qualitative PCR assay with a lower limit of detection of about 100 copies/mL to confirm HCV-RNA disappearance. HCV genotypes and subtypes were identified through a modification of the specific line probe assay (Inno-LiPAsystem; Innogenetics NV, Zwijnaarde, Belgium) as described by Stuyver and others (1996). Briefly, primers complementary to the conserved sequences of the 5 untranslated region of the different HCV genotypes were used in the reverse transcription-PCR. HCV RNA were extracted from patients' sera and amplified by reverse transcription-PCR with the incorporation of biotinylated deoxyuridine triphosphate. Oligonucleotide probes (16-mers) that were specific for the different HCV genotypes and subtypes were hybridized with the patient's amplified viral complementary DNA. Hybridization was detected with alkaline phosphatase-labeled streptavidin and nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate chromagens. The HCV genotypes were designated according to the nomenclature proposed by Simmonds and others (1994).

Histology

Liver biopsy was realized 6 months before the initiation of therapy and 6 months after the end of treatment. It was obtained using a modified Menghini technique. The specimen was fixed in neutral formaldehyde 4% solution for routine histological processing and evaluation. The Knodell and Ishak Histological activity index (HAI) score was used to assess the histological grading of the disease (Knodell and others 1981).

Short Form-36

The self-administered version of the SF-36 Health Survey was included to comprehensively measure HRQL (Ware and others 1993). The SF-36 is a generic health status measure that consists of 36 items and 8 domain scales. Domain scale scores are linearly transformed into a 0 (worst health) to 100 (best health) scale. Mental component summary and physical component summary scores were also generated. The SF-36 has demonstrated good reliability and validity in chronic disease populations, including patients with CHC (Bonkovsky and Woolley 1999; Foster 1999; Bernstein and others 2002).

Fatigue assessment

Severity of fatigue

Severity of fatigue was measured by the fatigue severity scale (FSS). The FSS is a self-assessed 9 questions ranging from 1 (no signs of fatigue) to 7 (most disabling fatigue). Here, the total score ranges from 9 to 63 and is directly related to the severity observed (Krupp and others 1989).

Nature of fatigue

Wessely's test and Powell's test were used to examine fatigue, both mental and physical. The Wessely and Powell score consists of 2 scales measuring physical fatigue [8 items scored from 0 (no fatigue) to 2 (highest possible fatigue); total score range: 0–16] and mental fatigue (5 items; total score range: 0–10) (Wessely and Powell 1989).

Efficacy and safety assessment

All enrolled patients were included in the intention-to-treat efficacy analysis, and patients who received at least one dose of IFN-α plus RBV were included in the safety analysis. Data were analyzed by an “intention to treat” principle. We considered patients as “sustained virological responders” (SVR) when they showed a nondetectable HCV RNA (<50 IU/mL) in serum at the end of the follow-up period. Relapse was defined as undetectable HCV-RNA levels at the end of treatment but detectable levels during the follow-up period. Adverse events were assessed by interviews, laboratory, and clinical examinations during treatment. They were graded as mild, moderate, and severe on the basis of World Health Organization score. The treatment was definitively stopped in the case of severe events, such as hematological toxicity, hepatic failure, and no compliance. In moderate and mild cases of adverse effects, a dose reduction of 50% was performed, until the resolution of the event when a full dose was restarted.

Statistical analysis

Results are expressed as means±standard deviations. Comparisons of quantitative data were made using the Student's t-test or Mann–Whitney test. Qualitative data were analyzed using the chi-square test. A P value of <0.05 was considered as indicating a statistically significant difference. All data management and statistical calculations were performed using SPSS 15.0 statistical package (Chicago, IL).

Results

Baseline characteristics

Baseline demographics characteristics and histological findings in liver biopsy were similar between the 2 treatment groups. The mean time since their CHC infection was comparable. The most frequent viral genotype in patients was 1b. Baseline viremia was parallel in the 2 groups. No significant differences were assessed between the 2 groups for ALT, AST, body mass index, HRQL, and fatigue score (Table 1).

Laboratory parameters

Effects of Peg-IFN-α plus RBV

In the group treated with Peg-IFN-α plus RBV, we observed a significant decrease in AST (P<0.001) and ALT (P<0.001) after 6, 12 months, and at follow up. Viremia was significantly reduced after 6 months (P<0.05), 12 months (P<0.001), and at follow up (P<0.001) (Table 2).

Table 2.

Laboratory Parameters of Subjects Included in the Study (Mean±Standard Deviation)

	Group A Peg-IFN-α + RBV (n=29)				Group B Peg-IFN-α + RBV + ALC (n=31)
	Baseline	After 6 months	After 12 months	Follow up	Baseline	After 6 months	After 12 months	Follow up
AST (IU/L)	131±40.2	78.1±35.4^a A	50.1±15.2^a B	61.2±14.2^a C	141.2±41.8	67.2±30.1^a A	30.8±14.2^a B	51.8±14.2^a C
ALT (IU/L)	168±41.8	81.2±39.2^a A	56.4±13.7^a B	51.4±19.7^a A	178.2±44.2	77.2±37.1^a A	43.4±13.7^a B	55.1±19.2^a A
Bilirubin (mM)	10.1±9.1	10.8±9.2^b A	10.1±7.0^b A	10.4±7.2^b A	10.3±7.0	10.4±6.1^b A	10.0±5.8^b A	10.2±5.6^b A
Albumin (g/dL)	4.3±0.8	4.1±0.9^b A	4.0±0.8^b A	4.2±0.9^b A	4.2±0.7	4.0±1.6^b A	4.1±0.6^b A	4.2±0.9^b A
Viremia (10⁶ copies/mL)	5.44±3.6	3.62±2.1^c A	2.18±1.2^a C	2.08±1.7^a A	5.43±3.08	2.44±2.^a A	1.6±1.0^a C	1.9±1.2^a A
HAI score	10.2±2.9	—	8.7±2.9^c A	—	10.4±3.1	—	7.9±2.6^a A	—

Comparison within group A and within group B according to the values before the treatment.

P<0.001; ^b P=NS; ^c P<0.05.

Comparison between groups A and B after treatment.

NS; ^B P<0.001; ^C P<0.05.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NS, not significant.

Effects of Peg-IFN-α plus RBV plus ALC

After 6, 12 months, and at follow up in the group treated with Peg-IFN-α plus RBV plus ALC, we observed a significant decrease in AST (P<0.001), ALT (P<0.001), and viremia (P<0.001) (Table 2).

Comparison between treatments

The comparison between group A (treated with Peg-IFN-α plus RBV) and group B (treated with Peg-IFN-α plus RBV plus ALC) showed a significant difference after 12 months in AST (−80.9 versus −110.3; P<0.001), ALT (−111.6 versus −134.7; P<0.001), and viremia (−3.26 versus −3.82; P<0.05). At follow up, we observed a significant difference in AST (−69.8 versus −89.3; P<0.05) (Table 2).

Quality of life

Effects of Peg-IFN-α plus RBV

In the group treated with Peg-IFN-α plus RBV, there was a significant increase in physical fatigue after 6 months (P<0.05), 12 months (P<0.001), and at follow up (P<0.05) (Table 3).

Table 3.

Comparison of Evaluated Parameters Within Groups and Between Groups (Mean±Standard Deviation)

	Group A Peg IFN-α + RBV (n=29)				Group B Peg IFN-α + RBV + ALC (n=31)
	Baseline	After 6 months	After 12 months	Follow up	Baseline	After 6 months	After 12 months	Follow up
Mental health	69±6	68±7^a A	69±9^a B	69±11^a A	67±7	70±8^a A	78±8^b B	70±7^a A
Role-emotional	70±5	69±6^a A	70±6^a A	70±7^a A	69±6	71±7^a A	73±7^c A	70±6^a A
Physical functioning	77±9	75±8^a C	76±9^a B	78±9^a A	76±5	79±6^c C	84±8^b B	80±7^c A
Role-physical	76±8	75±7^a A	77±8^a B	76±9^a A	75±9	78±10^a A	88±8^b B	80±8^c A
Bodily pain	58±7	57±8^a A	59±5^a B	58±6^a A	56±8	60±9^a A	68±7^b B	61±7^c A
General health	56±8	55±8^a C	58±4^a B	57±9^a A	54±7	61±7^c C	66±6^b B	60±6^c A
Vitality	55±9	56±10^a A	58±6^a B	56±9^a A	53±8	55±8^a A	66±9^b B	58±9^c A
Social functioning	75±7	76±8^a A	78±9^a B	77±7^a A	76±6	77±9^a A	86±9^b B	78±7^a A
Physical fatigue	11.0±1.9	12.2±2.1^c C	13.1±1.9^b B	12.4±2.6^c C	11.4±2	9.6±2.1^b B	6.0±2.7^b B	10.8±2.4^a C
Mental fatigue	6.4±1.5	5.9±1.6^a A	5.7±1.8^a B	6.0±1.6^a A	6.8±1.7	5.0±1.9^b A	4.1±1.6^b B	5.4±1.8^c A
Fatigue severity scale	47.6±7.2	46.4±7.8^a C	44.2±7.1^a B	45.9±7.4^a C	48.2±6.9	41.8±6.2^b C	36.2±6.1^b B	40.2±6.4^b C

Comparison within group A and within group B according to the values before the treatment.

P=NS; ^b P<0.001; ^c P<0.05.

Comparison between groups A and B after treatment.

NS ; ^B P<0.001; ^C P<0.05.

Effects of Peg-IFN-α plus RBV plus ALC

After 6 months in the group treated with Peg-IFN-α plus RBV plus ALC, we observed a significant increase in physical functioning (P<0.05) and general health (P<0.05). After 12 months, there was a significant increase in mental health (P<0.001), role-emotional (P<0.05), physical functioning (P<0.001), role-physical (P<0.001), bodily pain (P<0.001), general health (P<0.001), vitality (P<0.001), and social functioning (P<0.001). At follow up, we observed an increase in physical functioning (P<0.05), role-physical (P<0.05), bodily pain (P<0.05), general health (P<0.05), and vitality (P<0.05) (Table 3).

Comparison between treatments

In the comparison between group A (treated with Peg-IFN-α plus RBV) and group B (treated with Peg-IFN-α plus RBV plus ALC), we observed a significant difference after 6 months in physical functioning (2 versus 3; P<0.05) and general health (1 versus 7; P<0.05). After 12 months, we observed a significant difference in mental health (0 versus 11; P<0.001), physical functioning (−1 versus 8; P<0.001), role-physical (1 versus 13; P<0.001), bodily pain (1 versus 12; P<0.001), general health (3 versus 12; P<0.001), vitality (3 versus 13; P<0.001), and social functioning (3 versus 10; P<0.001) (Table 3).

Fatigue

Effects of Peg-IFN-α plus RBV

In the Peg-IFN-α plus RBV group, we observed a significant increase in physical fatigue after 6 months (P<0.05), 12 months (P<0.001), and at follow up (P<0.05) (Table 3).

Effects of Peg-IFN-α plus RBV plus ALC

After 6 and 12 months in the group treated with Peg-IFN-α plus RBV plus ALC, we observed a significant decrease in physical fatigue (P<0.001), mental fatigue (P<0.001), and FSS (P<0.001). At follow up, we observed significant differences in mental fatigue (P<0.05) and FSS (P<0.001) (Table 3).

Comparison between treatments

In the comparison between group A (treated with Peg-IFN-α plus RBV) and group B (treated with Peg-IFN-α plus RBV plus ALC), we observed a significant difference after 6 months in physical fatigue (1.2 versus −1.8; P<0.001) and FSS (−1.2 versus −6.4; P<0.05). After 12 months, we observed a significant difference in physical fatigue (2.1 versus −5.4; P<0.001), mental fatigue (−0.7 versus −2.7; P<0.001), and FSS (−3.4 versus −12; P<0.001). At follow up, there were significant differences in physical fatigue (1.4 versus −0.6; P<0.001) and FSS (−1.7 versus −8; P<0.001) (Table 3).

Virological response

In the comparison between group A (treated with Peg-IFN-α plus RBV) and group B (treated with Peg-IFN-α plus RBV plus ALC) after 12 months, we observed a significant improvement of SVR in 10 versus 15 patients (34% versus 48%), whereas the relapsers were 4 versus 3 (13% versus 9%) (odds ratio 0.5; 95% confidence interval=0.09–2.72). The responders were 14 versus 18 (48% versus 58%), and the nonresponders were 15 versus 13 (51% versus 41%) (odds ratio 0.6; 95% confidence interval=0.2–1.86) (Table 4).

Table 4.

Virological Response of the Subjects Included in the Study

	Group A Peg-IFN-α + RBV (n=29)	Group B Peg-IFN-α + RBV + ALC (n=31)
SVR	10	15
ETR	14	18
NR	15	13

SVR, sustained virological response; ETR, end of treatment response; NR, nonresponders.

Histological response

Effects of Peg-IFN-α plus RBV

In the Peg-IFN-α plus RBV group, we observed a significant decrease in HAI score after 12 months (P<0.05) (Table 2).

Effects of Peg-IFN-α plus RBV plus ALC

After 6 and 12 months in the group treated with Peg-IFN-α plus RBV plus ALC, we observed a significant decrease in HAI score (P<0.001) (Table 2).

Adverse events

No serious adverse events (World Health Organization grade 3 or 4) have been reported in the 2 groups. Six patients of the Peg-IFN plus RBV-treated group and 2 of the group treated with ALC supplementation showed mild psychological disorders such as anxiety, irritability, and depression. Median hemoglobin concentration significantly fell during the first 3 months of treatment in both groups, remaining stable for 3 months, and returning to values similar to the baseline within 3 months after the end of the treatment. Noteworthy, a higher decrease of hemoglobin values was observed in the Peg-IFN plus RBV alone treatment. The patients treated with Peg-IFN plus RBV experienced a fall in median hemoglobin concentration from 12.1 g/dL (range 10.7–13.0 g/dL) to 11.0 (range 10.4–13.0 g/dL) at the end of therapy. The patients treated with Peg-IFN plus RBV plus ALC experienced a fall in median hemoglobin concentration from 13.0 g/dL (range 11.4–15.1) to 11.4 g/dL (range 10.6–13.8 g/dL) at the end of therapy. The Peg-IFN plus RBV showed a significant decrease in the white cell blood count. The platelet counts did not significantly change in both groups. Further, other side effects registered in both groups were anorexia (12% in IFN plus RBV plus patients with ALC and 16% in IFN group plus RBV), nausea (20% and 24%, respectively), weight loss (5% versus 12%), headache (40% versus 48%), myalgia (30% versus 55%), musculoskeletal pain (27% versus 42%), irritability (18% versus 22%), hypertriglyceridemia (16% versus 34%), hypercholesterolemia (8% and 24%), and hyperglycemia (3% and 13%). Ten patients of Peg-IFN plus RBV-treated group discontinued treatment (2 patients after 8 months, 1 patient after 9 months, and 1 patient after 10 months for fatigue; 2 patients after 8 months, 4 patients after 9 months, and 2 patients after 10 months for decreased HRQL). Two patients of the group treated with ALC supplementation discontinued treatment (1 patient after 9 months for fatigue and 1 patient after 10 months for decreased HRQL).

Discussion

The effective management of chronic HCV infection is very important. The goal of treatment for chronic HCV infection is sustained virological response (SVR) accompanied by improvement of liver damages (Montalto and others 1998b). The results of our study indicated that patients with sustained response have an improvement in HRQL and a reduction in severity of mental and physical fatigue. Potential benefits of SVR would be decreased infectivity, prevention of liver damage, and improvement of the necro-inflammatory process. In the long run, SVR may decrease the risk of developing cirrhosis, decompensation, and HCC, along with prolonged survival and improved quality of life (Malaguarnera and others 1998; Neri and others 2003). However, the treatment with IFN-α, in all its formulations, provokes adverse effects including depression, anxiety, irritability, muscle aches, fatigue, and sleep disturbances (Dieperink and others 2000). Bonaccorso and others (2002) reported that IFN-α therapy in patients with HCV led to a decrease of plasma tryptophan and serotonin, increase of kynurenine, and also of depressive symptoms. Previous studies showed that ALC decreases the severity of physical and mental fatigue and improves the quality of life (Neri and others 2003; Pistone and others 2003; Malaguarnera and others 2006). ALC mobilizes acetyl groups, stimulates phospholipid synthesis, and increases acetyl-coenzyme A and choline uptake and acetylcholine release (Imperato and others 1989). It is also involved in the synthesis of glutamate; in fact, the acetyl moiety of ALC is metabolized mainly to glutamate, but also, glutamine, aspartate, and gamma-aminobutyric acid by way of the tricarboxylic acid cycle. Studies about the role of ALC in the aged rats' brain demonstrated that in the brain regions with lower amino acid levels, the release of neurotransmitter amino acids is below normal and ALC produces an increase in the extracellular level of neurotransmitter glutamate. On the other hand, ALC decreases glutamate dehydrogenase activity in the intrasynaptic mitochondria of the rat brain, suggesting that ALC interferes with glutamate metabolism. The increase of glutamate, caused by the elevated plasma ALC levels, also determines a protection against excitotoxic cell death. This is possible through the direct antagonism of glutamate receptors and the activation of gamma-aminobutyric acid receptors that cause neuronal hyperpolarization and, therefore, resistance to NMDA receptor activation, or to inhibition of secondary events. These secondary events could include activation of the mitochondrial permeability transition that can cause release of mitochondrial cytochrome c and stimulation reactive oxygen species production. The improvement of energetic metabolism in myocardial tissue and in muscular-skeletal tissue is probably the factor that reduces the presence and the severity of physical fatigue in subjects treated with ALC (Tomassini and others 2004). When ALC was administered to the elderly with lean body mass reduction, an increase of muscular mass up to 3-fold was observed, with resulting amelioration of muscular power and activity (Pistone and others 2003). Previous studies have shown that both fatigue and decreased HRQL are reasons often cited by patients for the discontinuation of combination therapy (Bernstein and others 2002; Fried and others 2002; Gaeta and others 2002). In this study, ALC supplementation reduced both mental and physical fatigue, improved HRQL and, therefore, has the potential to increase patient adherence to the combination regimen. This, in turn, may increase the percentage of patients achieving a SVR. Adherence to RBV therapy, in particular, has been shown to significantly impact SVR. Recent data suggest that the reduction of RBV dose alone during the first 12–20 weeks of treatment results in a significant decrease in SVR rates in a retreated population (Shiffman 2004). Although the results of this study do not indicate that ALC improves SVR, they clearly provide support for additional studies with adequate sample size to determine whether adjuvant ALC therapy is associated with a statistically significant improvement in SVR. This study demonstrated the significant beneficial effect of oral ALC added to IFN-α and RBV in lipid metabolism, in inflammation markers, and in steatosis and fibrosis The results keep them up after 12 months and at the follow-up visit; indeed, patients with HCV quite well tolerated ALC therapy. The limitation of our study includes the relatively small sample size and its open label design. A further weakness of the study is that no subanalysis has been performed for different HCV genotypes but it was because of the prevalence of genotype 1. This study shows that the supplementation with ALC is associated with significant improvements in patient energy levels, physical function, and mental status, as reported on HRQL instruments. Confirmation of these findings is important, because they imply that the decreased quality of life associated with HCV treatment can be improved with successful therapy.

Footnotes

Acknowledgment

This clinical trial was supported by a grant from Ministero dell'Università e Ricerca Scientifica e Tecnologica.

Author Disclosure Statement

No competing financial interests exist.

References

Bernstein

, Kleinman

, Barker

, Revicki

, Green

. 2002. Relationship of health related quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology, 35:704–708.

Blonsky

, Harrison

. 2008. Review article: nonalcoholic fatty liver disease and hepatitis C virus-partners in crime. Aliment Pharmacol Ther, 27:855–865.

Bonaccorso

, Marino

, Biondi

, Grimaldi

, Ippoliti

, Maes

. 2002. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord, 72:237–241.

Bonkovsky

, Woolley

. 1999. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology, 29:264–270.

Chevaliez

, Pawlotsky

. 2007. Interferon-based therapy of hepatitis C. Adv Drug Deliv Rev, 59:1222–1241.

Dieperink

, Willenbring

, Ho

. 2000. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry, 157:867–76.

Di Fazio

, Motta

, Musumeci

, Neri

, Pistone

, Malaguarnera

. 2004. Efficacy of human recombinant erythropoietin plus IFN-alpha in patients affected by chronic hepatitis C. J Interferon Cytokine Res, 24:594–599.

Di Marzio

, Moretti

, D'Alò

, Zazzeroni

, Marcellini

, Smacchia

, Alesse

, Cifone

, De Simone

. 1999. Acetyl-L-carnitine administration increases insulin-like growth factor 1 levels in asymptomatic HIV-1-infected subjects: correlation with its suppressive effect on lymphocyte apoptosis and ceramide generation. Clin Immunol, 92:103–110.

Foster

. 1999. Hepatitis C virus infection: quality of life and side effects of treatment. J Hepatol, 31,Suppl. 1:250–254.

10.

Fried

, Shiffman

, Reddy

, Smith

, Marino

, Goncales

, and others.2002. Pegylated interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med, 347:975–982.

11.

Gaeta

, Precone

, Felaco

, Bruno

, Spadaro

, Stornaiuolo

, Stanzione

, Ascione

, De Sena

, Campanone

, Filice

, Piccinino

. 2002. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in “real world” patients with chronic hepatitis C. Aliment Pharmacol Ther, 16:1633–1639.

12.

Hadziyannis

, Koskinas

. 2004. Differences in epidemiology, liver disease and treatment response among HCV genotypes. Hepatol Res, 29:129–135.

13.

Imperato

, Ramacci

, Angelucci

. 1989. Acetyl-L-carnitine enhances acetylcholine release in the striatum and hippocampus of awake freely moving rats. Neurosci Lett., 107:251–255.

14.

Knodell

, Ishak

, Black

. 1981. Formulation and application of numerical scoring system for assessing histological activity in a-symptomatic chronic active hepatitis. Hepatology, 1:431–435.

15.

Krupp

, LaRocca

, Muir-Nash

, Steinberg

. 1989. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol, 46:1121–1123.

16.

Malaguarnera

, Di Fazio

, Restuccia

, Pistone

, Ferlito

, Rampello

. 1998. Interferon alpha-induced depression in chronic hepatitis C patients: comparison between different types of interferon alpha. Neuropsychobiology, 37:93–97.

17.

Malaguarnera

, Di Mauro

, Gargante

, Rampello

. 2006. L-carnitine reduces severity of physical and mental fatigue and improves daily activities in the elderly. South Med J, 99:315–316.

18.

Malaguarnera

, Gargante

, Cristaldi

, Colonna

, Messano

, Koverech

, Neri

, Vacante

, Cammalleri

, Motta

. 2008a. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr., 46:181–90.

19.

Malaguarnera

, Laurino

, Di Fazio

, Pistone

, Castorina

, Guccione

, Rampello

. 2001. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res, 21:273–278.

20.

Malaguarnera

, Restuccia

, Trovato

, Siciliano

, Motta

, Trovato

. 1995. Interferon-a treatment in patients with chronic hepatitis C: a meta-analytic evaluation. Clin Drug Invest, 9:141–149.

21.

Malaguarnera

, Vicari

, Calogero

, Cammalleri

, Di Fazio

, Gargante

, Pennisi

, Risino

, Ranno

, Rampello

. 2008b. Sexual dysfunction in chronic hepatitis C virus patients treated with interferon alpha and ribavirin. J Interferon Cytokine Res, 28:603–609.

22.

Manns

, McHutchison

, Gordon

, Rustgi

, Shiffman

, Reindollar

, Goodman

, Koury

, Ling

, Albrecht

. 2001. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet, 358:958–965.

23.

Montalto

, Soresi

, Carroccio

, Anastasi

, Campagna

, Vasile

, Di Prima

, Cartabellotta

, Giannitrapani

, Fulco

. 1998a. Comparative responses to three different types of interferon-alpha in patients with chronic hepatitis C. Curr Med Res Opin, 14:235–241.

24.

Montalto

, Tripi

, Cartabellotta

, Fulco

, Soresi

, Di Gaetano

, Carroccio

, Levrero

. 1998b. Intravenous natural beta-interferon in white patients with chronic hepatitis C who are nonresponders to alpha-interferon. Am J Gastroenterol, 93:950–953.

25.

Neri

, Pistone

, Saraceno

, Pennisi

, Luca

, Malaguarnera

. 2003. L-carnitine decreases severity and type of fatigue induced by interferon-alpha in the treatment of patients with hepatitis C. Neuropsychobiology, 47:94–97.

26.

Pistone

, Marino

, Leotta

, Dell'Arte

, Finocchiaro

, Malaguarnera

. 2003. Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging, 20:761–767.

27.

Shiffman

. 2004. Retreatment of chronic hepatitis C virus infection in patients who failed to achieve sustained virologic response. Minerva Gastroenterol Dietol, 50:37–49.

28.

Simmonds

, Alberti

, Halter

, Bonino

, Bradley

, Brechot

, Brouwer

. 1994. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology, 19:1321–1324.

29.

Stuyver

, Wyseur

, van Arnhem

, Hernandez

, Maertens

. 1996. Second-generation line probe assay for hepatitis C virus genotyping. J Clin Microbiol, 34:2259–2266.

30.

Tomassini

, Pozzilli

, Onesti

, Pasqualetti

, Marinelli

, Pisani

, Fieschi

. 2004. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci, 218:103–108.

31.

Tripi

, Soresi

, Di Gaetano

, Carroccio

, Giannitrapani

, Vuturo

, Di Giovanni

, Montalto

. 2003. Leucocyte interferon-alpha for patients with chronic hepatitis C intolerant to other alpha-interferons. BioDrugs, 17:201–205.

32.

Ware

, Kosinski

, Snow

, Gandek

. 1993. SF-36 Health Survey: manual and interpretation guide. The Health Institute, New England Medical Center: Boston, MA.

33.

Ware

Jr. , Bayliss

, Mannocchia

, Davis

. 1999. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. The Interventional Therapy Group. Hepatology, 30:550–555.

34.

Wessely

, Powell

. 1989. Fatigue syndromes: a comparison of chronic postviral fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry, 52:940–948.

35.

World Medical Association Declaration of Helsinki. 1997. Recommendations guiding physicians in biomedical research involving human subjects. JAMA, 277:925–926.