Abstract
Fatigue is prevalent among patients with hepatitis C virus (HCV) and with HIV/AIDS but there are no established fatigue treatments for either condition or their combination. We analysed data from three trials of modafinil or armodafinil for HIV-positive patients with fatigue, including 36 co-infected with HCV, to compare treatment response and safety parameters related to HCV status. One hundred and twenty patients received active drug and 70 were randomized to placebo. Fatigue response rate to modafinil/armodafinil was 100% for patients with HCV (18/18) and 73% (74/102) for patients without HCV. Placebo response rate was 28% (5/18) and 29% (15/52), respectively. Depressive symptoms improved only when energy improved. Viral load declined from baseline after 12 and 26 weeks of active medication. CD4 cell count did not change, nor did alanine transaminase and aspartate aminotransferase for patients with HCV. Patients with haematocrit below the reference range responded, as well as patients whose values were within the reference range. Modafinil and armodafinil appear effective and well tolerated for treating fatigue among both HCV-positive and HCV-negative patients with HIV/AIDS, suggesting that they may hold promise for HIV-positive patients considering alpha interferon/ribavirin treatment for HCV. Further investigation in a focused trial is warranted.
INTRODUCTION
Fatigue is common among patients with HIV/AIDS, with estimated rates clustering around 50%, depending on the sample and method of elicitation. 1–4 Fatigue is also characteristic of chronic hepatitis C virus (HCV) infection, 5 with reported prevalence rates from 45–67% in recent studies. 6–9 Co-morbidity can exacerbate fatigue prevalence and severity. 10 While some subgroups have lower rates, about 25–40% of patients with HIV/AIDS are co-infected with HCV, with higher prevalence among injecting drug users. 11,12 When either or both HIV and HCV are present, fatigue can be debilitating and severe.
Fatigue is generally defined as a condition of low energy, tiredness and lack of stamina, often with daytime sleepiness. It occurs in the absence of physical exertion, is not relieved by adequate night-time sleep and negatively affects goal attainment and quality of life. It is distinguished from apathy, which is a lack of desire to act, and hypersomnia, which is defined as increased sleep time.
Fatigue has multiple and overlapping aetiologies. Causes for patients with either HIV or HCV may include concurrent conditions such as anaemia, hypothyroidism, hypogonadism or chronic insomnia. In addition, medications including some antiretrovirals for HIV, some antidepressants and some pain medications may cause or exacerbate fatigue. In neither condition is degree of disease progression a reliable predictor of fatigue. 13–19 In their comprehensive literature review, Jong et al. 20 found no consistent predictors of fatigue, either physiological or psychological, other than hypogonadism and symptoms of depression or anxiety.
Depressive symptoms and disorders are common both among patients with HCV 21 and those with HIV/AIDS, 22 and they frequently occur together. The substantial overlap between fatigue and depression in both HIV and HCV is somewhat circular, since fatigue is one of the nine criteria used to diagnose depression in DSM-IV, and is also related to poor concentration, which is another DSM-IV criterion for depression. 23 In addition, dysphoric mood may be secondary to fatigue. However, while the two conditions are associated, each may occur in the absence of the other.
Modafinil and armodafinil (its r isomer) are Schedule IV agents approved for treatment of narcolepsy, obstructive sleep apnoea and shift work-related sleep disorders. Its exact mechanism of action remains unknown. As summarized by Ballon and Feifel, 24 the mechanisms ‘are complex and distinct from other known wakefulness agents. Modulation of glutamate, GABA, histamine and hypocretin are involved, whereas effects of monoamine systems are less important. Anatomically, modafinil's effects focus on the hypothalamus-based wakefulness circuits rather than diffuse neural activation’. Modafinil-induced neuronal activation is more localized to wakefulness areas compared with amphetamine-induced neuronal activation. 25
Modafinil treatment of fatigue has been evaluated in studies of patients with neurological conditions including multiple sclerosis, 26 Parkinson's disease, 27 amyotrophic lateral sclerosis 28 and myotonic dystrophy, 29 which assessed daytime sleepiness, as well as cancer, as cited in Cooper's review, 30 with most studies finding positive effects. Modafinil was also evaluated in a case series of 42 patients with primary biliary cirrhosis; 31 74% responded. No significant side-effects were observed.
Fatigue treatment in the context of HCV has seldom been studied, and no effective treatments have been established. 18,32,33 Overall, as Seaman et al. 5 noted, ‘an effective and accepted intervention method remains elusive for patients with HCV and fatigue’. Since, according to Raison et al. 34 , ‘premorbid fatigue in patients with HCV has been reported to be a powerful predictor of the development of disabling fatigue during interferon therapy’, its treatment may increase willingness of patients to undergo such therapy.
In the HIV literature, several pharmacological agents have been shown to ameliorate fatigue, including dextroamphetamine, 35 methylphenidate, 36 pemoline 36 and testosterone. 37,38 While useful, these treatments have significant limitations regarding access and sustainability.
We report here on treatment for fatigue among patients with HIV/AIDS with or without HCV co-infection. Study eligibility required HIV-positive status; concurrent HCV was not specifically targeted but was not an exclusion criterion. The three studies employed the same measures and were combined to get enough HCV-positive patients to evaluate as a subgroup. This integrated data set represents a sample of convenience since patients were not selected for HCV.
METHODS
Sample
Data from three studies were combined. Study 1 (n = 30) was an open label pilot study of modafinil, conducted in 2003–2004. Study 2 was a placebo controlled double-blind trial of modafinil, conducted in 2004–2008 with 115 patients enrolled and 105 week 4 completers. Study 3 was a placebo controlled trial of armodafinil (the r isomer of modafinil), with 60 enrolled and 55 study completers, initiated in June 2008. The three studies had the same inclusion and exclusion criteria, shown in Box 1, with one exception: in 2008, when Cephalon issued an advisory about the risk of left ventricular hypertrophy or symptomatic mitral valve prolapse, an electrocardiogram (ECG) and cardiac history were performed and these conditions were added as exclusion criteria.
Inclusion and exclusion criteria
HIV+ and aged 18–70 years
Clinically significant fatigue (Fatigue Severity Scale score 41+, duration 3+ months)
Speaks English; able and willing to give informed consent
Primary care provider approves study participation
Fecund women using barrier methods of contraception
Unstable medical condition
Untreated hypogonadism (fT <241 ng/dL); hypothyroidism (TSH >5 IU/mL)
Untreated anaemia (haematocrit >30%); hypertension (>140/90)
Untreated or under-treated major depressive disorder
Current clinically significant suicidal ideation or Hamilton Rating Scale for Depression score >24
Initiated antidepressant medication or testosterone during past six weeks
Started or changed antiretroviral regimen in last four weeks if fatigue predated change; otherwise, change of regimen within past eight weeks
Significant untreated insomnia
History of non-substance-induced psychosis or bipolar disorder
Current/recent (past 4 months) substance use disorder
History or current psychosis, bipolar disorder
Currently taking psychostimulant medication
Left ventricular hypertrophy/mitral valve prolapse (added armodafinil trial)
Study design
All three studies conducted a four-week trial. In Studies 2 and 3, patients were randomized 1:1 to placebo or active medication. Placebo non-responders or relapsers were offered active medication at week 4. Open-label medication maintenance for two to three months of treatment was offered to responders to active drug, and three to four months for placebo non-responders or relapsers. Patients were randomly assigned in blocks of four according to a computer-generated list provided by the New York State Psychiatric Institute Research Pharmacy, which also packaged study medications. Active and placebo medication was identical in appearance; kits were assigned in order of enrollment and contained a sealed envelope with the code. (A duplicate sealed envelope was kept in a central box in the clinic in case the blind had to be broken on an emergency basis after business hours by the doctor on call.) Neither treating doctor nor patient knew which medication was being administered until the blind was broken by opening the sealed envelope in the patient's medication kit after all assessments were completed at week 4. For modafinil, starting dose was 50 mg/day, escalating by the end of week 4 to 200 mg/day in the absence of clinical response and dose limiting side-effects. For armodafinil (which has a longer half-life elimination and sustained plasma level versus racemic modafinil), starting dose of 50 mg/day could be raised to a maximum of 250 mg/day by week 4.
The protocols were approved by the New York State Psychiatric Institute Institutional Review Board, and all participants gave written informed consent after being informed of the procedures, risks and alternatives to study participation. Every patient was required to have a primary care provider who was sent information about the study and asked to state in writing that there were ‘no medical contraindications’ to their patient's participation.
Measures
Psychiatric study eligibility criteria were evaluated with the Structured Clinical Interview for DSM-IV (SCID) 39 module for depression to exclude major depressive disorders and to identify current minor depression and dysthymia, which were permitted. Screens were used to exclude patients with past or current psychotic conditions, bipolar disorder and current substance use disorders (plus urine toxicology assays at baseline and again during the trial).
Fatigue
The primary categorical endpoint was the Clinical Global Impressions-Improvement (CGI-I) Scale. 40 Scores range from 1 (very much improved) to 7 (very much worse). Responders were rated ‘1’ or ‘2’ on energy response compared with baseline; non-responders had scores of 3 (minimally improved) or worse. This global assessment is based on all available data including clinician judgment, patient self-reports and ratings. Patients were asked to answer ‘yes’ or ‘no’ to two outcome questions before the blind was broken: (1) ‘Does the medication you're taking in this study help with the problem you came here for?’ and (2) ‘Do you want to continue taking what you're taking?’ A ‘yes’ response to both was required for those considered responders.
Secondary endpoints include the Fatigue Severity Scale (FSS) and Epworth Sleepiness Scale (ESS). Nearly all modafinil trials have used the nine-item self-rated FSS, 41 which is unidimensional and measures the impact of fatigue on everyday functioning. 42 A total score of 41 or more was required for eligibility. The ESS 43 is also widely used in modafinil trials and concerns probability of dozing in various settings (0 = no chance; 3 = highly likely). Total scores are the item sum; range = 0–24.
Depression
In addition to the SCID modules for diagnosis of depressive disorders, we used the structured version of the 21-item Hamilton Rating Scale for Depression (HAM-D), 44 a clinician-rated scale to assess depressive severity, with scores in this version combining severity and frequency. The Beck Depression Inventory II (BDI) 45 is a 21-item self-report scale used to provide patient perspective on depressive symptoms. The CGI-I scale 40 was used to assess depression severity at baseline. ‘Responder’ at week 4 was defined as a CGI-I score compared with baseline of ‘much improved’ or ‘very much improved’, incorporating findings in the clinical interview, HAM-D and BDI scores.
Side-effects were measured at every study visit with a checklist modelled on SAFTEE (Systematic Assessment for Treatment Emergent Events). 46 A side-effect was considered ‘treatment emergent’ if the severity score at subsequent study visits was ≥2 points higher than at baseline (score range 1–5).
Laboratory tests
These included hematology, serum chemistry, thyroid panel (baseline only), CD4 cell subsets and HIV RNA viral load assay (detectable range, 48–1,000,000 copies), performed at study entry, after the four-week trial, after 12 weeks on active medication and at week 26 follow up. Urine toxicology screens were performed at initial evaluation and at a random study visit.
Statistical analysis
In the three studies combined, there were 16 dropouts (8%), of whom 14 had been randomized to placebo. However, because the focus of this report is the four-week treatment outcome for HIV-positive patients with and without HCV, only study completers are included except in analysis of adverse events. Treatment group outcomes were analysed with paired t-tests and repeated-measures analyses of variance and covariance. HCV-positive and HCV-negative patients were compared using χ 2 tests and t-tests for categorical and continuous variables, respectively. Following convention, log10 viral load was used. All tests were two-tailed, alpha = 0.05.
Results
Sample composition
In the integrated data set, 36 patients were co-infected with HCV and 154 patients were not, for a total sample of 190. As shown in Table 1, co-infected patients compared with mono-infected HIV-positive patients were more likely to be black (53% versus 30%), and were slightly older (aged 49 versus 46). Ninety-one percent were taking antiretrovirals.
Baseline demographic, psychiatric and medical characteristics of study patients (n = 190) and comparisons of HCV+ versus HCV− patients
MSM = men who have sex with men; HAM-D = Hamilton Rating Scale for Depression; BDI = Beck Depression Inventory II
*DSM diagnoses included: Dysthymia, Subthreshold Major Depressive Disorder (MDD), MDD in partial remission
† n = 153
‡ n = 184
Thirteen of the 36 HCV-positive patients had received HCV treatment that was completed prior to study enrollment; five patients reported ‘successful’ treatment, one recently completed treatment and sustained outcome could not yet be determined, outcome for one was not recorded, and six failed to respond to treatment.
Fatigue: week 4 treatment outcome
Response rate to modafinil or armodafinil based on CGI-I scores was 77% (92/120), and to placebo, 28.6% (χ 2 = 42.26, 1df, P < 0.001), number needed to treat (NNT) 47 = 3 (confidence interval [CI] 1.6–2.9). Eighteen co-infected patients were randomized to modafinil or armodafinil, and 18 to placebo (in Studies 2 and 3). Their response rate to active medication (100%) was significantly better than that of HIV mono-infected patients (73%; Fisher's exact test [FET] = 0.007). For the 18 HCV-positive patients randomized to placebo, there was no difference in the rate of placebo response compared with HCV-negative patients (28.8% versus 27.8%; χ 2 = 0.007, 1df, FET = 0.593).
Of the five HCV-positive patients who reported sustained virological response to treatment, two had been randomized to active medication and three to placebo. When treatment outcome was recalculated after these five patients were removed from analysis, results were unchanged. On active medication, 73% of HCV-negative patients and 100% of HCV-positive patients responded (χ 2 = 5.619, 1df, P = 0.018). On placebo, 29% of HCV-negative and 28% of HCV-positive patients responded (χ 2 = 0.212, 1df, P = 0.645).
As shown in Table 2, both measures of fatigue (FSS) and sleepiness (ESS) showed significant improvement at week 4 across the board, regardless of treatment type or HCV status. Mean FSS scores for patients on active medication fell below the threshold for ‘clinically significant’ fatigue at week 4, while mean scores for placebo patients remained slightly above this threshold, regardless of HCV status. In repeated-measures analysis of variance, there was a significant difference for treatment group on the FSS and a trend difference (P = 0.056) on the ESS. HCV status was unrelated to FSS change, but had a significant effect on the ESS: HCV-positive patients reported more sleepiness at baseline, and showed greater improvement over time. There were no significant interactions between treatment group and HCV status.
Repeated-measures Anova of Fatigue Severity Scale (FSS) and Epworth Sleepiness Scale (ESS) by treatment group and hepatitis C virus (HCV) status, and paired t-tests within groups of changes in scores from week 0 to week 4
CGI = Clinical Global Impressions
We also performed a multivariate regression analysis to determine whether baseline variables of age, AIDS status, depression score or fatigue severity (FSS score) influenced response to treatment (n = 190). Only fatigue severity was significantly and positively related to outcome of FSS score at week 4 (beta = 0.194, t = 2.59, P = 0.01).
Open-label treatment after week 4
Ten of the 18 HCV-positive patients in the placebo group subsequently initiated a four-week trial of modafinil or armodafinil. One dropped out; eight of the remaining nine (89%) were responders. Of the 52 HCV-negative placebo patients, 43 had a trial of active medication of whom 35 (81%) responded.
Treatment outcome: depression
At study entry, 47% (90/190) of the patients had a DSM-IV depression diagnosis other than current major depressive disorder, of whom 61 were randomized to active medication and 29 to placebo. CGI ratings of depression (based on clinical interview, BDI and HAM-D ratings) were used to assess change from baseline to week 4. Only patients whose depressed mood was rated ‘much improved’ or ‘very much improved’ (scores of 2 or 1) were rated depression ‘responders’. As shown in Table 3, categorical outcomes (responder versus non-responder) were the same for both fatigue and depression for 82%: either both improved or neither did. Depression improved almost exclusively when fatigue also improved.
Response rates for fatigue and depression among patients depressed at study baseline (as defined by DSM-IV diagnosis)
Within the placebo group, seven of the 29 patients were HCV-positive. Placebo response rates did not differ by HCV status: 14% (1/7) had improved mood, compared with 23% (5/22) for HCV-negative patients (χ 2 = 2.79, FET = 1.0). In the active medication group, 11 of the 61 patients were HCV-positive. Their response rate of 64% was equivalent to that the 68% response of HCV-negative patients (χ 2= 0.078, FET = 1.0).
Looking at depression scale scores, as shown in Table 4, a more nuanced picture emerges. Scores on both the BDI and HAM-D improved over time for patients on either active medication or placebo. In repeated-measures analysis of covariance (covarying for fatigue) to examine the interaction of HCV status by treatment group for HAM-D scores, FSS scores at week 0 were marginally significant as a covariate, whereas the week 4 scores were significant. For the BDI, the FSS scores at both weeks 0 and 4 were significant as covariates. When controlling for fatigue, change in depression scores did not vary by HCV status.
Repeated-measures analysis of covariance of Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory, II (BDI-II) by treatment group and hepatitis C virus (HCV) status, covarying for fatigue (Fatigue Severity Scale scores) at weeks 0 and 4, and paired t-tests within groups of changes in scores from week 0 to week 4
In order to see whether depression scores declined due to changes in somatic symptoms alone, or whether the key symptoms of depressed mood, loss of interest and suicidal ideation also changed, we performed item analyses on the HAM-D for each of these symptoms. We selected patients in the two randomized trials with depression at baseline who received active medication and who were rated responders in terms of both energy and mood (n = 26). Each item has a 4-point rating scale. For all three items (mood, interest and suicidal thoughts), the means declined significantly (P < 0.001): mood mean declined from 2.12 at baseline to 0.15 at week 4; loss of interest declined from 1.5 to 0.8 and suicidal ideation means declined from 0.38 (representing 7 patients who had thoughts about ending their lives) to 0 (no reports).
Safety of modafinil and armodafinil
Effects on CD4 cell count and HIV RNA viral load
During the double-blind phase, neither CD4 nor HIV RNA viral load showed significant change in either treatment group. Performing repeated-measures analyses that included occasion, treatment arm and HCV status, for CD4 there were no interactions (F = 0.019, P = 0.890). HIV RNA viral load declined for HCV-negative but not for HCV-positive for patients randomized to active medication of trend significance (F = 3.79, P = 0.053).
After 12 weeks of active medication, viral load diminished (t = 2.84, df, P = 0.005), although the mean decrease of 0.22 log was not clinically significant. Using repeated-measures analysis of CD4 and HIV RNA viral load including HCV status, comparing baseline and week 12 values, no significant effect for HCV status was found either for CD4 cell count (F = 0.044, P = 0.834) or HIV RNA viral load (F = 1.158, P = 0.284). At week 26, comparing patients still taking modafinil or armodafinil with those who were not, CD4 cell count did not change but viral load declined only in the group still taking modafinil or armodafinil.
Effects on liver function tests aspartate aminotransferase and alanine transaminase
For patients randomized to active medication with complete laboratory data (n = 107), we compared baseline values for HCV-positive patients (n = 16) and HCV-negative patients (n = 91), and then examined change over time for each subgroup. Both alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were significantly higher in HCV-positive patients. Using paired t-tests, there were no statistically significant changes over time on either assay, for either HCV-positive or HCV-negative subgroups (data not shown).
Haematocrit and fatigue
At study entry, 34 patients (18%) had haematocrit levels below the reference range (<38.5%) but above the cut-off for exclusion which was <30%. Those <38.5% were nearly equally divided between HCV-positive and HCV-negative patients (17% versus 18%). Haematocrit was not correlated with fatigue scores (r = 0.025, P = 0.732 at baseline, and r = 0.087, P = 0.238 at week 4).
Among the 120 patients randomized to active medication, 18 had haematocrit levels below the reference range. Response rate was 75% (76/102) for patients with normal levels, and 89% (16/18) for patients with haematocrit values below the reference range, which ranged from 31.1% to 38.4% (χ 2 = 1.77, 1 df, P = 0.15).
Treatment-emergent side-effects
These were not related to treatment arm during the first four weeks of treatment. Headache was the most commonly reported (12%), followed by insomnia (5%). The only side-effect reported exclusively by patients on active medication was irritability (4% versus 0 on placebo), although with such small numbers no differences were statistically significant and were too small to permit analysis by HCV status. Of the 16 dropouts, four patients did so because of side-effects; all were on placebo.
Discussion
Our goal was to determine whether co-infected patients with fatigue respond to modafinil/armodafinil treatment as well as mono-infected HIV-positive patients: in this small sample HCV-positive patients were more likely to respond. Both modafinil and armodafinil were effective in alleviating clinically significant fatigue in HIV-positive patients, with a large effect size compared with placebo (NNT = 3). 47
At study entry, 47% (n = 90) of the total sample of 190 had an Axis I depressive disorder other than major depressive disorder. Depression prevalence was not related to HCV status. Modafinil or armodafinil did not have an independent antidepressant effect in the absence of improved energy. Nearly all patients with baseline depression whose depressive symptoms (e.g. low mood, loss of interest, thoughts of death/suicidal thoughts) diminished did so only when energy also improved. We found no relationship between age, AIDS status or baseline depression severity and fatigue treatment outcome or mood response, which is largely consistent with findings from a much longer longitudinal observational study of fatigue predictors in a sample of 128 HIV-positive patients. 48
Markers of immunological and virological status were monitored for safety reasons because of the theoretical possibility of an inducer effect of modafinil or armodafinil on the cytochrome P450 metabolic system (CYP) system. No negative effects of modafinil or armodafinil on markers of immunosuppression in HIV-positive patients were observed regardless of HCV status. We found no significant change in aminotransferase levels (AST and ALT) over four weeks for patients of either HCV status.
Mono-infected HIV-positive patients were more likely to have been diagnosed recently and yet were more likely to have an AIDS diagnosis. While the reason for the higher rate of AIDS diagnosis is unclear, perhaps the greater rate of HCV infection in earlier years is associated with decline of injecting drug use over time.
Study limitations include the ad hoc nature of inquiry regarding HCV status, and lack of information about HCV genotype or disease stage. The number of HCV-positive participants was small. Women were under-represented, and we excluded otherwise eligible patients with active substance use, probably limiting the number of HCV-positive participants.
In summary, modafinil and armodafinil were widely effective and well tolerated. HCV-positive patients reported improved energy at the same rate as HCV-negative patients did, with no evidence of negative effects on liver function. The finding that patients with low haematocrit responded to modafinil/armodafinil as well as other patients is also encouraging and may indicate that patients with fatigue associated with IFN-induced anaemia may benefit from modafinil/armodafinil. In addition, most patients with both depression and fatigue experienced improved mood when fatigue also improved. Overall, the next step is to conduct a prospective trial of armodafinil with HIV-positive monoinfected and HIV/HCV-infected patients to replicate and extend our findings. In addition, our data provide some evidence for a clinical trial of armodafinil to be initiated either before or at the outset of HCV treatment, since depressive symptoms and fatigue are common sequelae of treatment even if not present beforehand. Since HCV treatment uptake is likely to increase with the introduction of directly acting antivirals for HCV, the first of which are expected to be approved in 2011, this finding is particularly salient.
Footnotes
ACKNOWLEDGEMENTS
We thank Manuel de la Nuez and Amy Withers for their assistance in study management, and the patients for their participation. The randomized placebo controlled trials (Studies 2 and 3) were partially supported by a grant from the National Institute of Mental Health (5 R01 MH072383). Product and matching placebo was provided by Cephalon for the last two years of the modafinil study, and for the armodafinil study which was initiated after armodafinil was approved by the FDA but before it was marketed.