Fatigue on Atripla (Efavirenz+Truvada)

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I know someone posted an email about extreme fatigue while taking Atrpla. Have your doctor swictch you to Isentress plus Truvada, or boosted Reyataz plus Truvada (assuming that your virus does not have resistance to those drugs)...and wait for a few days to see if you feel any better.Clinical Infectious Diseases 2004;38:430–432© 2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2004/3803-0020$15.00DOI: 10.1086/380791HIV/AIDSBRIEF REPORTAnalyzing Sleep Abnormalities in HIVâ€Infected Patients Treated with EfavirenzLucía Gallego,1 Pablo Barreiro,1 del Río,3 González de Requena,2 Apolinar Rodríguezâ€Albariño,3 Gonzálezâ€Lahoz,1 and Soriano11Service of Infectious Diseases and 2Service of Pharmacy, Hospital III, Instituto de Salud III, and3Service of Clinical Neurophysiology, Hospital La Paz, Madrid, SpainAmbulatory electroencephalogram monitoring was performed for 18 HIVâ€infected subjects treated with efavirenz with and without insomnia and for 13 healthy control subjects. All patients receiving efavirenz had longer sleep latencies and shorter duration of deep sleep, although poor sleepers also showed reduced sleep efficiency and shorter duration of rapid eye movement sleep. Efavirenz plasma levels were higher in patients with insomnia and/or reduced sleep efficiency. From HIV MedicineEfavirenz and Chronic Neuropsychiatric Symptoms: a

Cross-sectional Case Control StudyT.A. Rihs1,2; K. Begley1; D.E. 1; J. Sarangapany1; A. Callaghan1; M. 3; J.J. Post1,4,5; J. Gold1Posted: 01/31/2007; HIV Medicine. 2006;7(8):544-548. © 2006 Blackwell PublishingAbstract and IntroductionAbstractObjective: The aim of the study was to investigate symptoms of long-term central nervous system (CNS) toxicity in HIV-positive patients treated with efavirenz (EFV).Methods: We carried out a single-centre, cross-sectional case-control study comparing patients treated with EFV for at least 6 months with a matched control group. Self-administered, standardized questionnaires including the Depression, Anxiety and Stress Scales (DASS), the Cognitive Failures Questionnaire (CFQ)

and a questionnaire on unusual dreams, insomnia, fatigue, dizziness, depersonalization and derealization were administered.Results: Data for 32 matched pairs were analysed. Significantly higher total stress scores (P=0.008) were found in the EFV group. Of the patients in this group, 19% also reported severe to extremely severe levels of stress (P=0.014), indicating increased difficulty in relaxing, and being more irritable, impatient, agitated and easily upset. Nineteen per cent of patients treated with EFV also reported severe levels of anxiety (P=0.059) as assessed with the DASS scale. This patient group also reported a higher rate of unusual dreams (P=0.049). No significant differences between groups were found for measures of cognitive impairments, fatigue, dizziness, derealization or depersonalization.Conclusion: EFV-treated patients reported higher levels of severe stress and anxiety as

well as a higher rate of unusual dreams than patients not treated with EFV. These differences may be an expression of persisting CNS side effects in patients who remain on EFV for a prolonged period.IntroductionEfavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that is of proven effectiveness in the suppression of HIV-1 replication in combination with other antiretroviral agents.[1] Acute central nervous system (CNS)

effects are well-recognized adverse events associated with EFV therapy and have been reported in up to 50% of patients.[2] One prospective study showed discontinuation rates because of acute CNS symptoms in 13% of patients during the first 2 weeks of EFV treatment.[3] Typically, such side effects begin after the first dose and resolve within 1 month of therapy.[1,4,5] In certain patients, the toxicity may not completely resolve and persisting CNS side effects have been reported in 6-13% of patients.[6,7] Ongoing CNS toxicity was reported to be the reason for cessation of EFV after 1 month of therapy in 4-10% of patients.[6,8-10] Assessment of neuropsychiatric

adverse events in the Sensio study concluded that such events mainly occur during the first month but often persist thereafter.[11] Recently, a cross-sectional study concluded that neuropsychiatric disorders may persist in the long term in a significant proportion of patients on EFV.[12] Given these differences, there is considerable controversy regarding the duration of chronic CNS side effects of EFV. The difficulty of describing and measuring this chronic CNS toxicity contributes to this controversy. For this reason, it is important to describe this phenomenon using standardized methods that have been validated in other clinical settings.The aim of this study was to compare the prevalence of neuropsychiatric disorders in patients stable on an EFV-containing regimen for more than 6 months with that in controls on non-EFV-containing regimens. The main focus of the study was the assessment of symptoms of anxiety, depression, stress and mild cognitive impairments using self-administered and standardized questionnaires.The assessment of sleep disturbance and unusual dreams was included as these symptoms are well described as being part of the acute CNS toxicity of EFV. Reduced but persistent sleep disturbance or poor quality sleep has been suggested to be a mechanism underlying EFV-associated chronic CNS toxicity.[4,13] Other frequently reported side effects, such as dizziness, lightheadedness, derealization and depersonalization, were also assessed.MethodsDesignIn a single-centre,

cross-sectional study we compared a cohort of patients who had been treated with EFV [600 mg once a day (qd)] as part of their combination antiretroviral regimen for at least 6 months with a matched cohort who were stable on non-EFV combination antiretroviral therapy for a minimum duration of 6 months.SubjectsThis study was approved by the Ethics Committee of the South-Eastern Area Health Service in Sydney and recruitment took place over a 12-month period at the Albion Street Centre, an ambulatory HIV

clinic in Sydney, Australia. Subjects were informed that the survey was assessing side effects of EFV-containing therapy. None of the specific outcome variables such as stress or anxiety were outlined in the subject information. All participants gave their informed consent.Patients with severe cognitive or psychiatric impairment, with evidence of past or present drug or alcohol dependence or with a diagnosis of AIDS dementia complex were excluded from the study. Measures were taken once by means of a set of self-administered questionnaires.A total of 258 eligible patients for the EFV (87) and control (171) groups were identified from the clinic pharmacy antiretroviral drug database and screened for eligibility. In the EFV group, 56 patients were eligible and approached for participation in the study. Five patients declined to participate and three patients did not return the questionnaires. Forty-eight questionnaires were completed.During the matching process, each subject in the EFV group was matched with a subject of the same age range (within 5-year groups), CD4 cell count category (<200, 200-499 and >500 cells/μL) and HIV RNA viral load (<1.7, 1.7-5.18 and >5.18 log10 HIV-1 RNA copies/mL) from the control database. Of the 171 cases, 65 patients

were identified as eligible and meeting the matching criteria for the control group. Forty-two patients presented for routine appointments and were approached for participation. Three patients declined to participate and five patients did not return the questionnaires. Thirty-three completed matches were obtained.MeasuresSymptoms of depression, anxiety and stress were assessed with the Depression Anxiety and Stress Scale (DASS).[14] This scale

was chosen for its high internal consistency, temporal stability and stable factor structure applying to clinical as well as normal samples.[14,15] The scale is a standardized self-report questionnaire that provides a clear distinction between the constructs of anxiety, depression and stress.[14,15] The DASS scale distinguishes among normal, mild, moderate, severe and extremely severe degrees of depression anxiety or stress.Cognitive symptoms were investigated by the Cognitive Failures Questionnaire (CFQ) to assess the frequency of cognitive slips and errors.[16] These

include cognitive impairments such as difficulties with concentration, mental confusion, forgetfulness and aggressiveness in situations of daily life. The CFQ is unrelated to standard personality and intelligence scores and is believed to measure success at appropriately distributing attention, especially under stress and across multiple tasks.[16,17] The CFQ is a 25-item self-administered instrument that measures a general cognitive failures factor.[17]Further symptoms relevant to the assessment of CNS side effects of EFV were assessed by additional questions. These included sleep disturbance, fatigue and unusual dreams, feelings of

depersonalization, derealization, dizziness, light-headedness, restlessness and agitation. Questions were assessed by dichotomous questions or Likert-type scales (with a grading from 1 to 7).Drug and alcohol consumption and benzodiazepine use were recorded, as well as adherence (missed doses in the last week) to antiretroviral treatment and concomitant medications. Medical records were reviewed for reports of depressive symptoms and prescribed antidepressants prior to and after starting current combination therapy. Reports of depressive symptoms were only recorded if made by a medical practitioner or a psychologist.StatisticsPaired t-tests were used for a between-group comparison of questionnaire scores for the EFV group and the control group. Nonparametric tests (Wilcoxon's signed rank test) were used if data were not normally distributed or categorical. χ2 tests or Fisher's exact tests were used for between- and within-group comparisons of dichotomous and categorical variables. All tests (except Fisher's exact test) were two-sided with a significance level of 0.05.ResultsFrom the 48 EFV subjects and 34 controls, 33 matches were found. One subject did not complete the DASS questionnaire, resulting in 32 matched pairs for DASS analyses. There were no significant differences between the two groups in terms of the following characteristics: age, sex, HIV viral load, CD4 cell count, time in months since HIV positive diagnosis, total months on antiretrovirals and highest level of education. The two groups were significantly different with regard to their time on the most recent antiretroviral

combination. In the EFV group, the mean duration was 14±5 months whereas it was 24±14 months in the control group (P=0.001) ( Table 1 ). The EFV group reported a higher adherence rate (two subjects missed one dose in the past week) than the control group (seven subjects missed one dose in the past week); however, this was not significant. Groups did not differ on reported depression prior to commencing treatment. No differences for alcohol consumption or use of illicit drugs (cannabis, speed, ecstasy, heroin or cocaine), antidepressants or benzodiazepines were found.Table 1. Baseline Demographic and Clinical Indicators for the two GroupsThere were significantly higher levels of stress reported in patients taking EFV, as indicated in the pairedt-test comparison for the total DASS stress scores (P=0.008), Furthermore, nonsignificant trends were observed towards higher total scores for depression (P=0.077) and anxiety (P=0.083) in patients taking EFV (Fig. 1). More than 60% of patients taking EFV reported normal levels of depression, anxiety or stress. However, in a comparison of the degree of severity for the matched pairs, six (19%) of the patients taking EFV experienced severe to extremely severe levels of stress, compared with none in the control group (P=0.014). Severe to extremely severe levels of anxiety were experienced by six (19%) vs one (3%) subject in the EFV and

control groups, respectively (P=0.059). Three (9%) of the subjects in the EFV group reported severe or extremely severe levels of depression (P=0.083) compared with none in the control group ( Table 2 ).Table 3. Degrees of Severity for Depression, Anxiety and Stress Scores on the Depression, Anxiety and Stress Scales (DASS) for the Matched PairsFigure 1. Mean total scores for depression, stress and anxiety on the Depression, Anxiety and Stress Scales (DASS) for the efavirenz (EFV) group (hatched bars) and the control (CTR) group (solid bars) for 32 patients in each group. Error bars indicate the standard error of the mean.Further analysis of the subscales for the stress score in the matched pairs indicated that the EFV group reported having more difficulty relaxing (P=0.029), being more easily upset and agitated (P=0.025), being more irritable and overreactive (P=0.009) and being more impatient (P=0.007).A difference was also found for reports of unusual dreams (P=0.049). In the EFV group, 19 patients (58%) reported unusual dreams in the past 7 days compared with 10 (32%) in the control group. No significant differences were observed with regard to quality of sleep, number of awakenings per night or fatigue. Furthermore, no differences between groups were found for measures of cognitive impairments in daily living (CFQ),

feelings of derealization and depersonalization, dizziness or light-headedness.In addition to the matched pairs analysis, the DASS scales were also compared for the unmatched total sample. The percentages for the severity scores of the DASS were similar between the two analyses. In the unmatched group, 19% of subjects on EFV reported severe to extremely severe levels of stress (P=0.08). Nineteen per cent of subjects also reported severe to extremely severe levels of anxiety and 11% severe to extremely severe levels of depression. Similarly, patients in the EFV group reported significantly more severe to extremely severe anxiety than controls (P=0.032) and demonstrated borderline significant levels of severe to extremely severe

depression (P=0.054) in this analysis.Because of the differences in length of treatment between EFV and controls, a secondary analysis was undertaken to determine if length of treatment was correlated with DASS scores. There was no significant correlation between treatment length and total DASS scores for stress (Ï=0.176, P=0.183), anxiety (Ï=0.076, P=0.566) or depression (Ï=0.103, P=0.437).DiscussionSignificant differences were observed for the DASS stress scores, with trends towards differences for DASS depression and anxiety scores. A detailed analysis of levels of severity for the DASS scores revealed 19% of the subjects on EFV experienced severe to extremely severe levels of stress and anxiety. This was not observed in the control group. Analysis of subscales of the DASS stress factor revealed that patients in the EFV group reported being more irritable, overreactive and impatient, being more easily upset and more agitated and experiencing more difficulties with relaxing than patients in the control group. Furthermore, results indicated that the EFV group experienced more unusual dreams than those in the control group.

Other studies have reported increased levels of anxiety, agitation and sleep disorders but not stress in EFV-treated patients. However, no previous studies have used the DASS assessment, which has greater sensitivity in detecting stress levels than the more commonly used Profile of Mood States-Adult (POMS-A) questionnaire. The finding of increased stress and anxiety levels and unusual dreams may have important implications for the clinical management of a group of patients who apparently tolerate EFV over the long term.No measurable differences were found in questions regarding difficulties with concentration, dizziness, feelings of derealization and depersonalization, and fatigue. These features are commonly described as the acute CNS toxicity

associated with EFV. This may confirm that some of the characteristic CNS side effects resolve after the acute phase.Limitations of the study are its cross-sectional nature and its small sample size. However, the distribution of severe levels of stress, anxiety and depression remained stable for patients on EFV and controls, when the total number of unmatched patients (n=82) was also analysed, thereby strengthening the observations made for the matched groups. There may also have been a potential for a reporting bias where the subjects taking EFV may have been more likely to report symptoms than the subjects in the control group. This may have been the case with the easily identifiable item of unusual dreams which is commonly linked to

side effects of EFV. It is unlikely that a reporting bias occurred with the DASS questionnaire for the items of depression, anxiety and stress as the DASS is designed to minimize such bias. Additional bias may have been associated with the longer duration on therapy in the control group, indicating that subjects were tolerating their non-EFV regimen for a longer time. However, in this study no correlation was found between DASS scores and duration on treatment. Therefore, we do not believe that duration on treatment affected these results.Although an a priori difference between the two groups in this cross-sectional study cannot be ruled out, the occurrence of increased irritability, restlessness and agitation as symptoms of

increased stress, persisting unusual dreams, severe to extremely severe anxiety and to a lesser extent depressive symptoms may point to long-term effects of EFV in a subgroup of patients. These results are consistent with previous observations of long-term CNS effects and may indicate that some individuals are more likely to experience psychological side effects, including feeling more irritable, being more easily upset and being more agitated.[9] However, manifestations of CNS toxicity found in other studies such as dizziness, mood changes and impaired concentration in EFV- compared with PI-treated subjects were not observed in this study.[8] Our findings are also consistent with those of a study by Hawkins et al.suggesting that neuropsychiatric features (anxiety, hostility and depression) are seen with long-term EFV

use.[18] This is further supported by a recent report suggesting that as many as half of patients may develop delayed neuropsychiatric disorders with EFV.[19]This may indicate that a subgroup of patients stable on EFV for a mean of over 1 year experience chronic CNS toxicity, as measured with a combination of standardized instruments and customized questionnaires. Further understanding of this phenomenon is paramount in finding clinical associates that will lead to improved management strategies for such toxicity.CLICK HERE for subscription information about this journal.ReferencesStaszewski S, Morales- J, Tashima K et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999; 341: 1865-1873DuPont Pharmaceuticals. Product Information Sustiva. Efavirenz. : DuPont

Pharmaceuticals, 1998Blanch J, ez E, Rousaud A et al. Preliminary Data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr 2001; 27: 336-343Adkins JC, Nobles S. Efavirenz. Drugs 1998; 56: 1055-1066Clifford DB, S, Yang Y et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714-721Marzolini C, Telenti A, Decosterd LA et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1 infected patients. AIDS 2001; 15: 71-75Fumaz CR, Tuldra A, Ferrer MJ et al. Quality of life, emotional status and adherence in patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Immune Defic Syndr 2002; 29: 244-253Manfredi R, Calza L, Chiodo F. Efavirenz versus nevirapine in current clinical

practice: a prospective, open-label observational study. J Acquir Immune Defic Syndr 2004; 35: 492-502-Molina JA. Safety and tolerance of efavirenz regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin Trials 2002; 3: 279-286Sabbatani S, Fulgaro C, Rosticelli E. Efficacy of efavirenz in a mixed population of patients. Identification of drop-out causes. Infez Med 2002; 10: 163-168Lochet P, Peyriere H, Lotthe A, Mauboussin JM, Delmas B, Reynes J. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003; 4: 62-66Fumaz CR, Munoz-Moreno JA, Molto J et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues and adherence. J Acquir Immune Defic Syndr 2005; 38: 560-565Moyle G. Efavirenz: shifting the HAART paradigm in adult HIV-1 infection. Exp Opin Invest Drugs 1999;

8: 473-486Lovibond SH, Lovibond PF. Manual for the Depression Anxiety Stress Scales (DASS).Psychology Foundation Monograph. : University of New South Wales, 1993Brown TA, Chorpita BF, Korotitsch W, Barlow DH. Psychometric properties of the Depression Anxiety Stress Scales (DASS) in clinical samples. Behav Res Ther 1997; 1: 79-89Broadbent DE, PF, FitzGerald P, Parkes K. The Cognitive Failures Questionnaire and its correlates. Br J Clin Psychol 1982; 21: 1-16Larson GE, Alderton DL, Neideffer M et al. Further evidence on dimensionality and correlates of the Cognitive Failures Questionnaire. Br J Psychol 1997; 88: 29-38Hawkins T, Geist C, Young B et al. Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clin Trials 2005; 6: 187-196Gutierrez F, Navarro A, Padilla S et al. Prediction of neuropsychiatric adverse events

associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 2005; 41: 1648-1653Authors and DisclosuresT.A. Rihs1,2, K. Begley1, D.E. 1, J. Sarangapany1, A. Callaghan1, M. 3, J.J. Post1,4,5,and J. Gold1 1Albion Street Centre, Sydney, Australia2University Medical Center, University Hospital of Geneva, Geneva, Switzerland3AIDS Medical Unit, Brisbane, Australia4Department of Infectious Diseases, Prince of Wales Hospital, Sydney, Australia5School of Medical Sciences, University of New South Wales, Sydney, AustraliaAcknowledgmentsWe would like to thank all patients who participated in this study. We would also like to thank the following staff members from the medical unit, the

psychology unit and the pharmacy for their active support in conducting this study: Sylvia Bridle, Coote, Virginia Furner, Ruth Hennessy, Henry Mackellar Michelmore and Charmaine Turton.Reprint AddressTonia A. Rihs, University Medical Center, University Hospital of Geneva, CH-1211 Geneva, Switzerland. Tel: +41 22 379 5463; fax: +41 22 379 5452; e-mail: tonia.rihs@...HIV Medicine. 2006;7(8):544-548. © 2006 Blackwell Publishing Regards, Vergelpowerusa dot org