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Psychosomatics 45:394-402, October 2004
© 2004 The Academy of Psychosomatic Medicine

Depressive Symptoms, Neurocognitive Impairment, and Adherence to Highly Active Antiretroviral Therapy Among HIV-Infected Persons

Adriana Ammassari, M.D., Andrea Antinori, M.D., Maria Stella Aloisi, M.S., Maria Paola Trotta, M.D., Rita Murri, M.D., Luca Bartoli, M.D., Antonella d'Arminio Monforte, M.D., Albert W. Wu, M.D., M.P.H., and Fabrizio Starace, M.D.

Received March 21, 2003; revision received Sept. 12, 2003; accepted Oct. 17, 2003. From Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore, Rome; Istituto Nazionale per le Malattie Infettive, Lazzaro Spallanzani Istituto di Ricovero e Cura a Caratterre Scientifico, Rome; Servizio Psichiatria di Consultazione ed Epidemiologia Comportamentale, Ospedale Domenico Cotugno, Naples; Istituto di Malattie Infettive e Tropicali, Università di Milano, Milan; and the Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore. Address reprint requests to Dr. Ammassari, Department of Infectious Diseases, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy; aammassari{at}libero.it (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
The association of depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy (HAART) was evaluated in 135 HIV-infected persons. Thirty percent reported nonadherence to HAART. Depressive symptoms (assessed with the Montgomery-Åsberg Depression Rating Scale) and neurocognitive impairment (assessed with a neuropsychological test battery) were documented in 24% and 12%, respectively, of the study participants. Nonadherence to HAART was independently associated with worse depression rating scale scores (odds ratio=1.05, 95% confidence interval [CI]=1.00–1.10), acquisition of HIV through injection of drugs (odds ratio=2.59, 95% CI=1.05–6.39), and complaints about impairment of sexual activity (odds ratio=6.62, 95% CI=1.16–37.6). The presence of depressive symptoms, but not neurocognitive impairment, was associated with nonadherence.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
With the advent of new classes of antiretroviral drugs and combination antiretroviral therapy, there is the potential for HIV/AIDS to be managed for years and perhaps decades. Nevertheless, as in other treatable chronic fatal illnesses, medication adherence is essential. Treatment interruptions and inconsistent drug intake can lead to inadequate virologic suppression or immunologic response, development and spread of resistant viral strains, and clinical disease progression.1–4 Although Paterson et al.3 found that a medication adherence rate of greater than 95% was needed to suppress HIV replication in 81% of treated participants, several studies2–6 have reported that 28%–100% of treated persons fall below this threshold.

Anxiety and depression are common among persons living with HIV/AIDS, with a prevalence of nearly 50% in a U.S. screening sample of 2,864 HIV-infected persons.7 It is not known whether the introduction of highly active antiretroviral therapy (HAART) has led to a decline in depression and anxiety disorders among HIV-infected persons.8 Cognitive impairment is the most common central nervous system consequence of HIV infection and ranges in severity from minor cognitive motor disorder to HIV-1-associated dementia. Although recent studies showed that the incidence and prevalence of HIV-1-associated dementia9,10 and minor cognitive motor disorders11,12 have significantly declined in the HAART era, these conditions still represent important HIV-related cerebral complications.13,14

The presence of depression and anxiety has been shown to be an important patient-related barrier to adequate adherence to HAART,2,3,5,15,16 as it has to adherence to medications for other disorders.17 Despite the consistent association between depression and HAART adherence behavior, there have been few detailed analyses of this issue. It is also possible that HIV-associated neurocognitive disturbances, which become more prominent as HIV disease advances, might be responsible for nonadherence. However, to our knowledge, the relationship between adherence to HAART and neuropsychological performance has been assessed in only one recent study, which suggested a negative effect of neuropsychological impairment on adherence to antiretrovirals.18

The main purposes of this study were to examine the association between HAART adherence and depressive symptoms as well as minor neurocognitive impairment. Furthermore, to assess for possible confounders, we wanted to explore other patient-, treatment-, or provider-related variables that could have a negative effect on adherence. Finally, factors related to the presence of prominent depressive symptoms were investigated.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design and Participants
This investigation was a substudy of the Italian Cohort Naive Antiretrovirals (ICONA) study, a multicenter observational study begun in 1997 to examine the natural history of HIV disease among adults who were previously naive to antiretroviral drugs.19 The current analysis included all participants enrolled in both the AdICONA20 and the NeuroICONA21 substudies, which were focused, respectively, on adherence and on psychoneurological function and disease. A total of 11 clinical centers recruited all consecutive patients observed during one of the 6-month follow-up visits of the ICONA study between November 1999 and February 2000. The inclusion criterion for participants recruited into AdICONA was treatment with HAART, including at least one protease inhibitor or nonnucleoside reverse transcriptase inhibitor, for at least 1 month; exclusion criteria were inability to complete the questionnaire, HIV-1-associated dementia ≥ grade 2,22 and hospitalization at the time of enrollment. The inclusion criterion for enrollment in the NeuroICONA study was the same as that for the ICONA study;19 the exclusion criterion was the presence of severe psychiatric disease (e.g., delirium, dementia, schizophrenia, bipolar disorder, or mental retardation).

Adherence Assessment (AdICONA Study)
Participants in the study were asked to complete a 16-item self-administered questionnaire previously tested in another Italian patient population with HIV disease.23 The questionnaire was designed to collect data on knowledge about the current HAART treatment regimen (ability to correctly recall name, color, and timing of prescribed drugs), adherence behavior, use of reminder methods, interruptions in drug supply (running out of pills between visits), knowledge about current HIV disease stage (most recent CD4 cell count and plasma HIV RNA), beliefs about treatment, reasons for missing or discontinuing drugs, perceived health status, psychological well-being, social support, symptoms, satisfaction with health care, patient-provider relationship, treatment with complementary medicine, use of alcohol or recreational drugs (heroin, cocaine, amphetamine, "ecstasy"), level of education, type of housing, employment status, monthly income, number of children, and residence with other HIV-positive persons. On average, 10 minutes were required to fill out the questionnaire. Each questionnaire was labeled with an identification number, collected in a sealed envelope to preserve participants' anonymity, and delivered to the coordinating center.

Adherence to HAART was assessed by asking about the timing of the last missed dose in the previous 4 weeks (response options: yesterday, last week, 1–2 weeks ago, 3–4 weeks ago, never). Twelve possible reasons for missing or discontinuing drugs were investigated by asking the participant to rate their importance on a 4-point adjective-rating scale (response options: not at all, a little, a fair amount, a lot). The questionnaire included a 24-item checklist of common HIV- and HAART-related symptoms, identified from previously published studies24,25 and clinical experience. Participants were asked to identify the symptoms they experienced during the last 4 weeks and to indicate the perceived intensity on a 4-point adjective-rating scale (response options: absent, mild, moderate, severe). Health status was measured by using a visual analogue scale from 0 (worst) to 100 (best). The Mental Health Index-526 was used to assess psychological well-being.

Neuropsychological and Mood Assessments (NeuroICONA Study)
The neuropsychiatric assessment was administered by using the Italian version of the Montgomery-Åsberg Depression Rating Scale,27 a checklist of subjective cognitive complaints, and a neuropsychological test battery.28 The neuropsychological test battery has been shown to be sensitive to a wide spectrum of cognitive domains, including motor speed (measured by the timed gait test), fine motor control, selective attention, and short-term memory (WAIS-R digit symbol subtest),29 verbal production (Verbal Fluency Test), verbal memory (Auditory Verbal Learning Test, trials 1–5), fine motor control, sustained and selective attention, and cognitive flexibility (Color Trails 2). The investigators were trained in the use of the evaluation instruments during a focused, intensive workshop, where interrater reliability in the use of the Montgomery-Åsberg Depression Rating Scale was measured by the independent evaluation of a series of videotaped interviews of HIV-infected persons (Cohen's k=0.94).30

Statistical Analysis
On the basis of published data regarding the general population17 and observations in HIV-infected people,3,5,15,16 we examined the association of depressive symptoms and suboptimal HAART adherence and further investigated which of the specific depression-related items might be related to poor adherence. Furthermore, we hypothesized that suboptimal adherence to HAART would be associated with minor neurocognitive impairment as measured by neuropsychological tests.

The internal consistency reliability of the multiitem questions of the adherence questionnaire was evaluated by using Cronbach's alpha.

Nonadherence to HAART was defined in terms of the patient's report of having missed at least one HAART dose in the previous week (missing a dose yesterday or in the last week versus missing a dose 1–2 weeks ago, 3–4 weeks ago, or never). This definition of nonadherence was used to maximize sensitivity to detect suboptimal HAART adherence. Neuropsychological test scores were first analyzed as continuous measures. Participants were then also rated as neuropsychologically impaired or depressed on the basis of their performance relative to a cutoff score. Impairment was defined as a performance 1.5 or more standard deviations worse than the published age-matched norms.30 Global impairment was defined as impaired performance on at least two of the five tests in the neuropsychological test battery. Prominent depressive symptoms were defined as a Montgomery-Åsberg Depression Rating Scale score above 19.27 Other ordinal independent variables, such as importance of reasons for missing or discontinuing drugs and self-reported symptoms, were dichotomized by combining response options (reasons for missing or discontinuing drugs: "not at all" was combined with "a little" and "a fair amount" with "a lot"; self-reported symptoms: "absent" was combined with "mild" and "moderate" with "severe").

Between-group comparisons of categorical variables were conducted by using chi-square tests and odds ratios with 95% confidence intervals (95% CI). The Wilcoxon rank sum test was used to assess overall differences between adherent and nonadherent participants on Montgomery-Åsberg Depression Rating Scale scores and neuropsychological test scores.

Multivariate analysis was performed by using a multiple logistic regression, with nonadherence as the dependent variable and the Montgomery-Åsberg Depression Rating Scale global score as well as the other variables significantly associated on univariate analysis with nonadherence (p≤0.05) as the independent variable.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
Descriptive Characteristics
A total of 135 persons participated in both studies (37.7% of the AdICONA participants and 34.2% of the NeuroICONA participants) and therefore were eligible for this analysis. Of these, 87 (64%) were men. The median age was 35.4 years (range=19–64). The route of HIV transmission was drug injection for 42 (31%) participants, men having sex with men for 34 (25%), and heterosexual sex for 51 (38%). At the time of interview, 9% of participants reported active use of recreational drugs, and 10% reported a daily alcohol intake of more than one glass of spirits or half a liter of wine or beer. Forty-two percent of participants reported educational attainment ≤8 years, 24% were unemployed, and 19% had a monthly income of <$350. No significant differences in general characteristics were found between this subset of patients and the entire ICONA study population.

Participants had been taking their current HAART regimen, which included a mean of three antiretroviral drugs, for a median of 0.87 years. The mean CD4 cell count was 591 x 106 cells/liter, and 10% of the participants had a CD4 cell count less than 200 x 106 cells/liter. The mean HIV-RNA count was 2.5 log10 copies/ml. Seventeen participants had had a previous AIDS-defining event.

Internal consistency values for the composite scales were 0.89 for reasons for missing or discontinuing drugs (12-item scale), 0.79 for psychological well-being (5-item scale), 0.93 for HIV- and HAART-related symptoms (24-item scale), and 0.74 for quality of the patient-provider relationship (7-item scale).

Forty-one (30%) of the 135 participants, reported having missed at least one dose of HAART in the last week and were categorized as nonadherent. Prominent depressive symptoms were found in 32 (24%) of the 135 participants. Neuropsychological test scores indicated impairment on the timed gait test in 32 (24%) participants, on the Verbal Fluency Test in 12 (9%), on the Color Trails 2 test in 18 (13%), on the Auditory Verbal Learning Test in four (3%), and on the digit symbol subtest in nine (7%). Global neurocognitive impairment was documented in 16 (12%) participants. Subjective cognitive complaints included memory disturbances in 38 (28%) participants, concentration problems in 26 (19%), speech problems in 36 (27%), slowness in thinking in 26 (19%), and loss of interest in 45 (33%).

Adherence, Neuropsychological, and Mood Assessments
Mean values on the global score and on individual items of the Montgomery-Åsberg Depression Rating Scale are shown in Table 1. All scores were significantly higher in the nonadherent group, compared with the adherent group (p≤0.03). The proportion of participants who displayed prominent depressive symptoms was 39% in the nonadherent group and 17% in the adherent group (odds ratio=3.12, 95% CI=1.36–7.13, p=0.008).


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TABLE 1. Scores on Measures of Depression and Neuropsychological Performance and Presence of Subjective Cognitive Complaints Among HIV-Infected Patients, by Adherence or Nonadherence to Highly Active Antiretroviral Therapy (HAART)a



Regarding neuropsychological assessments, there were no statistically significant differences between the adherent group and the nonadherent group on any of the individual tests (Table 1). The prevalence of impairment on each neuropsychological test and the prevalence of global neuropsychological impairment were similar in the two groups (11% of the participants in the adherent group, compared with 14% of the participants in the nonadherent group).

All of the subjective cognitive complaints, with the exception of slowness in thinking, were significantly more frequent among the nonadherent participants (Table 1). Loss of interests was most strongly associated with nonadherence (odds ratio=3.06, 95% CI=1.42–6.60, p=0.005).

Other Variables Predictive of Nonadherence to HAART
In univariate analyses, nonadherent persons had a significantly lower mean CD4 cell count, compared to those who reported having taken all HAART doses in the last week (mean=509 x 106 cells/liter [SD=362] versus 637 x 106 cells/liter [SD=341], p=0.05). Moreover, suboptimal adherence was found in participants who self-reported the following characteristics (Table 2): injection drug use as HIV transmission mode (p=0.001), active use of recreational drugs (p=0.007), an overly complicated HAART regimen (p=0.02), previous side effects (p=0.02), fatigue (p=0.002), taste perversion (p=0.02), diarrhea (p=0.04), insomnia (p=0.02), confusion (p=0.007), vision troubles (p=0.001), or impairment of sexual activity (p=0.001). The mean Mental Health Index-5 score was lower in participants who reported missing HAART doses, compared to those who reported adherence (mean=63.9 [SD=19.9] versus 55.6 [SD=19.6], p= 0.02). Global health status did not significantly differ among the two groups (mean=61.6 [SD=20.5] in adherent and 57.7 [SD=46.7] in nonadherent persons, p=0.61). There was no significant between-group difference in the overall time participants had been taking antiretroviral therapy or had been taking the current HAART regimen.


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TABLE 2. Characteristics of HIV-Infected Patients, by Adherence or Nonadherence to Highly Active Antiretroviral Therapy (HAART)a



Variables Associated With Prominent Depressive Symptoms
The following variables were associated with above-threshold depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale: active drug use (odds ratio=22.90, 95% CI=4.69–112.20, p<0.001); unemployment (odds ratio=4.30, 95% CI=1.78–10.30, p=0.002); history of an AIDS-defining event (odds ratio=3.48, 95% CI=1.21–9.79, p=0.03); complicated HAART regimen (odds ratio=2.67, 95% CI=1.14–6.27, p=0.03); and having had side effects (odds ratio=2.67, 95% CI=1.14–6.27, p=0.03), anorexia (odds ratio=5.71, 95% CI=1.50–21.70, p=0.01), anxiety (odds ratio=4.56, 95% CI=1.88–11.10, p=0.01), taste perversion (odds ratio=4.58, 95% CI=1.15–18.20, p=0.03), confusion (odds ratio=5.48, 95% CI=1.60–18.70, p= 0.007), breast enlargement (odds ratio=3.48, 95% CI=1.21–9.97, p=0.03), abnormal fat distribution (odds ratio=2.89, 95% CI=1.13–7.37, p=0.03), insomnia (odds ratio=5.36, 95% CI=1.80–15.90, p=0.003), vision troubles (odds ratio=7.21, 95% CI=1.25–41.10, p= 0.03), or vertigo (odds ratio=10.50, 95% CI=1.05–105.30, p=0.04). The presence of depressive symptoms was not related to the overall time participants had been taking antiretroviral therapy or had been taking the current HAART regimen.

Performance on individual neuropsychological tests was not associated with depressive symptoms. On the other hand, depressive symptoms were significantly associated with subjective cognitive complaints, including memory disturbances (odds ratio=4.42, 95% CI=1.90–10.30, p=0.001), concentration problems (odds ratio=15.30, 95% CI=5.59–41.70, p<0.001), speech problems (odds ratio=6.07, 95% CI=2.55–14.40, p<0.001), slowness in thinking (odds ratio=3.81, 95% CI=1.53–9.48, p=0.005), and loss of interest (odds ratio=14.80, 95% CI=5.61–39.00, p<0.001).

Variables Associated With Nonadherence: Multivariate Analysis
In a multivariable logistic regression analysis that included 17 variables, nonadherence to HAART was associated with worse Montgomery-Åsberg Depression Rating Scale scores (odds ratio=1.05, 95% CI=1.00–1.10, p=0.03), acquisition of HIV through injection of recreational drugs (odds ratio=2.59, 95% CI=1.05–6.39, p=0.03), and complaints about impairment of sexual activity (odds ratio=6.62, 95% CI=1.16–37.60, p=0.03).


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this study, conducted with a group of persons living with HIV/AIDS and receiving HAART, show a strong relationship between adherence behavior and depressive symptoms but no significant association between adherence behavior and minor neurocognitive impairment. In our study, participants who showed depressive symptoms were three times as likely as persons without depressive symptoms to be nonadherent to the medication regimen. This finding is consistent with findings from a meta-analysis of studies conducted with non-HIV-infected subjects.17 It is noteworthy that Ickovics et al.31 showed that depressed HIV-infected women display an accelerated disease progression, independent of virologic and immunologic markers, clinical stage, use of antiretroviral treatment, and sociodemographic characteristics. The authors concluded that a health-damaging behavior, such as suboptimal adherence to medications, may well be one of the possible underlying mechanisms for the poorer disease prognosis found in depressed persons. Unfortunately, the cross-sectional design of our study does not allow inferences about the causal direction of the association between HAART adherence and depressive symptoms.

The association we found only in the univariate analyses between subjective cognitive complaints and suboptimal HAART adherence could be explained by the fact that depressive symptoms generally correlate with perceived neuropsychological and somatic symptoms.8,32 In our study it was not possible to determine whether the depressed participants actually experienced more symptoms or were more likely to report them.

HIV-infected subjects in several studies2,33 reported "forgetting" as one of the most common reasons for nonadherence with antiretroviral drugs. In fact, while it is reasonable to suppose that patients with full-blown dementia are at highest risk for suboptimal adherence, this association can be hypothesized only for subjects with minor neurocognitive impairment. In our study, we could not find an association between minor cognitive impairment and adherence behavior. This finding is in contrast with the findings of Hinkin and colleagues,18 who reported a significantly greater risk of poor adherence to HAART in HIV-infected persons with neuropsychological impairment. We think that the discrepancy in the results might be due to differences in the study populations (i.e., younger mean age, higher frequency of female gender, higher proportion of injection drug users, lower socioeconomic status, and more frequent neuropsychiatric comorbidity among the participants in our study), and we suggest that in the presence of a high prevalence of depressive symptoms, barriers other than organic neurological disorders may play a more relevant role in determining suboptimal adherence.

Although recent studies have shown an association between HAART adherence and self-reported symptoms, a negative relationship of sexual dysfunction and medication intake has not been reported.20,34 Psychosexual problems are frequently reported by persons with HIV infection,35 and recent studies have shown that HAART regimens that include protease inhibitors are associated with sexual dysfunction as a medication side effect.36,37 It is possible that sexual dysfunction that is thought to be the result of antiretroviral side effects might lead to suboptimal adherence. Moreover, sexual dysfunction might cause or worsen depressive symptoms, which would have an even greater effect on adherence. We think that the association between adherence behavior and satisfaction with sexual life should be considered as an important finding, especially in light of the now long-term life perspective of HIV-infected persons and the need to ensure that they have an adequate quality of life.

Finally, our results documented a significantly higher risk of HAART nonadherence in persons who acquired HIV through injection of recreational drugs. This finding is in agreement with previous studies that have shown an association of nonadherence with self-reported current use of injection drugs.2,5,38,39 Because the effect of this variable was independent from that of depressive symptoms, an explanation could be that persons with past or current drug abuse might have major social barriers or might concomitantly be treated with other medications (methadone or psychiatric drugs) that interfere with correct HAART intake.

Several limitations of this study should be mentioned. First, because of the cross-sectional design it was not possible to infer a causal relationship between adherence and depression. Although it is more likely that depressive symptoms affect patients' willingness and ability to follow through with medical advice, it is possible that nonadherence might worsen depressive symptoms because of the absence of treatment effects. Combination antiretroviral regimens may mitigate depressive symptoms elicited by anatomical or functional abnormalities produced by HIV. Nonadherence might have prevented the "neuroprotective effect" exerted by HAART. Second, our study methods, including use of a depression rating scale instead of a standardized psychiatric interview, limited our ability to make conclusions about the prevalence of mood disorders. The application of a more detailed psychiatric assessment was deemed less feasible in the context of the ICONA study, which was a naturalistic study carried out in infectious diseases units. A Montgomery-Åsberg Depression Rating Scale score above the selected threshold, however, is generally accepted as an indicator of a depressive syndrome.27 Third, care should be taken in generalizing these results to other groups of HIV-infected patients. The participants in this study cannot be considered representative of all HIV-infected individuals. In addition, the relatively high median CD4 cell count found among the participants together with the amount of time they had spent in antiretroviral treatment may explain the low prevalence of neurocognitive impairment, which resulted in insufficient power to detect an association between adherence and neurocognitive impairment.

In conclusion, the results of this study emphasize the need for increasing awareness of depressive symptoms and perceived dysfunction in sexual activity as possible determinants of nonadherence to HAART. Early detection and intervention training of health care providers could significantly improve the management of adherence problems in HIV-infected persons. Although HAART seems to have a favorable effect on occurrence of depressive symptoms among HIV-infected persons,8,9 enhanced attention to and appropriate treatment of psychiatric comorbidity by the treating physician could represent a fundamental variable in optimizing adherence to antiretroviral therapy, especially in antiretroviral naive persons.


  ACKNOWLEDGMENTS

 
This research has been realized through the contributions of the AdICONA and NeuroICONA Study Group members: E. Pizzigallo and M. D'Alessandro in Chieti, Italy; F. Soscia and L. Tacconi in Latina, Italy; M. Moroni (Scientific Committee), A. d'Arminio Monforte (Scientific Committee), and L. Ravasio in Milan, Italy; M. Piazza, N. Abrescia, M.C. Izzo, M. De Marco, E. Manzillo, S. Nappa, and F. Starace (NeuroICONA Study Coordinator) in Naples, Italy; M.S. Aloisi (Scientific Committee), A. Ammassari (Scientific Committee), A. Antinori (AdICONA Study Coordinator), G. Antonucci, P. De Longis, G. D'Offizi, G. Ippolito (Scientific Committee), R. Murri (Scientific Committee), L. Ortona (Scientific Committee), P. Narciso, P. Noto, N. Petrosillo, P. Pezzotti (Scientific Committee), G. Rezza (Scientific Committee), M.P. Trotta (Scientific Committee), and M. Zaccarelli in Rome; P. Caramello and G.C. Orofino in Torino, Italy; and A.W. Wu (Scientific Committee) in Baltimore.

Supported by Istituto Superiore di Sanità – II and III Programma Nazionale di Ricerca sull'AIDS and Ricerca Corrente e Finalizzata degli Istituti di Ricovero e Cura a Caratterre Scientifico. The ICONA network is supported by an educational grant from GlaxoSmithKline, Italy.

The authors thank O.A. Selnes, J. Catalan, M. Guarinieri, and M.R. Iardino for their helpful suggestions.


  REFERENCES

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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