Baseline characteristics
At baseline (M0), 543 patients with HIV infection were enrolled (Fig. 1). The mean age was 35 years (SD: 11), 98.4% were male, and 91.9% were Han. The mean body mass index (BMI) was 22.5 kg/m2 (SD: 4.8), and 26.8% were obese. In terms of education levels, 356 (65.6%) patients had attained a college degree or higher, 125 (23.0%) were married, 40 (7.4%) were students, and 91 (16.8%) were unemployed. Ninety-seven (17.9%) patients began treatment within a week from HIV diagnosis, and 284 (52.3%) received treatment one to four weeks after HIV diagnosis. The mean CD4 + cell count at enrolment was 335 cells/mm3 (SD: 233), and 317 (58.4%) patients had CD4 + cell counts ranging from 200 to 499 cells/mm3. The mean HIV-1 ribonucleic acid (RNA) level was 19,175 [15]copies/mL. The other clinical characteristics, complications, and laboratory indices of all HIV patients are shown in Table 1.
Table 1
Demographic, clinical, and psychosocial characteristics of HIV patients.
|
|
Total participants
|
Characteristics
|
Category
|
N = 543
|
%
|
Sex
|
Male
|
532
|
97.97
|
|
Female
|
11
|
2.03
|
Age, years
|
< 30
|
215
|
39.59
|
|
30–50
|
264
|
48.62
|
|
> 50
|
64
|
11.79
|
Ethnicity
|
Han
|
492
|
90.61
|
|
Others
|
51
|
9.39
|
Education
|
High school or lower
|
187
|
34.44
|
|
College or higher
|
356
|
65.56
|
Marital status
|
Married
|
125
|
23.02
|
|
Divorced/separated
|
39
|
7.18
|
|
Single
|
379
|
69.80
|
Employment type
|
White-collar
|
223
|
41.07
|
|
Blue-collar
|
189
|
34.81
|
|
Student
|
40
|
7.37
|
|
Unemployed
|
91
|
16.76
|
BMI
|
< 18.5
|
53
|
9.76
|
|
18.5–24
|
345
|
63.54
|
|
24–28
|
108
|
19.89
|
|
> 28
|
37
|
6.81
|
Alcohol use in the past three months
|
No
|
398
|
73.30
|
|
Yes
|
145
|
26.70
|
Cigarette use in the past three months
|
No
|
403
|
74.22
|
|
Yes
|
140
|
25.78
|
Other chronic diseases
|
Hepatitis C coinfection
|
8
|
1.47
|
|
Hepatitis B coinfection
|
33
|
6.08
|
|
TB
|
4
|
0.74
|
|
Diabetes
|
113
|
20.81
|
|
Hypertension
|
98
|
18.05
|
Time since HIV diagnosis
|
< 1 week
|
97
|
17.86
|
|
1 week- 1 month
|
284
|
52.30
|
|
> 1 month
|
162
|
29.83
|
Sexual transmission route
|
Homosexual/bisexual
|
494
|
90.98
|
|
Heterosexual
|
27
|
4.97
|
|
Unknown
|
22
|
4.05
|
HIV-1 RNA (copies/mL)
|
< 100 000
|
201
|
37.02
|
|
10000–50000
|
169
|
31.12
|
|
> 500 000
|
173
|
31.86
|
CD4 + cell count, cells/ul
|
< 50
|
37
|
6.81
|
|
50–199
|
90
|
16.57
|
|
200–499
|
317
|
58.38
|
|
> 500
|
99
|
18.23
|
WHO Stage
|
I
|
391
|
72.01
|
|
II
|
112
|
20.63
|
|
III/IV
|
40
|
7.37
|
cART initiated
|
TDF + 3TC + EFV
|
497
|
91.53
|
|
AZT + 3TC + EFV
|
46
|
8.47
|
HIV, human immunodeficiency virus; BMI, body mass index; TB, tuberculosis; RNA, ribonucleic acid; CD4+, cluster of differentiation 4-positive; WHO, World Health Organization; cART, combination antiretroviral therapy; TDF, tenofovir; 3TC, lamivudine; EFV, efavirenz; AZT, zidovudine |
Incidence of drug discontinuation
In this study, 444 patients (81.8%) completed all assessments during the 12-month follow-up and were included in the final analysis (Fig. 1), while 99 were excluded due to lack of data throughout the whole 12-month follow-up period. A total of 51 (9.4%) patients discontinued treatment, 20 (3.7%) of which were due to EFV-related side effects, five (0.9%) were due to EFV resistance, and 26 (4.8%) were due to other causes. Of the 20 patients who discontinued treatment due to EFV-related adverse event, six (1.1%) discontinued due to NPAEs, 12 (2.2%) due to rash, one (0.2%) due to abnormal liver function, and one (0.2%) due to dyslipidaemia. In those with NPAEs, two discontinued within the first two weeks, one at one to two months, two at three to six months, and one at nine to twelve months after starting EFV treatment.
Anxiety, depression and sleep disturbance at baseline (M0)
The mean HADS-A and HADS-D scores of the 543 enrolled patients at M0 were 5.83 ± 4.13 and 4.94 ± 3.87, respectively. Of these, 165 (30.4%) patients had anxiety and 123 (22.7%) had depression at M0 based on the HADS-A and HADS-D scores. The mean PSQI score at M0 was 7.09 ± 3.08, and 370 (68.1%) patients were suffering from sleep disturbances.
Baseline anxiety, depression, and sleep quality scores for all 543 patients enrolled at the start of the study, the 444 patients who completed the 12-month follow-up, and the 51 patients with drug discontinuation are listed in Table 2. There were no significant differences in any M0 scores between any two of these three groups.
Table 2
Classification of the patients’ anxiety, depression and sleep quality at baseline.
Parameter
|
Score
|
Participants enrolled at baseline
|
Participants completing the 12-month follow-up
|
Participants with drug discontinuation
|
(n = 543)
Frequency (%)
|
(n = 444)
Frequency (%)
|
(n = 51)
Frequency (%)
|
Anxiety
|
Normal (0–7)
|
380 (70.0)
|
314 (70.7)
|
33 (64.7)
|
|
Mild (8–10)
|
94 (17.3)
|
73 (16.4)
|
10 (19.6)
|
|
Moderate (11–14)
|
47 (8.7)
|
40 (9.0)
|
5 (9.8)
|
|
Severe (15–21)
|
22 (4.1)
|
17 (3.8)
|
2 (3.9)
|
Depression
|
Normal (0.7)
|
420 (77.4)
|
346 (77.9)
|
40 (78.4)
|
|
Mild (8–10)
|
69 (12.7)
|
58 (13.1)
|
6 (11.8)
|
|
Moderate (11–14)
|
38 (7.0)
|
29 (6.5)
|
4 (7.8)
|
|
Severe (15–21)
|
16 (2.9)
|
11 (2.5)
|
1 (2.0)
|
Sleep quality
|
Normal (0–5)
|
173 (31.9)
|
138 (31.1)
|
13 (25.5)
|
|
Poor sleep (6–10)
|
299 (55.1)
|
253 (56.9)
|
31 (60.8)
|
|
Severely poor sleep (11–21)
|
71 (13.1)
|
53 (11.9)
|
7 (13.7)
|
Anxiety, depression and sleep quality were assessed and categorized based on the Hospital Anxiety and Depression Scale (HADS-A, HADS-D) and the Pittsburgh Sleep Quality Index (PSQI), respectively. |
HADS-D and HADS-A scores decreased over the 12-month follow-up
HADS-A and HADS-D scores steadily and significantly decreased at M0.5, M1, M3, M6, M9, and M12 compared to M0 baseline levels (Table 3, all p-values < 0.001). Based on HADS-A and HADS-D scores at M0, patients were stratified into normal M0-HADS-A (n = 314) and normal M0-HADS-D (n = 346) groups, and abnormal M0-HADS-A (n = 130) and abnormal M0-HADS-D (n = 98) groups. In both abnormal groups, the HADS-A and HADS-D scores significantly decreased at M0.5 compared to M0 (p < 0.001); scores continued to decrease until M12 (Fig. 2). In the normal group, the HADS-A and HADS-D scores were significantly lower compared to M0 from M3 (p < 0.01) and M9 (p < 0.001) onward, respectively, reaching their lowest values by M12 (Fig. 2a,b).
Table 3
Mean differences (95% CI) and the significance of changes in HADS-A, HADS-D, and PSQI scores between each time point of follow-up versus baseline (using paired t-test with missing values excluded pairwise).
|
HADS-A
|
HADS-D
|
PSQI
|
|
mean diff.
|
95% CI
|
p-value
|
mean diff.
|
95% CI
|
p-value
|
mean diff.
|
95% CI
|
p-value
|
M0 vs. M0.5
|
1.03
|
0.53 to 1.53
|
< 0.0001
|
0.79
|
0.30 to 1.27
|
< 0.0001
|
0.17
|
-0.24 to 0.59
|
0.9061
|
M0 vs. M1
|
1.46
|
0.92 to 1.99
|
< 0.0001
|
0.89
|
0.39 to 1.39
|
< 0.0001
|
0.64
|
0.22 to 1.06
|
0.0002
|
M0 vs. M3
|
1.78
|
1.21 to 2.34
|
< 0.0001
|
1.20
|
0.69 to 1.71
|
< 0.0001
|
1.16
|
0.74 to 1.59
|
< 0.0001
|
M0 vs. M6
|
2.19
|
1.61 to 2.76
|
< 0.0001
|
1.54
|
0.98 to 2.10
|
< 0.0001
|
1.32
|
0.84 to 1.79
|
< 0.0001
|
M0 vs. M9
|
2.37
|
1.82 to 2.92
|
< 0.0001
|
1.73
|
1.18 to 2.29
|
< 0.0001
|
1.62
|
1.16 to 2.09
|
< 0.0001
|
M0 vs. M12
|
2.69
|
2.08 to 3.29
|
< 0.0001
|
2.03
|
1.49 to 2.56
|
< 0.0001
|
1.64
|
1.17 to 2.10
|
< 0.0001
|
HADS-A, Hospital Anxiety and Depression Scale-Anxiety subscale; HADS-D, Hospital Anxiety and Depression Scale-Depression subscale; PSQI, Pittsburgh Sleep Quality Index; CI, confidence interval; M, month. |
Based on the HADS-A and HADS-D scores, the frequencies of mild anxiety and depression at M0.5 were slightly higher compared to M0 (14.2% vs. 13.1% for HADS-D, and 18.0% vs. 16.4% for HADS-A, respectively), but the differences were not statistically significant. These frequencies decreased from M1 onward, reaching their lowest values at M12 (7.9% for HADS-D and 8.6% for HADS-A). For moderate and severe anxiety, the frequencies decreased significantly at M0.5, M1, M3, M6, M9, and M12 compared to M0 (Fig. 3a,all p-values < 0.01). For moderate and severe depression, the frequencies significantly decreased at M6 and M9, respectively, compared to M0 (p < 0.01). No severe anxiety or depression scores were observed at M9 or M12 (Fig. 3a,b).
Sleep quality over the 12-month follow-up
For all 444 patients, PSQI scores significantly decreased at M1, M3, M6, M9, and M12 compared to M0 (all p-values < 0.001, Table 3). Patients were stratified into two groups based on PSQI scores at M0 into a normal M0-PSQI (n = 138) and an abnormal M0-PSQI (n = 306) group. In the abnormal M0-PSQI group, the PSQI scores decreased significantly from M0.5 onward, reaching the lowest values at M12 (Fig. 2c). However, in the normal M0-PSQI group, PSQI scores increased significantly at M0.5 compared to M0 (p < 0.0001, Fig. 2c), then continually decreased from M1 to M12, although the PSQI score at M12 was still significantly higher than baseline M0 values (p < 0.05).
The frequency of mild sleep disturbance significantly decreased from M3 onward, reaching the lowest values at M12 (p < 0.0001). The rate of severe sleep disturbance significantly decreased at M1, M3, M6, M9 and M12 compared to M0 (Fig. 3c).
Risk factors for severe anxiety, depression, and sleep disturbances
To overcome the negative impact of NPAEs during EFV treatment, it is necessary to identify risk factors associated with severe anxiety, depression, and sleep disturbance. In our study, 89 (20.0%), 51 (11.5%), and 54 (12.2%) patients experienced at least one episode of severe anxiety, depression, and sleep disturbance at some point during the 12-month period. In order to assess predictive factors for these severe NPAEs, univariate logistic regression was performed (Table 4). High school education or lower (p = 0.04), being a student (p = 0.003) or unemployed (p = 0.001), and WHO stages of III/IV (p = 0.004) were associated with higher probability of severe anxiety. High school education or lower (p = 0.001), being a blue-collar worker (p = 0.02), unemployed (p < 0.001), or divorced/separated (p = 0.007) were associated with severe depression. A high school education or lower (p = 0.047), being unemployed (0.008), and having a viral load > 50,000 copies/mL (p = 0.035) were associated with severely poor sleep. In addition, abnormal HADS-A, HADS-D, and PSQI scores at M0 were all associated with high probabilities of severe anxiety, depression, and sleep disturbance over the 12-month follow-up (Table 4).
Table 4
Univariate and multivariate logistic regression analyses to identify associations between demographic characteristics and severe anxiety, depression, and sleep disturbance over the 12-month follow-up period.
|
Univariate
|
|
Multivariate
|
|
Variable
|
OR (95% CI)
|
p value
|
OR (95% CI)
|
p value
|
Factors for severe anxiety
|
Level of Education
|
|
|
|
|
College or higher (reference)
|
1
|
|
1
|
|
High school or lower
|
2.07(1.03–4.15)
|
0.040
|
1.68(0.69–4.07)
|
0.254
|
Employment type
|
|
|
|
|
White-collar (reference)
|
1
|
|
1
|
|
Blue-collar
|
1.98(0.93–4.22)
|
0.076
|
2.13(0.88–5.20)
|
0.095
|
Student
|
4.83(1.71–13.62)
|
0.003
|
6.26(1.93–20.31)
|
0.002
|
Unemployed
|
4.14(1.85–9.28)
|
0.001
|
3.4(1.29–8.92)
|
0.013
|
WHO stage
|
|
|
|
|
I (reference)
|
1
|
|
1
|
|
II
|
1.53(0.77–3.07)
|
0.227
|
1.58(0.73–3.45)
|
0.247
|
III/IV
|
3.73(1.52–9.17)
|
0.004
|
4.39(0.77–6.84)
|
0.007
|
Baseline HADS-A > 7
|
5.72(3.13–10.47)
|
< 0.001
|
3.53(1.69–7.39)
|
0.001
|
Baseline HADS-D > 7
|
5.4(2.98–9.78)
|
< 0.001
|
2.71(1.28–5.71)
|
0.009
|
Baseline PSQI > 5
|
2.47(1.17–5.21)
|
0.017
|
1.43(0.62–3.31)
|
0.400
|
Factors for severe depression
|
Level of Education
|
|
|
|
|
College or higher (reference)
|
1
|
|
1
|
|
High school or lower
|
3.13(1.57–6.28)
|
0.001
|
1.94(0.80–4.73)
|
0.144
|
Employment
|
|
|
|
|
White-collar (reference)
|
1
|
|
1
|
|
Blue-collar
|
2.55(1.16–5.63)
|
0.020
|
2.5(0.94–6.63)
|
0.065
|
Student
|
2.11(0.54–8.20)
|
0.280
|
2.58(0.56–11.93)
|
0.224
|
Unemployed
|
5.87(2.56–13.47)
|
< 0.001
|
5.14(1.85–14.29)
|
0.002
|
Marital status
|
|
|
|
|
Single (reference)
|
1
|
|
1
|
|
Married
|
1.87(0.97–3.63)
|
0.062
|
1.28(0.57–2.91)
|
0.552
|
Divorced/separated
|
3.71(1.44–9.59)
|
0.007
|
3.89(1.18–12.85)
|
0.026
|
Baseline HADS-A > 7
|
5.59(3.01–10.38)
|
< 0.001
|
2.45(1.13–5.30)
|
0.023
|
Baseline HADS-D > 7
|
9.25(4.91–17.42)
|
< 0.001
|
5.08(2.33–11.08)
|
< 0.001
|
Baseline PSQI > 5
|
3.14(1.38–7.17)
|
0.006
|
1.68(0.66–4.27)
|
0.279
|
Factors for severe sleep disturbance
|
Level of Education
|
|
|
|
|
College or higher (reference)
|
1
|
|
1
|
|
High school or lower
|
1.78(0.98–3.24)
|
0.047
|
1.55(0.78–3.08)
|
0.211
|
Employment
|
|
|
|
|
White-collar (reference)
|
1
|
|
1
|
|
Blue-collar
|
1.37(0.79–2.39)
|
0.260
|
1.18(0.61–2.26)
|
0.626
|
Student
|
1.48(0.55–3.96)
|
0.438
|
1.69(0.59–4.84)
|
0.328
|
Unemployed
|
2.38(1.26–4.51)
|
0.008
|
1.73(0.83–3.58)
|
0.143
|
Viral load (copies/ml)
|
|
|
|
|
≤100,000 (reference)
|
1
|
|
1
|
|
10,000–50,000
|
0.95(0.52–1.75)
|
0.881
|
0.99(0.52–1.89)
|
0.985
|
༞50,000
|
1.81(1.04–3.14)
|
0.035
|
1.72(0.96–3.09)
|
0.071
|
Baseline HADS-A > 7
|
2.4(1.49–3.89)
|
< 0.001
|
1.2(0.67–2.14)
|
0.543
|
Baseline HADS-D > 7
|
3.66(2.21–6.06)
|
< 0.001
|
2.69(1.48–4.91)
|
0.001
|
Baseline PSQI > 5
|
4.45(2.23–8.90)
|
< 0.001
|
3.49(1.70–7.15)
|
0.001
|
OR, odds ratio; CI, confidence interval; M12, month twelve; WHO, World Health Organization; HADS-A, Hospital Anxiety and Depression Scale- Anxiety subscale; HADS-D, Hospital Anxiety and Depression Scale- Depression subscale; PSQI, Pittsburgh Sleep Quality Index. |
All factors were included in the multivariate logistic regression analysis using the forward stepwise (conditional) method, which revealed that HADS-A (M0 > 7 (p < 0.001), HADS-D (M0) > 7 (p < 0.001), being a student (p = 0.002) or unemployed (p = 0.013), and WHO stages of III/IV (p = 0.007) were independent predictive factors for severe anxiety. Being unemployed (p = 0.002), divorced/separated (p = 0.026), and scores of HADS-A (M0) > 7 and HADS-D (M0) > 7 (p < 0.001) were predictive factors associated with severe depression. HADS-D (M0) > 7 (p = 0.001) and PSQI (M0) > 5 (p = 0.001) were independent predictive factors for severe sleep disturbances (Table 4).
Risk factors for anxiety, depression and sleep disturbance 12 months after EFV treatment
As shown in Table 5, univariate and multivariate logistic regression analyses were performed to assess the risk factors associated with neuropsychiatric disorders at M12. Abnormal HADS-A, HADS-D, and PSQI scores at M0 were significant factors associated with anxiety, depression, and sleep disturbance at M12 based on univariate logistic analyses (Table 5). High school education or lower (p = 0.032), viral loads > 50,000 copies/mL (p = 0.039), and WHO stages III/IV (p = 0.031) were associated with anxiety at M12. WHO stage III/IV (p = 0.018) was associated with depression and a high school education or lower (p = 0.036) was associated with sleep disturbances at M12. Multivariate analyses revealed that HADS-A (M0) > 7 (p = 0.036), HADS-D(M0) > 7 (p = 0.040), and PSQI (M0) > 5 (p = 0.024) were independent factors associated with higher probability of anxiety, HADS-A (M0) > 7 (p = 0.021) and HADS-D(M0) > 7 (p = 0.001) were associated with depression, and HADS-A (M0) > 7 (p < 0.001) was associated with higher risk of sleep disturbance at M12.
Table 5
Logistic regression analysis to identify associations between demographic characteristics and anxiety, depression, and sleep disturbance at M12.
|
Univariate
|
|
Multivariate
|
|
Variable
|
OR (95% CI)
|
p value
|
OR (95% CI)
|
p value
|
Factors for anxiety at M12
|
|
|
|
|
Level of Education
|
|
|
|
|
College or above (reference)
|
1
|
|
1
|
|
High school or less
|
1.246(0.583–2.662)
|
0.040
|
1.212(0.522–2.815)
|
0.654
|
Viral load (copies/ml)
|
|
|
|
|
≤100,000 (reference)
|
1
|
|
1
|
|
10,000–50,000
|
0.594(0.256–1.378)
|
0.225
|
0.783(0.365–1.678)
|
0.529
|
༞50,000
|
1.358(0.676–4.727)
|
0.039
|
0.451(0.180–1.127)
|
0.088
|
WHO stage
|
|
|
|
|
I (reference)
|
1
|
|
1
|
|
II
|
0.628(0.254–1.552)
|
0.313
|
0.772(0.291–2.047)
|
0.603
|
III/IV
|
1.957(0.696–5.501)
|
0.031
|
0.801(0.248–2.590)
|
0.711
|
Baseline HADS-A > 7
|
4.311(2.279–8.152)
|
< 0.001
|
2.267(1.055–4.871)
|
0.036
|
Baseline HADS-D > 7
|
3.292(1.740–6.231)
|
< 0.001
|
2.273(1.036–4.987)
|
0.040
|
Baseline PSQI > 5
|
5.183(1.818–14.774)
|
0.002
|
3.562(1.182–10.737)
|
0.024
|
Factors for depression at M12
|
|
|
|
|
WHO stage
|
|
|
|
|
I (reference)
|
1
|
|
1
|
|
II
|
0.768(0.326–1.805)
|
0.545
|
0.686(0.263–1.792)
|
0.442
|
III/IV
|
2.027(0.719–5.709)
|
0.018
|
1.053(0.314–3.539)
|
0.933
|
Baseline HADS-A
|
4.796(2.521–9.125)
|
< 0.001
|
2.526(1.151–5.546)
|
0.021
|
Baseline HADS-D
|
6.215(3.263–11.836)
|
< 0.001
|
3.628(1.652–7.968)
|
0.001
|
Baseline PSQI
|
2.654(1.154–6.102)
|
0.022
|
1.351(0.544–3.358)
|
0.517
|
Factors for sleep disturbance at M12
|
|
|
|
|
Level of Education
|
|
|
|
|
College or above (reference)
|
1
|
1
|
|
1
|
High school or less
|
1.578(0.938–2.653)
|
0.036
|
1.594(0.925–2.745)
|
0.093
|
Baseline HADS-A > 7
|
2.864(1.865–4.397)
|
< 0.001
|
2.635(1.603–4.333)
|
< 0.001
|
Baseline HADS-D > 7
|
1.800(1.140–2.841)
|
0.012
|
1.056(0.615–1.813)
|
0.843
|
Baseline PSQI > 5
|
1.935(1.283–2.920)
|
0.002
|
1.497(0.965–2.322)
|
0.072
|
OR, odds ratio; CI, confidence interval; M12, month twelve; WHO, World Health Organization; HADS-A, Hospital Anxiety and Depression Scale- Anxiety subscale; HADS-D, Hospital Anxiety and Depression Scale- Depression subscale; PSQI, Pittsburgh Sleep Quality Index. |