Supplementary Material
Table S1. Comparisons of characteristics between serum cryptococcal antigen testers and non- testers among newly diagnosed people living with HIV who had CD4 lymphocyte count less than 100 cells/μL
Total N=1150
CrAg testers N=800
CrAg non- testers N=350
p- value
Age, median (IQR), years 33.8 (28.6, 43.0) 34.8 (29.4, 43.9) 31.8 (27.4, 39.7) <0.001
Male sex at birth, n (%) 1110 (96.5) 764 (96.6) 346 (96.4) 0.863
Geographic location, n (%)
Northern Taiwan 526 (45.7) 363 (45.9) 163 (45.4) 0.974
Central Taiwan 182 (15.8) 126 (15.9) 56 (15.6)
Southern Taiwan 442 (38.4) 302 (38.2) 140 (39)
Risk group for HIV acquisition, n (%)
MSM 888 (77.2) 606 (76.6) 282 (78.6) 0.495
IDU 19 (1.7) 11 (1.4) 8 (2.2) 0.322
Year of HIV diagnosis, n (%)
2009-11 305 (26.5) 202 (25.5) 103 (28.7) 0.004
2012-13 285 (24.8) 179 (22.6) 106 (29.5)
2014-15 253 (22.0) 176 (22.3) 77 (21.4)
2016-18 307 (26.7) 234 (29.6) 73 (20.3)
Being outpatients at the time of HIV diagnosis, n (%)
597 (51.9) 341 (43.1) 256 (71.3) <0.001
Any opportunistic infections other than cryptococcosis, n (%)
650 (56.5) 491 (62.1) 159 (44.3) <0.001
Anti-HAV IgG, n (%) (N = 928) 258 (27.8) 196 (30.4) 62 (21.8) 0.007
HBsAg, n (%) (N = 1124) 184 (16.4) 129 (16.7) 55 (15.6) 0.665
Anti-HCV, n (%) (N = 1131) 52 (4.6) 34 (4.4) 18 (5.1) 0.646
Rapid plasma reagin titer ≥1:4, n (%) (N = 1128)
178 (15.8) 119 (15.3) 59 (16.8) 0.537
White blood-cell count (N = 1147)
Leukopenia (<4,000 cells/μL) 403 (35.1) 268 (33.9) 135 (37.8) 0.018
1
Normal (4,000 – 9,999 cells/μL) 611 (53.3) 417 (52.8) 194 (54.3) Leukocytosis (≥10,000 cells/μL) 133 (11.6) 105 (13.3) 28 (7.8) Anemia (hemoglobin <12 g/dL), n
(%) (N = 1145)
619 (54.1) 447 (56.7) 172 (48.3) 0.010
Abnormal liver function, n (%) 539 (46.9) 395 (49.9) 144 (40.1) 0.002 Nadir CD4 lymphocyte count,
median (IQR), cells/μL
33.5 (15.9, 58.4) 31 (14, 54) 42 (19.5, 68.5) <0.001 CD4 <50 cells/μL, n (%) 769 (66.9) 561 (70.9) 208 (57.9) <0.001 Plasma HIV RNA load, median (IQR),
log10 copies/ml (N = 1134)
5.4 (5.0, 5.8) 5.4 (5.0, 5.8) 5.3 (4.9, 5.8) 0.067
>5 log10 copies/ml, n (%) 857 (75.6) 603 (77.3) 254 (71.8) 0.052 Abbreviations: IDU, injection drug user; IQR, interquartile range; HAV, hepatitis A virus; HBsAg,
hepatitis B virus surface antigen; HCV, hepatitis C virus; MSM, men who have sex with men.
Table S2. Comparisons between people living with HIV (PLWH) with positive serum cryptococcal antigen (CrAg) and those with negative serum CrAg among 2252 newly diagnosed PLWH
Total N=2252
Positive CrAg N=76
Negative CrAg N=2176
Univariate p-value
Multivariate p-value Age, median (IQR), years 30.8 (25.4, 38.2) 33.5 (29.5, 41.5) 30.7 (25.3, 38.0) 0.002 0.279
Male sex at birth, n (%) 2190 (97.2) 76 (100.0) 2114 (97.2) 0.270
Geographic location, n (%)
Northern Taiwan 1051 (46.7) 28 (36.8) 1023 (47) 0.221
Central Taiwan 335 (14.9) 13 (17.1) 322 (14.8)
Southern Taiwan 866 (38.5) 35 (46.1) 831 (38.2)
Risk group for HIV acquisition, n (%)
MSM 1825 (81) 58 (76.3) 1767 (81.2) 0.297
IDU 66 (2.9) 0 (0.0) 66 (3.0) 0.169
Year of HIV diagnosis, n (%)
2009-11 493 (21.9) 26 (34.2) 467 (21.5) 0.061 Ref
2012-13 404 (17.9) 13 (17.1) 391 (18.0) 0.168
2014-15 562 (25.0) 13 (17.1) 549 (25.2) 0.176
2016-18 793 (35.2) 24 (31.6) 769 (35.3) 0.395
Being outpatients at the time of HIV diagnosis, n (%)
1572 (69.8) 24 (31.6) 1548 (71.1) <0.001 <0.001
Any opportunistic infections other than cryptococcosis, n (%)
632 (28.1) 64 (84.2) 568 (26.1) <0.001 0.051
Anti-HAV IgG, n (%) (N = 2014) 441 (21.9) 18 (30.0) 423 (21.6) 0.152
HBsAg, n (%) (N = 2212) 241 (10.9) 11 (14.9) 230 (10.8) 0.255
Anti-HCV, n (%) (N = 2231) 168 (7.5) 5 (6.8) 163 (7.6) >0.999
Rapid plasma reagin titer ≥1:4, n (%) (N = 2229)
357 (16.0) 13 (17.3) 344 (16.0) 0.749
White blood-cell count (N = 2251)
Leukopenia (<4,000 cells/μL) 449 (19.9) 29 (38.2) 420 (19.3) 0.001 0.586
Normal (4,000 – 9,999 cells/μL) 1632 (72.5) 41 (53.9) 1591 (73.1) Ref
Leukocytosis (≥10,000 cells/μL) 170 (7.6) 6 (7.9) 164 (7.5) 0.338
Anemia (hemoglobin <12 g/dL), n (%) (N
= 2245)
646 (28.8) 50 (65.8) 596 (27.5) <0.001 0.012
3
Abnormal liver function, n (%) 835 (37.1) 36 (47.4) 799 (36.7) 0.070 0.690 Nadir CD4 lymphocyte count, median
(IQR), cells/μL
208 (50, 378) 37 (14, 70) 217 (54, 383) <0.001 <0.001
<100, n (%) 791 (35.1) 62 (81.6) 729 (33.5) <0.001
100-200, n (%) 313 (13.9) 8 (10.5) 305 (14.0)
>200, n (%) 1148 (51.0) 6 (7.9) 1142 (52.5)
Plasma HIV RNA load, median (IQR), log10
copies/ml (N = 2237)
5 (4.4, 5.5) 5.2 (4.6, 5.6) 5 (4.4, 5.5) 0.037
>5 log10 copies/ml, n (%) 1087 (48.6) 51 (67.1) 1036 (47.9) 0.001 0.100
Abbreviations: IDU, injection drug user; IQR, interquartile range; HAV, hepatitis A virus; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; MSM, men who have sex with men.
Figure S1. (a) Proportions and (b) numbers of people living with HIV who presented with baseline CD4 lymphocyte counts of <100, 100-199, and ≥200 cells/µL from 2009 to 2018
(a)
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Year of diagnosis
Precentage CD4 count
<100 100−199
>=200
(b)
108 94 103 150 135 105 148 104 112 91 47 61 76
86 78 69
96
80 56 59 213 271
340 433
388 460 435
387 328
249
0 200 400 600
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Year of diagnosis
Number of patients
CD4 count
<100 100−199
>=200
5
Figure S2. Annual prevalence of (a) cryptococcal antigenemia and (b) cryptococcal antigen (CrAg) titer ≥1:8 by CD4 lymphocyte group among newly diagnosed people living with HIV who tested for CrAg from 2009 to 2018
(a) p for trend = 0.356
p for trend = 0.006
p for trend = 0.122 0.0%
5.0%
10.0%
15.0%
20.0%
2009 2010 2011 2012 2013 20142014.5 2015 2016 2017 2018
Prevalence (%)
CD4
<100 100−199
>=200
(b) p for trend = 0.110
p for trend = 0.007
p for trend = 0.091 0.0%
5.0%
10.0%
15.0%
20.0%
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Year
Prevalence (%)
CD4
<100 100−199
>=200
Figure S3. Kaplan-Meier plot demonstrating 6-month all-cause mortality stratified by CD4 category among people living with HIV who tested for cryptococcal antigen
++++ ++++++
+++++++ +
+ + + ++
++ ++ + + + + + ++ ++++ ++ + + + +++ + +
++ + + + + +
++ ++++++++++++++ + ++++ ++++ ++ + +++++++ ++ ++ +++++ +++++++++
p < 0.0001
0.85 0.90 0.95 1.00
0 30 60 90 120 150 180
Time after HIV diagnosis (days)
Survival probability
+ CD4 <100 + CD4 100−199 + CD4 >=200
7
Figure S4. Kaplan-Meier plot demonstrating 6-month all-cause mortality by timing of cryptococcal antigen (CrAg) testing and outpatient/inpatient status at the time of HIV diagnosis among people living with HIV who presented with initial CD4 lymphocyte count less than 200 cells/µL
Figure S5. Kaplan-Meier plot demonstrating (a) 6-month all-cause mortality by timing of
cryptococcal antigen (CrAg) testing and outpatient/inpatient status at the time of HIV diagnosis, and (b) 12-month all-cause mortality by timing of CrAg among people living with HIV who presented with initial CD4 lymphocyte count less than 100 cells/µL
(a)
++
+ +
+
++ + + +
+ +
+ ++
+
+ + + +
+ + + +
+ +++ +
+ + + + + +++ + +
+
+ + +
+ +
+
p = 0.0033
0.75 0.80 0.85 0.90 0.95 1.00
0 30 60 90 120 150 180
Time after HIV diagnosis (days)
Survival probability
+ +
+ +
+ +
CrAg before HIV, inpatient CrAg before HIV, outpatient
Early CrAg, inpatient Early CrAg, outpatient
Late CrAg, inpatient Late CrAg, outpatient
(b)
+
+ + + + + + +
++++
+ + ++ ++++ +
+ +++++ + ++++ +++ + +
+ +
+
+ + +
p = 0.13
0.85 0.90 0.95 1.00
0 60 120 180 240 300 360
Time after HIV diagnosis (days)
Survival probability
+ CrAg before HIV + Early CrAg + Late CrAg
9
Figure S6. Kaplan-Meier plot demonstrating 12-month all-cause hospital admission by the timing of cryptococcal antigen testing among people who received HIV diagnosis as outpatients and
presented with initial CD4 lymphocyte count less than 200 cells/µL
+ +
+ ++ +++ +++ + + ++ +++++++++ ++ ++++ + +++
+
+ + + + + + + + +
p = 0.024
0.5 0.6 0.7 0.8 0.9 1.0
0 60 120 180 240 300 360
Time after HIV diagnosis (days)
Free of hospitalization