Increased mortality among HIV-positive men on antiretroviral therapy: survival differences between sexes explained by late initiation in Uganda

Figures & data

Figure 1 Illustration of causal pathways.

Notes: The objective of the mediational analysis was to separate the effect of gender into the part explained by baseline CD4, referred to as the indirect effect, and that explained by everything else, referred to here as the direct effect. Additionally, confounders to these pathways are included in the model, but excluded from this figure.

Table A1 A comparison of demographic, behavioral, and clinical characteristics across survival groups

Variable	Alive (n = 4575)	Dead (n = 200)	P-value
Age [median (IQR)]	33 (27, 40)	34 (27.5, 41)	0.0721
Sex
Female	2983 (65.2%)	116 (58.0%)	0.0409
Male	1592 (34.8%)	84 (42.0%)
Marital status
Married/partner	1326 (29.0%)	54 (27.0%)	0.1982
Widowed/single	970 (21.2%)	34 (17.0%)
NA/not reported	2279 (49.8%)	112 (56.0%)
Education
Primary or less	1203 (26.3%)	49 (24.5%)	0.7300
Some secondary or more	1155 (25.2%)	55 (27.5%)
Not reported	2217 (48.5%)	96 (48.0%)
Sexually active at BL
Yes	1562 (34.1%)	57 (28.5%)	0.1246
No	2030 (44.4%)	103 (51.5%)
Not reported	983 (21.5%)	40 (20.0%)
Disclose to partner
Yes	1289 (87.5%)	45 (83.3%)	0.3966
Some	4 (0.3%)	0 (0%)
No	174 (12.2%)	9 (16.7%)
Partner has tested
Yes	1112 (79.5%)	37 (68.5%)	0.1121
Some	8 (0.6%)	0 (0%)
No	278 (19.9%)	17 (31.5%)
Syphilis
Yes	396 (14.5%)	16 (12.9%)	0.6960
No	2340 (85.5%)	108 (87.1%)
Hepatitis B
Yes	228 (5.0%)	16 (8.0%)	0.1072
No	4347 (95.0%)	184 (92.0%)
Hepatitis C
Positive	20 (0.4%)	0 (0%)	1.000
Negative	4555 (99.6%)	200 (100%)
Anemic
Positive	113 (2.5%)	40 (21.2%)	<0.0001
Negative	4391 (97.5%)	149 (78.8%)
Malaria
Positive	98 (7.2%)	3 (3.1%)	0.1483
Negative	1270 (92.8%)	93 (96.9%)

Abbreviations: BL, baseline; IQR, interquartile range.

Table 1 A comparison of demographic, behavioral, and clinical characteristics in men and women

Variable	Women (n = 3099)	Men (n = 1676)	P-value
Age (median [IQR])	32 (27–39)	35 (28–41)	<0.0001
Marital status
Married/partner	727 (23.5%)	653 (39.0%)	<0.0001
Widowed/single	778 (25.1%)	226 (13.5%)
NA/not reported	1594 (51.4%)	797 (47.6%)
Education
Primary or less	834 (26.9%)	418 (24.9%)	0.0095
Some secondary or more	742 (23.9%)	468 (27.9%)
Not reported	1523 (49.1%)	790 (47.1%)
Sexually active at BL
Yes	911 (29.4%)	708 (42.2%)	<0.0001
No	1516 (48.9%)	617 (36.8%)
Not reported	672 (21.7%)	351 (20.9%)
Disclose to partner
Yes	668 (83.6%)	621 (91.7%)	<0.0001
Some	2 (0.3%)	2 (0.3%)
No	129 (16.1%)	54 (8.0%)
Partner has tested
Yes	565 (72.8%)	584 (86.4%)	<0.0001
Not reported	6 (0.8%)	2 (0.3%)
No	205 (26.4%)	90 (13.3%)
Syphilis
Yes	247 (13.4%)	153 (15.1%)	0.1946
No	1603 (86.6%)	857 (84.9%)
Hepatitis B
Yes	139 (4.5%)	105 (6.3%)	0.0091
No	2960 (95.5%)	1571 (93.7%)
Hepatitis C
Positive	15 (0.5%)	5 (0.3%)	0.4822
Negative	3084 (99.5%)	1671 (99.7%)
Anemic
Positive	105 (3.4%)	48 (2.9%)	0.3890
Negative	2955 (96.6%)	1585 (97.1%)
Malaria
Positive	60 (6.2%)	41 (8.2%)	0.1576
Negative	906 (93.8%)	457 (91.8%)

Abbreviations: BL, baseline; IQR, interquartile range.

Figure 2 Kaplan–Meier survival curves for full cohort (Panel A), and Kaplan–Meier survival curves for restricted cohort (Panel B).

Table 2 Comparing disease progression at baseline between men and women with adjustments for antenatal care

Sample	Variable	Women n (%) or median (IQR)	Men n (%) or median (IQR)	P-value	Effect of gender (95% CI)
PMTCT removed (n = 4537)	WHO stage
	I and II	1915 (67%)	973 (58%)	<0.0001	OR: 1.46
	III and IV	946 (33%)	703 (42%)		(1.29, 1.66)
All included (n = 4775)	WHO stage
	I and II	2111 (68%)	973 (58%)	<0.0001	OR: 1.54
	III and IV	988 (32%)	703 (42%)		(1.37, 1.75)
PMTCT removed (n = 4537)	Baseline CD4 (cells/mm^3)	147 (68, 212)	124 (43, 205)	<0.0001	18 (11, 25)*
All included (n = 4775)	Baseline CD4 (cells/mm^3)	149 (71, 215)	124 (43, 205)	<0.0001	20 (13, 27)*

Note:

* These are confidence intervals for the difference in mean CD4 cell counts at baseline between women and men.

Abbreviations: CI, confidence interval; OR, odds ratio; IQR, interquartile range, PMTCT, prevention of mother to child transmission; WHO, World Health Organization.

Table A2 Partitioning the effect of gender through the Weibull model for all four cases analyzed

Variable	Full cohort, LoF adjusted	Reduced cohort, LoF adjusted	Full cohort	Reduced cohort
Direct effect	−0.33 (−0.65, 0.01)	−0.37 (−0.77, 0.03)	−0.30 (−0.65, 0.05)	−0.34 (−0.73, 0.05)
Indirect effect	−0.17 (−0.21, −0.13)	−0.17 (−0.22, −0.13)	−0.20 (−0.26, −0.15)	−0.21 (−0.27, −0.16)
Total effect	−0.49 (−0.82, −0.17)	−0.54 (−0.90, −0.19)	−0.50 (−0.85, −0.15)	−0.54 (−0.89, −0.19)
Indirect effect/total effect*	0.41 (0.18, 0.89)	0.35 (0.15, 0.84)	0.43 (0.22, 1.13)	0.34 (0.15, 0.87)

Note:

* The ratio of indirect effect to total effect represents the proportion of the effect of gender on mortality explained by CD4 cell count at baseline.

Abbreviation: LoF, lost to follow-up.

Table A3 Survival analysis using an Accelerated Failure Time model with a Weibull distribution (sensitivity analyses)

Variable	Unadjusted hazard ratios (95% confidence interval)	Adjusted hazard ratios (95% confidence interval)
Restricted cohort with adjustments for loss to follow-up
Gender
Male vs female	1.35 (1.04, 1.76)	1.23 (0.96, 1.61)
CD4 count (fourth root)	0.59 (0.51, 0.67)	0.59 (0.51, 0.67)
Age at initiation	1.01 (1.00, 1.02)	1.01 (1.00, 1.02)
Scale	N/A	1.76 (1.56, 1.99)
Full cohort without adjustments for loss to follow-up
Gender
Male vs female	1.34 (1.01, 1.76)	1.18 (0.88, 1.57)
CD4 count (fourth root)	0.60 (0.47, 0.76)	0.59 (0.47, 0.76)
Age at initiation	1.02 (1.00, 1.03)	1.02 (1.01, 1.03)
Scale	N/A	1.88 (1.63, 2.15)
Restricted cohort without adjustments for loss to follow-up
Gender
Male vs female	1.38 (1.03, 1.83)	1.20 (0.95, 1.64)
CD4 count (fourth root)	0.58 (0.45, 0.74)	0.58 (0.45, 0.74)
Age at initiation	1.02 (1.00, 1.03)	1.02 (1.01, 1.03)
Scale	N/A	1.87 (1.64, 2.14)

Table 3 Survival analysis using an Accelerated Failure Time model with a Weibull distribution

Variable	Unadjusted hazard ratios (95% confidence interval)	Adjusted hazard ratios (95% confidence interval)
Gender
Male vs female	1.38 (1.03, 1.83)	1.20 (0.95, 1.64)
CD4 count (fourth root)	0.58 (0.45, 0.74)	0.58 (0.45, 0.74)
Age at initiation	1.02 (1.00, 1.03)	1.02 (1.01, 1.03)
Scale	N/A	1.87 (1.64, 2.14)

Table 4 Partitioning the effect of gender through the Weibull model

Effect	Estimate (95% confidence interval)
Direct effect	−0.30 (−0.65, 0.05)
Indirect effect	−0.20 (−0.26, −0.15)
Total effect	−0.50 (−0.85, −0.15)
Indirect effect/total effect*	0.43 (0.22, 1.13)

Note:

* The ratio of indirect effect to total effect represents the proportion of the effect of gender on mortality explained by CD4 cell count at baseline.