Co-occurrence of injection drug use and hepatitis C increases epigenetic age acceleration that contributes to all-cause mortality among people living with HIV

Figures & data

Table 1. Demographic and clinical characterizations.

Variable	IDU+HCV+ (414)	IDU-HCV- (513)	P-value
age	53.04 ± 5.44	50.17 ± 9.39	8.20E–09
BMI	24.92 ± 4.02	26.49 ± 4.89	1.02E–07
ln(PEth)	2.01 ± 1.87	1.78 ± 1.69	6.80E–02
alcohol (AUDIT-C)	3.52 ± 2.85	3.22 ± 2.56	1.73E–01
log10VL	2.63 ± 1.15	2.67 ± 1.25	6.29E–01
survival years	7.37 ± 2.85	8.34 ± 1.93	7.46E–09
sex (male)	100%	100%	NA
race (AA)	83.33%	80.70%	3.39E–01
smoking	69.85%	48.02%	1.77E–09
ART adherence	76.01%	79.91%	2.30E–01
cannabis	87.84%	68.39%	2.10E–10
cocaine	91.60%	52.07%	1.08E–33
stimulant	60.10%	23.95%	3.15E–33
opiate	78.22%	21.96%	3.00E–68

NOTE: ln(PEth): natural logarithm of phosphatidylethanol, an objective measure of alcohol consumption.

AUDIT-C: Alcohol Use Disorders Identification Test-Consumption, first three questions of the Alcohol Use Disorders Identification Test.

VL: viral load.

race: self-reported race/ethnicity; AA: African American.

ART adherence: adherence to antiretroviral therapy.

Cannabis, cocaine, stimulant, and opiate use in the VACS cohort were based on self-reported.

Welch’s two-sample t-test was used to compare means between two groups; chi-square test was used to compare percentages between two groups.

P-values<0.05 are shown in bold.

Figure 1. The workflow of mediation analysis. IDUHCV: comorbid injection drug use with hepatitis C virus status. EAA: Epigenetic Age Acceleration.

Figure 2. The results of mediation analysis. a. Kaplan-Meier curves of IDU+HCV+ and IDU-HCV-. b. Comparison of estimations of Epigenetic Age Acceleration (EAA) between IDU+HCV+ and IDU-HCV-. c. Mediation effect of EAA of IDUHCV on all-cause mortality. IDU+HCV+: People who Inject Drugs Use also co-infected with Hepatitis C Virus; IDU-HCV-: People who without Injection Drugs Use and without Hepatitis C Virus infection.

Table 2. Cox proportional hazards regression analysis for assessing the association of comorbid injection drug use with hepatitis C virus (IDUHCV) with survival rate.

Variable	HR	lower.95	upper.95	p
IDU+HCV+	2.23	1.617	3.085	1.09E–06
age	1.04	1.019	1.065	2.08E–04
race (AA)	1.34	0.853	2.089	2.06E–01
BMI	0.95	0.914	0.988	1.01E–02
smoking	1.33	0.960	1.847	8.60E–02
ln(PEth)	1.00	0.918	1.083	9.47E–01

NOTE: race: self-reported race/ethnicity; BMI: Body Mass Index.

ln(PEth):natural logarithm of phosphatidylethanol, an objective measure of alcohol consumption.

Table 3. Association between comorbid injection drug use with hepatitis C virus (IDUHCV) and Epigenetic Age Acceleration (EAA) among people living with HIV.

Method	Beta	95% CI	p	MDEAA
EAAHorvath	−0.13	(−1.030, 0.766)	7.74E–01	−0.42
EAAHannum	1.53	(0.632, 2.430)	8.90E–04	1.36
EAAPheno	1.79	(0.640, 2.932)	2.34E–03	2.02
EAAGrim	3.22	(2.283, 4.155)	3.33E–11	4.16

NOTE: Adjusted variables include age, self-reported race/ethnicity, body mass index, smoking status, and alcohol consumption.

Table 4. Result of Cox proportional hazards regression analysis for assessing the association between EAA and survival rate with adjustment for the comorbid injection drug use with hepatitis C virus (IDUHCV) status and covariates (age, self-reported race/ethnicity, body mass index, smoking status, alcohol consumption).

Variable	coefficient	HR	lower.95	upper.95	p
EAAHorvath	0.01	1.01	0.99	1.04	3.85E–01
IDUHCV	0.80	2.23	1.61	3.08	1.15E–06
age	0.04	1.04	1.02	1.06	2.28E–04
race	0.30	1.36	0.87	2.13	1.83E–01
BMI	−0.05	0.95	0.91	0.99	9.51E–03
smoking	0.30	1.35	0.97	1.87	7.65E–02
ln(PEth)	−0.01	0.99	0.91	1.08	8.62E–01
EAAHannum	0.03	1.03	1.00	1.06	2.80E–02
IDUHCV	0.76	2.15	1.55	2.98	4.52E–06
age	0.04	1.04	1.02	1.06	1.77E–04
race	0.34	1.41	0.90	2.21	1.36E–01
BMI	−0.05	0.95	0.92	0.99	1.70E–02
smoking	0.29	1.33	0.96	1.85	8.58E–02
ln(PEth)	−0.01	0.99	0.91	1.07	7.27E–01
EAAPheno	0.03	1.03	1.01	1.05	9.86E–03
IDUHCV	0.76	2.14	1.54	2.96	4.80E–06
age	0.04	1.04	1.02	1.06	2.59E–04
race	0.30	1.34	0.86	2.10	1.96E–01
BMI	−0.05	0.95	0.92	0.99	1.34E–02
smoking	0.23	1.26	0.90	1.75	1.74E–01
ln(PEth)	−0.01	0.99	0.91	1.07	7.36E–01
EAAGrim	0.03	1.03	1.01	1.06	1.17E–02
IDUHCV	0.70	2.01	1.44	2.80	3.72E–05
age	0.04	1.04	1.02	1.07	1.40E–04
race	0.19	1.21	0.77	1.91	4.07E–01
BMI	−0.05	0.95	0.92	0.99	1.90E–02
smoking	0.14	1.15	0.81	1.62	4.43E–01
ln(PEth)	−0.01	0.99	0.91	1.07	7.79E–01

NOTE: EAA: Epigenetic Age Acceleration of the four epigenetic clocks (i.e., Horvath [EAA_Horvath], Hannum [EAA_Hannum], Pheno [EAA_Pheno], Grim [EAA_Grim]).

race: self-reported race; BMI: Body Mass Index.

ln(PEth):natural logarithm of phosphatidylethanol, an objective measure of alcohol consumption.